Dosing regimens and formulations of suzetrigine for use in the treatment of acute and chronic pain

Abstract

Disclosed herein are methods of treating pain, comprising administering suzetrigine or a pharmaceutically acceptable salt thereof, and a process of preparation of suzetrigine.

Description

Attorney Docket No.67573-418077 (VPI / 23-025 WO) DOSING REGIMENS FOR TREATING PAIN CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 607,387, filed December 7, 2023, U.S. Provisional Application No.63 / 609,206, filed December 12, 2023, U.S. Provisional Application No.63 / 625,906, filed January 26, 2024, and U.S. Provisional Application No. 63 / 626,017, filed January 28, 2024, each of which is incorporated by reference in its entirety. BACKGROUND

[0002] Pain is a protective mechanism that enables healthy persons and animals to avoid tissue damage and to prevent further damage to injured tissue. Managing pain in the clinical setting, in both acute and chronic clinical settings, remains a high unmet need. In addition to acute pain, there are many conditions where chronic pain persists beyond its protective role (neuropathic pain) where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008.137(3): p.681-8). Neuropathic pain can be divided into two categories: pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury. The metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain. Neuropathic pain is a major cause or disability worldwide, negatively affecting patient’s sleep, mood, and functionality. Clin. Ther.201840(6): p.828-49.

[0003] Current pain therapies suffer from poor efficacy and a high risk of adverse events (AEs). For example, lidocaine (a nonselective sodium channel blocker) may effectively reduce pain, but its utility is limited because of prominent side effects when given at dose levels required for pain relief. Opioid pain medications have a high abuse liability, leading to frequent deaths due to overdose. In addition, opioid-induced hyperalgesia also limits the long term use of opioids. Opioid-induced hyperalgesia is encountered regularly in clinical practice and creates significant challenges in pain management.

[0004] Antidepressants and anticonvulsants remain the first line treatment for neuropathic pain despite not being designated for such purpose. Their use is often limited by an arsenal of side effects or inadequate pain relief. Clinical development has exhibited a considerable lack of recent progress and innovation of new medications to treat both acute and chronic pain. Over the last decades, most approved analgesic drugs for the treatment of neuropathic pain either act on the serotonin- norepinephrine system (such as the serotonin-norepinephrine reuptake inhibitor duloxetine) or on voltage-gated calcium channels (such as the gabapentinoid pregabalin). Given the limited treatment options for pain, combined with a growing awareness of the risks and relative ineffectiveness of thecurrent standards of care, the development of analgesics targeting specific pathophysiology mechanisms with improved efficacy and safety profiles is vital for better pain management and patient health outcomes.

[0005] Voltage-gated sodium channels (NaVs) are involved in pain signaling. NaVs are biological mediators of electrical signaling as they mediate the rapid upstroke of the action potential of many excitable cell types (e.g., neurons, skeletal myocytes, cardiac myocytes). Support for the assertion that NaVs play a critical and central role in pain signaling arises from (1) evaluation of the role NaVs plays in normal physiology, (2) pathological states arising from mutations in the Nav1.8 gene (SCN10A). (3) preclinical work in animal models, and (4) pharmacology of known Nav1.8- modulating agents. In addition, because Nav1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., the dorsal root ganglia), NaV1.8 inhibitors are less likely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse liability associated with opioid therapies. Therefore, targeting the underlying biology of pain through selective NaV1.8 inhibition represents a novel approach to analgesic drug development that has the potential to address an urgent unmet need for safe and effective acute and chronic pain therapies (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels. Mol. Interv., 2007.7(4): p.192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol.8 (1), p.50-56 (2008)). Because of the role NaVs play in the initiation and propagation of neuronal signals, antagonists that reduce NaVcurrents can prevent or reduce neural signaling and NaVchannels have been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p.144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of NaVchannels. The local anesthetic drugs such as lidocaine block pain by inhibiting NaVchannels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p.3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na+currents by antidepressant sertraline and paroxetine. J. Membr. Biol.222 (2), p.79-90 (2008)).

[0006] The NaVs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated NaV1.1 – NaV1.9. The tissue localizations of the nine isoforms vary. NaV1.4 is the primary sodium channel of skeletal muscle, and NaV1.5 is the primary sodium channel of cardiac myocytes. NaV1.7, NaV1.8 and NaV1.9 are primarily localized to the peripheral nervous system, while NaV1.1, NaV1.2, NaV1.3, and NaV1.6 are neuronal channels found in both the central and peripheralnervous systems. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev.57 (4), p.397 (2005)).

[0007] Upon their discovery, NaV1.8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996.379(6562): p.257-62). Since then, NaV1.8 has been shown to be a carrier of the sodium current that maintains action potential firing in small DRG neurons, supporting its potential as a target for multiple indications or across multiple pain types (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+current, and Ca2+current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p.10277-90). NaV1.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550(Pt 3): p.921-6; Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007.104(20): p.8520-5; Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006.123(1-2): pp.75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain, 2002.95(1-2): p.143-52; Dong, X.W., et al., Small interfering RNA- mediated selective knockdown of Na(V)1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146(2): p.812-21; Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper- excitable nerves. Mol. Pain, 2008.4: p.33; Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008.64(6): p.644-53; Coward, K., et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000.85(1-2): p.41-50; Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000.467(2-3): p.249-52; Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem.286(46): p.39836-47). The small DRG neurons where NaV1.8 is expressed include the nociceptors involved in pain signaling. NaV1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+current, TTX-resistant Na+current, and Ca2+current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002.22(23): p.10277-90). NaV1.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons (Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computersimulation study. J. Neurophysiol.106(6): p.3173-84; Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution of Na(V)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001.86(2): p.629-40; Roza, C., et al., The tetrodotoxin-resistant Na+channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003.550(Pt 3): p.921-6). In depolarized or damaged DRG neurons, NaV1.8 appears to be a driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p.8245-50). In some animal pain models, NaV1.8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008.12(5): p.564-72; Qiu, F., et al., Increased expression of tetrodotoxin- resistant sodium channels NaV1.8 and NaV1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p.61-6). SUMMARY

[0008] In one aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1: (Compound 1), or a15-80 per day. In some aspects, about 70 mg per day of Compound 1 is administered to the subject. In some aspects, 70 mg per day of Compound 1 is administered to the subject.

[0009] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours. In some aspects, the first dose is about 100 mg, followed by subsequent doses of about 50 mg every 12 hours. In some aspects, the first dose is 100 mg, followed by subsequent doses of 50 mg every 12 hours.

[0010] In another aspect, the disclosure relates to a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant.

[0011] In another aspect, the disclosure relates to a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant.

[0012] In another aspect, the disclosure relates to a process for preparing Compound 1, comprising transforming a compound of formula 5: to Compound 1.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 depicts an XRPD pattern of the spray-dried dispersion of Compound 1 of Example 2.

[0014] Figure 2A depicts an XRPD pattern of the SDD tablet composition of Example 2 over the range of about 3° to about 40°2θ.

[0015] Figure 2B depicts an XRPD pattern of the SDD tablet composition of Example 2 over the range of about 14° to about 16°2θ.

[0016] Figure 3A depicts a solid state19F NMR spectrum characteristic of the SDD tablet composition of Example 2.

[0017] Figure 3B depicts a solid state13C NMR spectrum characteristic of a powder of the SDD tablet composition of Example 2.

[0018] Figure 4 depicts a graph of mean NPRS score versus time for each treatment group in the study described in Example 5.

[0019] Figure 5 depicts a graph of mean NPRS score versus time for each treatment group in the study described in Example 6. DETAILED DESCRIPTION Definitions

[0020] The chemical elements are identified herein in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith,M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0021] As used herein, the term “amorphous” refers to a solid material having no long-range order in the position of its molecules. The molecules in an amorphous solid are generally arranged in a random manner with no well-defined arrangement. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.

[0022] As used herein, the term “substantially amorphous” refers to a solid material having little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). The term ‘substantially amorphous’ includes materials having no (0%) crystallinity.

[0023] As used herein, the term “dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase. In other embodiments, a solid dispersion includes the drug constituting the dispersed phase, and the polymer constituting the continuous phase.

[0024] As used herein, the term “Compound 1,” and the structure and chemical name corresponding to the “Compound 1,” refer to a collection of molecules having identical chemical structures, namely the structure corresponding to the “Compound 1,” except that there may be isotopic variation among the constituent atoms of the molecules. The term “Compound 1” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “Compound 1” includes such a collection of molecules in pure form or in a mixture (e.g., solution, suspension, or colloid) with one or more other substances.

[0025] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in Compound 1 is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0026] As used herein, the term “filler,” when referring to an excipient in a pharmaceutical composition, such as a tablet, refers to an excipient that increases the volume of the pharmaceutical composition. Examples of fillers include starches (e.g., microcrystalline cellulose), lactose, sucrose, glucose, mannitol, and silicic acid.

[0027] As used herein, the term “disintegrant,” when referring to an excipient in a pharmaceutical composition, such as a tablet, refers to an excipient that causes the pharmaceutical composition, to break down into smaller pieces when it comes into contact with a liquid, such as water. Examples of disintegrants include agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, sodium starch glycolate, croscarmellose sodium, and crospovidone.

[0028] As used herein, the term “lubricant,” when referring to an excipient in a pharmaceutical composition, such as a tablet, refers to an excipient that facilitates the flow of a powder mixture and prevents the adhesion of the mixture to the surfaces of the die and punches during tablet compression. Examples of lubricants include calcium stearate, stearic acid, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.

[0029] As used herein, the term “glidant,” when referring to an excipient in a pharmaceutical composition, such as a tablet, refers to an excipient that enhances the flow of a granular or powder mixture by reducing interparticle friction, surface charge, and / or cohesion. Examples of glidants include talc and colloidal silicon dioxide.

[0030] As used herein, the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0031] As used herein, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen and, therefore, a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0032] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, includes each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0033] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, includes one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labelled” compound or salt). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H,13C,15N,18O,17O, and31P, respectively.

[0034] The terms “Compound 1” and “pharmaceutically acceptable salt thereof” include the Compound 1 and any pharmaceutically acceptable salt thereof in any form, including any solid form thereof (including any amorphous or crystalline form thereof), any solvate, hydrate, or cocrystal form thereof, and any solution or suspension thereof.

[0035] As used herein, the term “about” includes the value of a specified amount or a range encompassing that specified amount that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified amount. The term “about” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the term “about” means within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% or 0.5% of a given value or range. In some embodiments, the term “about” means within 20% of a given value or range. In some embodiments, the term “about” means within 15% of a given value or range. In some embodiments, the term “about” means within 10% of a given value or range. In some embodiments, the term “about” means within 5% of a given value or range. In some embodiments, the term “about” means within 1% of a given value or range. In some embodiments, the term “about” means within 0.5% of a given value or range.

[0036] As used herein in connection with a medical condition (e.g., chronic pain or acute pain), the term “treating” includes both providing full relief from the condition (e.g., providing full pain relief) and providing partial relief from the condition (e.g., providing partial pain relief or lessening the severity of the pain).

[0037] As used herein, the term “subject” or “patient” means an animal, preferably a mammal, and most preferably a human.

[0038] As used herein, the term “amount,” when referring to an amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject, refers to the mass of an equimolar amount of (2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide, regardless of the actual mass of any salt, solvate, hydrate, or cocrystal form that may be administered.

[0039] In certain embodiments, an “effective amount” of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating one or more of the conditions recited herein.

[0040] As used herein, the term “course of treatment,” when referring to Compound 1, or a pharmaceutically acceptable salt thereof, refers to the administration of one or more doses of the compound or salt during a period of time that is separate from any earlier or later administration of the compound or salt. Typically, Compound 1 and any metabolites thereof are substantially eliminated from a subject’s systemic circulation between courses of treatment.

[0041] As used herein, the term “dose,” when referring to the administration of Compound 1, or a pharmaceutically acceptable salt thereof, refers to an amount of the compound or salt administered ina discrete period of time, separate from other amounts of the compound or salt that may be administered at other times during the same day or course of treatment. When a dose is administered orally, the dose may be administered in a single tablet, capsule, or other oral dosage form, or in multiple such dosage forms.

[0042] As used herein, the term “first dose” refers to the first dose of Compound 1, or a pharmaceutically acceptable salt thereof, that is administered in a given course of treatment.

[0043] As used herein, the term “subsequent dose” refers to any dose of Compound 1, or a pharmaceutically acceptable salt thereof, that is administered after the first dose in a given course of treatment.

[0044] As used herein, the term “baseline pain score” refers to a subject’s pain score, such as a score on the 11-point Numeric Pain Rating Scale or Verbal Categorical Rating Scale, prior to beginning a course of treatment with Compound 1, or a pharmaceutically acceptable salt thereof.

[0045] As used herein, the term “11-point Numeric Pain Rating Scale” (also known as “NPRS”) refers to a pain rating scale on which a subject rates his or her pain intensity on a scale of 0 to 10, where a score of 0 denotes no pain, and a score of 10 denotes the worst pain intensity imaginable.

[0046] As used herein, the term “Verbal Categorical Rating Scale” refers to a pain rating scale on which a subject rates his or her pain intensity as none, mild, moderate, or severe.

[0047] As used herein, the term “adverse event” is defined as any untoward medical occurrence in a subject during a study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or worsening of a pre-existing condition (e.g., increase in its severity or frequency).

[0048] As used herein, an abnormal study assessment is considered “clinically significant” if the subject has 1 or more of the following: concomitant signs or symptoms related to the abnormal study assessment, further diagnostic testing or medical / surgical intervention, a change in the dose of study drug or discontinuation from the study. The determination of whether the study assessment results are clinically significant will be made by the investigator. Medical Uses of Compound 1 or a Pharmaceutically Acceptable Salt Thereof Methods of Treatment

[0049] In yet another aspect, the disclosure relates to a method of treating pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0050] In yet another aspect, the disclosure relates to a method of treating chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiacarrhythmia in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0051] In yet another aspect, the disclosure relates to a method of treating chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0052] In yet another aspect, the disclosure relates to a method of treating gut pain in a subject, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0053] In yet another aspect, the disclosure relates to a method of treating neuropathic pain in a subject comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.

[0054] In yet another aspect, the disclosure relates to a method of treating neuropathic pain in a subject, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV- associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0055] In yet another aspect, the disclosure relates to a method of treating musculoskeletal pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0056] In yet another aspect, the disclosure relates to a method of treating musculoskeletal pain in a subject, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain ordental pain wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0057] In yet another aspect, the disclosure relates to a method of treating inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0058] In yet another aspect, the disclosure relates to a method of treating inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0059] In yet another aspect, the disclosure relates to a method of treating idiopathic pain in a subject, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0060] In yet another aspect, the disclosure relates to a method of treating idiopathic pain in a subject, wherein idiopathic pain comprises reflex sympathetic dystrophy pain, wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0061] In yet another aspect, the disclosure relates to a method of treating pathological cough in a subject, wherein said method comprises administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0062] In yet another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the acute pain comprises acute post-operative pain.

[0063] In yet another aspect, the disclosure relates to a method of treating postsurgical pain in a subject (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0064] In yet another aspect, the disclosure relates to a method of treating bunionectomy pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0065] In yet another aspect, the disclosure relates to a method of treating shoulder arthroplasty pain or shoulder arthroscopy pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0066] In yet another aspect, the disclosure relates to a method of treating herniorrhaphy pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0067] In yet another aspect, the disclosure relates to a method of treating abdominoplasty pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0068] In yet another aspect, the disclosure relates to a method of treating visceral pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0069] In yet another aspect, the disclosure relates to a method of treating a neurodegenerative disease in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0070] In yet another aspect, the disclosure relates to a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0071] In another aspect, the disclosure relates to a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0072] In another aspect, the disclosure relates to a method of treating acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post- thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures,ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0073] In another aspect, the disclosure relates to a method of treating femur cancer pain; non- malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain in a subject, comprisingadministering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0074] In another aspect, the disclosure relates to a method of treating trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain in a subject, comprising administering an effective amount of Compound 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0075] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0076] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale). In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0077] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain). In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose isabout 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0078] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale). In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0079] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0080] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subjectexperiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0081] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and thesubsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0082] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0083] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, thesubject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0084] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about - 4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0085] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a change of about -2.5 to about-4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0086] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0087] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point NumericPain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about - 4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0088] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11- point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg,and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0089] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about - 3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0090] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about - 3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0091] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subjectexperiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0092] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about - 3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein theacute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0093] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0094] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a time-weighted sum ofpain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about - 3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0095] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-pointNumeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0096] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable saltthereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0097] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about - 3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0098] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate orsevere on a Verbal Categorical Rating Scale), wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 100 mg, followed by subsequent doses of 50 mg every 12 hours, wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale).

[0099] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS)after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0100] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0101] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, thesubject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0102] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0103] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or - 3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0104] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS)after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0105] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0106] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, thesubject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0107] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0108] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or - 3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0109] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in painintensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0110] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0111] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about - 4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0112] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference fromplacebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about - 4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0113] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg,and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0114] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or - 3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0115] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subjectexperiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0116] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about - 4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and thesubsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0117] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0118] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain), wherein the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale), wherein the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119minutes) after administration of the first dose. In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11- point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0119] In another aspect, the disclosure relates to a method of treating or lessening the severity of acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours. In some embodiments, the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, herniorrhaphy pain). In some embodiments, the acute pain is moderate to severe acute pain (e.g., wherein the subject has a baseline pain score of ≥4 on an 11- point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale). In some embodiments, the subject experiences a time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0 (e.g., 95.0 to 105.0, or about 99.9). In some embodiments, the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0 (e.g., 25.0 to 35.0, or about 29.3). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 51% reduction (e.g., a 51% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes (e.g., 210 to 270 minutes, or about 240 minutes) after administration of the first dose. In some embodiments, the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0 (e.g., 113.0 to 123.0, or about 118.4). In some embodiments, the subject experiences a difference from placebo in time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0 (e.g., 43.0 to 53.0, or about 48.4). In some embodiments, the subject experiences a change of about -2.5 to about -4.5 (e.g., -2.5 to -4.5, or about -3.0 to about -4.0, or -3.0 to -4.0, or about -3.4, or -3.4) in pain intensity on an 11- point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences about a 47% reduction (e.g., a 47% reduction) in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline. In some embodiments, the subject experiences a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes (e.g., 100 to 140 minutes, or about 119 minutes) after administration of the first dose. In some embodiments, the acute pain is fully relieved in the subject. In some embodiments, the acute pain is lessened in the subject. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0120] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in a first dose of 85-115 mg, followed by subsequent doses of 40-60 mg every 12 hours, wherein Compound 1 is administered in a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant. In some embodiments, the one or more fillers comprise microcrystalline cellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of microcrystalline cellulose; 2-4 wt % of croscarmellose sodium; and 0.5-1.5 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the tablet core composition is coated with a tablet coating (e.g., Opadry Blue). In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1. In some embodiments, the polymer is HPMCAS. In some embodiments, the solid dispersion comprises 70-80 wt % of the polymer and 20-30 wt % of Compound 1 (e.g., about 75 wt % of the polymer and about 25 wt % of Compound 1). In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion; about 46 wt % of microcrystalline cellulose; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion,wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; about 46 wt % of microcrystalline cellulose; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 50 wt % of the solid dispersion, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; 46 wt % of microcrystalline cellulose; 3 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 50 wt % of the solid dispersion, wherein the solid dispersion comprises 75 wt % of the polymer (e.g., HPMCAS) and 25 wt % of Compound 1; 46 wt % of microcrystalline cellulose; 3 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 184 mg of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 12 mg of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 4 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 200 mg of a solid dispersion comprising a polymer and Compound 1. In some embodiments, the pharmaceutical composition comprises about 200 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 150 mg of the polymer (e.g., HPMCAS) and about 50 mg of Compound 1; about 184 mg of microcrystalline cellulose; about 12 mg of croscarmellose sodium; and about 4 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 200 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 150 mg of the polymer (e.g., HPMCAS) and 50 mg of Compound 1; 184 mg of microcrystalline cellulose; 12 mg of croscarmellose sodium; and 4 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises an intragranular blend and extragranular blend. In some embodiments, the intragranular blend comprises 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of a filler; 1-2 wt % of a disintegrant; and 0-0.2 wt % of a lubricant; and the extragranular blend comprises 20-25 wt % of a filler; 1-2 wt % of a disintegrant; and 0.8-1.0 wt % of a lubricant, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of microcrystalline cellulose; 1-2 wt % of croscarmellose sodium; and 0-0.2 wt % of magnesium stearate; and the extragranular blend comprises 20-25 wt % of microcrystalline cellulose; 1-2 wt % of croscarmellose sodium; and 0.8-1.0 wt % of magnesium stearate, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises about 50 wt % of a solid dispersion comprising a polymer and Compound 1, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; about 23.4 wt % of microcrystalline cellulose; about 1.5 wt % of croscarmellose sodium; and about 0.1 wt % of magnesium stearate; and theextragranular blend comprises about 22.6 wt % of microcrystalline cellulose; about 1.5 wt % of croscarmellose sodium; and about 0.9 wt % of magnesium stearate, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises 50 wt % of a solid dispersion comprising a polymer and Compound 1, wherein the solid dispersion comprises 75 wt % of the polymer (e.g., HPMCAS) and 25 wt % of Compound 1; 23.4 wt % of microcrystalline cellulose; 1.5 wt % of croscarmellose sodium; and 0.1 wt % of magnesium stearate; and the extragranular blend comprises 22.6 wt % of microcrystalline cellulose; 1.5 wt % of croscarmellose sodium; and 0.9 wt % of magnesium stearate, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises about 200 mg of the solid dispersion, about 93.6 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 0.4 mg of magnesium stearate; and the extragranular blend comprises about 90.4 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises about 200 mg of the solid dispersion, wherein the solid dispersion comprises about 150 mg of the polymer (e.g., HPMCAS) and about 50 mg of Compound 1, about 93.6 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 0.4 mg of magnesium stearate; and the extragranular blend comprises about 90.4 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises 200 mg of the solid dispersion, wherein the solid dispersion comprises 150 mg of the polymer (e.g., HPMCAS) and 50 mg of Compound 1, 93.6 mg of microcrystalline cellulose, 6.0 mg of croscarmellose sodium, and 0.4 mg of magnesium stearate; and the extragranular blend comprises 90.4 mg of microcrystalline cellulose, 6.0 mg of croscarmellose sodium, and 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises about 0.4 mg of magnesium stearate, and the extragranular blend comprises about 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises 0.4 mg of magnesium stearate, and the extragranular blend comprises 3.6 mg of magnesium stearate. In some embodiments, the first dose is about 85 to about 115 mg, and the subsequent doses are about 40 to about 60 mg every 12 hours. In some embodiments, the first dose is about 100 mg, and the subsequent doses are about 50 mg every 12 hours. In some embodiments, the first dose is 100 mg, and the subsequent doses are 50 mg every 12 hours.

[0121] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, isadministered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 45 mg per day. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 70 mg per day.

[0122] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is moderate to severe chronic pain. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 45 mg per day, wherein the chronic pain is moderate to severe chronic pain. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is moderate to severe chronic pain. In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administeringCompound 1, or a pharmaceutically acceptable salt thereof, in an amount of 70 mg per day, wherein the chronic pain is moderate to severe chronic pain.

[0123] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small- fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy, pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40- 50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy, pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy, pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy, pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy,pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain.

[0124] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small- fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain(e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is neuropathic pain (e.g., post- herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)).

[0125] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is diabetic peripheral neuropathy. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is diabetic peripheral neuropathy. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is diabetic peripheral neuropathy. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is diabetic peripheral neuropathy. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is diabetic peripheral neuropathy.

[0126] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average painscore of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)).

[0127] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is lumbosacral radiculopathy. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprisingadministering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is lumbosacral radiculopathy. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is lumbosacral radiculopathy. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is lumbosacral radiculopathy. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is lumbosacral radiculopathy.

[0128] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is lumbosacral radiculopathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4, or ≥4 and ≤10, or ≥4 and ≤9, on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is lumbosacral radiculopathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4, or ≥4 and ≤10, or ≥4 and ≤9, on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is lumbosacral radiculopathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4, or ≥4 and ≤10, or ≥4 and ≤9, on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is lumbosacral radiculopathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4, or ≥4 and ≤10, or ≥4 and ≤9, on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the disclosure relates to a method of treating chronic pain in asubject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is lumbosacral radiculopathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4, or ≥4 and ≤10, or ≥4 and ≤9, on an 11-point Numeric Pain Rating Scale (NPRS)).

[0129] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or - 2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40- 50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the subject experiences a change of -1 to - 4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In someembodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0130] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or - 2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40- 50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is moderate to severe chronic pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11- point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 45 mg per day, wherein the chronic pain is moderate to severe chronic pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is moderate to severe chronic pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 70 mg per day, wherein the chronic pain is moderate to severe chronic pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment,relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0131] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small- fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the subject experiences a change of -1 to -4 (e.g., - 2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabeticperipheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0132] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small- fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g.,wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0133] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the subjectexperiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11- point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18 or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0134] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average painscore of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)), wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day, wherein the chronic pain is diabetic peripheral neuropathy, wherein the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)),wherein the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0135] In another aspect, the disclosure relates to a method of treating or lessening the severity of chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day. In some embodiments, the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 15 to about 80 mg per day, or about 20 to about 75 mg per day, or about 20 to about 30 mg per day, or about 40 about 50 mg per day, or about 60 to about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day, or 20-30 mg per day, or 40-50 mg per day, or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg per day, or about 23 mg per day, or about 25 mg per day, or about 45 mg per day, or about 46 mg per day, or about 50 mg per day, or about 65 mg per day, or about 69 mg per day, or about 70 mg per day. In some embodiments, the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0136] In some embodiments, the disclosure relates to a method of treating or lessening the severity of chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 46 mg per day. In some embodiments, the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0137] In some embodiments, the disclosure relates to a method of treating or lessening the severity of chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 45 mg per day. In some embodiments, the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0138] In some embodiments, the disclosure relates to a method of treating or lessening the severity of chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 69 mg per day. In some embodiments, the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0139] In some embodiments, the disclosure relates to a method of treating or lessening the severity of chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 70 mg per day. In some embodiments, the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy)), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the chronic pain is moderate to severe chronic pain (e.g., wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS)). In some embodiments, the subject experiences a change of -1 to -4 (e.g., -2.0 to -2.5, or -2.18, or -2.11, or -2.26) in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline. In some embodiments, the chronic pain is fully relieved in the subject. In some embodiments, the chronic pain is lessened in the subject.

[0140] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of 15-80 mg per day, wherein Compound 1 is administered in a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; 0.5-1.5 wt % of a lubricant; and 0.05-0.8 wt % (e.g., 0.1-0.3 wt %) of a glidant. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant. In some embodiments, the one or more fillers comprise microcrystalline cellulose and mannitol. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of microcrystalline cellulose; 20-25 wt % of mannitol; 2-4 wt % of croscarmellose sodium; 0.5-1.5 wt % of magnesium stearate; and 0.1-0.3 wt % of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of microcrystalline cellulose; 20-25 wt % of mannitol; 2-4 wt % of croscarmellose sodium; and 0.5-1.5 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the tablet core composition is coated with a tablet coating (e.g., Opadry Blue). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1. In some embodiments, the polymer is HPMCAS. In some embodiments, the solid dispersion comprises 70-80 wt % of the polymer and 20-30 wt % of Compound 1 (e.g., about 75 wt % of the polymer and about 25 wt % of Compound 1). In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; about 1.0 wt % of magnesium stearate; and about 0.2 wt % of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 50 wt % of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; about 1.0 wt % of magnesium stearate; and about 0.2 wt % of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 50 wt % of of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 75 wt % of the polymer (e.g., HPMCAS) and 25 wt % of Compound 1; 22.9 wt % of microcrystalline cellulose; 22.9 wt % of mannitol; 3 wt % of croscarmellose sodium; 1.0 wt % of magnesium stearate; and 0.2 wt %of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 127- 129 mg of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises 127-129 mg of mannitol. In some embodiments, the pharmaceutical composition comprises 16-18 mg of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises 5-6 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 1.0-1.2 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer and Compound 1. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer and Compound 1; 127-129 mg of microcrystalline cellulose; 127-129 mg of mannitol; 16-18 mg of croscarmellose sodium; 5-6 mg of magnesium stearate; and 1.0-1.2 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 210 mg of the polymer (e.g., HPMCAS) and about 70 mg of Compound 1; 127-129 mg of microcrystalline cellulose; 127-129 mg of mannitol; 16-18 mg of croscarmellose sodium; 5-6 mg of magnesium stearate; and 1.0-1.2 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 210 mg of the polymer (e.g., HPMCAS) and about 70 mg of Compound 1; about 128.2 mg of microcrystalline cellulose; about 128.2 mg of mannitol; about 16.8 mg of croscarmellose sodium; about 5.6 mg of magnesium stearate; and about 1.1 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 210 mg of the polymer (e.g., HPMCAS) and about 70 mg of Compound 1; about 128.24 mg of microcrystalline cellulose; about 128.24 mg of mannitol; about 16.8 mg of croscarmellose sodium; about 5.6 mg of magnesium stearate; and about 1.12 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 210 mg of the polymer (e.g., HPMCAS) and 70 mg of Compound 1; 128.2 mg of microcrystalline cellulose; 128.2 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.1 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 210 mg of the polymer (e.g., HPMCAS) and 70 mg of Compound 1; 128.24 mg of microcrystalline cellulose; 128.24 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.12 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer and Compound 1; 128.2 mg of microcrystalline cellulose; 128.2 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.1 mg of colloidal silicon dioxide. Insome embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer and Compound 1; 128.24 mg of microcrystalline cellulose; 128.24 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.12 mg of colloidal silicon dioxide. In some embodiments the pharmaceutical composition is suitable for tableting by direct compression. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 20-75 mg per day or 60-70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 70 mg per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 70 mg per day. Compound, Pharmaceutically Acceptable Salts, and Compositions for Use

[0141] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating pain in a subject in accordance with the method described herein (including any embodiment thereof).

[0142] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0143] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0144] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating gut pain in a subject, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain.

[0145] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating neuropathic pain in a subject. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.

[0146] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating neuropathic pain in a subject,wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV- associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

[0147] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0148] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating musculoskeletal pain in a subject, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

[0149] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia.

[0150] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain.

[0151] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating idiopathic pain in a subject, wherein idiopathic pain comprises fibromyalgia pain.

[0152] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating idiopathic pain in a subject, wherein idiopathic pain comprises reflex sympathetic dystrophy pain.

[0153] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating pathological cough in a subject.

[0154] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating acute pain in a subject. In some aspects, the acute pain comprises acute post-operative pain.

[0155] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) in a subject.

[0156] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating bunionectomy pain in a subject.

[0157] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0158] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating herniorrhaphy pain in a subject.

[0159] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating abdominoplasty pain in a subject.

[0160] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating visceral pain in a subject. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0161] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0162] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0163] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0164] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post- thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility in a subject.

[0165] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating femur cancer pain; non- malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet’s disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’s disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain in a subject.

[0166] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain in a subject. Manufacture of Medicaments

[0167] In another aspect, the disclosure relates to the use of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for treating pain in a subject in accordance with the method described herein (including any embodiment thereof).

[0168] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0169] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0170] In yet another aspect, the disclosure relates to the use of Compound 1, pharmaceutically acceptable salt, or pharmaceutical composition described herein for the manufacture of a medicament for use in treating gut pain in a subject, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain.

[0171] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicamentfor use in treating neuropathic pain in a subject. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0172] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in a treating neuropathic pain in a subject, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

[0173] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0174] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating musculoskeletal pain in a subject, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

[0175] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia.

[0176] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating inflammatory pain in a subject, wherein inflammatory pain comprises rheumatoid arthritis pain.

[0177] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating idiopathic pain in a subject, wherein idiopathic pain comprises fibromyalgia pain.

[0178] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicamentfor use in treating idiopathic pain in a subject, wherein idiopathic pain comprises reflex sympathetic dystrophy pain.

[0179] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating pathological cough in a subject.

[0180] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating acute pain in a subject. In some aspects, the acute pain comprises acute post- operative pain.

[0181] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post- thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) in a subject.

[0182] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating herniorrhaphy pain in a subject.

[0183] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating bunionectomy pain in a subject.

[0184] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0185] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating abdominoplasty pain in a subject.

[0186] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating visceral pain in a subject. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0187] In another aspect, the disclosure relates to the use of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0188] In yet another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicamentfor use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0189] In another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility in a subject.

[0190] In another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminalneuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’s disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain in a subject.

[0191] In another aspect, the disclosure relates to the use of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain in a subject. Pharmaceutically Acceptable Salts, Pharmaceutical Compositions, Dosage Forms and Routes of Administration Pharmaceutically Acceptable Salts

[0192] The methods described and claimed herein comprise administering to a subject Compound 1, or a pharmaceutically acceptable salt thereof. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of Compound 1 includes any non-toxic salt that, uponadministration to a recipient, is capable of providing, either directly or indirectly, Compound 1 or an inhibitorily active metabolite or residue thereof (e.g., the parent compound of a prodrug). The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

[0193] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Pharmaceutical Compositions

[0194] In the methods described and claimed herein, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered in the form of a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0195] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” includes any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with Compound 1, or a pharmaceutically acceptable salt thereof, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols, such a propylene glycol or polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Dosage Forms and Routes of Administration

[0196] The methods described and claimed herein may involve the administration of Compound 1, or a pharmaceutically acceptable salt thereof, by any route of administration effective for treating one or more of the pain diseases recited herein. Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated in dosage unit form for ease of administration and uniformity of dosage. The term “dosage unit form,” as used herein, refers to a physically discrete unit of agent appropriate for the subject to be treated.

[0197] Compound 1, or pharmaceutically acceptable salt thereof, can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the condition being treated.

[0198] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition toCompound 1, or a pharmaceutically acceptable salt thereof, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0199] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0200] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0201] In order to prolong the therapeutic effect of Compound 1, it may be desirable to slow the absorption of the compound, or a pharmaceutically acceptable salt thereof, from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0202] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing Compound 1, or a pharmaceutically acceptable salt thereof, with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax whichare solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0203] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, Compound 1, or a pharmaceutically acceptable salt thereof, is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0204] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0205] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0206] Dosage forms for topical or transdermal administration of Compound 1, or a pharmaceutically acceptable salt thereof, include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which havethe added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0207] In another aspect, the disclosure relates to a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant. In some embodiments, the one or more fillers comprise microcrystalline cellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of microcrystalline cellulose; 2-4 wt % of croscarmellose sodium; and 0.5- 1.5 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the tablet core composition is coated with a tablet coating (e.g., Opadry Blue). In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1. In some embodiments, the polymer is HPMCAS. In some embodiments, the solid dispersion comprises 70-80 wt % of the polymer and 20-30 wt % of Compound 1 (e.g., about 75 wt % of the polymer and about 25 wt % of Compound 1). In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion; about 46 wt % of microcrystalline cellulose; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; about 46 wt % of microcrystalline cellulose; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 50 wt % of the solid dispersion, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; 46 wt % of microcrystalline cellulose; 3 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 50 wt % of the solid dispersion, wherein the solid dispersion comprises 75 wt % of the polymer (e.g., HPMCAS) and 25 wt % of Compound 1; 46 wt % of microcrystalline cellulose; 3 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 184 mg of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 12 mg of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 4 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 200 mg of a solid dispersion comprising a polymer and Compound 1. In some embodiments, the pharmaceutical composition comprises about 200 mg of a solid dispersion comprising a polymer and Compound 1; 184 mg of microcrystalline cellulose; 12 mg ofcroscarmellose sodium; and 4 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 200 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 150 mg of the polymer (e.g., HPMCAS) and about 50 mg of Compound 1; about 184 mg of microcrystalline cellulose; about 12 mg of croscarmellose sodium; and about 4 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 200 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 150 mg of the polymer (e.g., HPMCAS) and 50 mg of Compound 1; 184 mg of microcrystalline cellulose; 12 mg of croscarmellose sodium; and 4 mg of magnesium stearate.

[0208] In some embodiments, the pharmaceutical composition comprises an intragranular blend and extragranular blend. In some embodiments, the intragranular blend comprises 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of a filler; 1-2 wt % of a disintegrant; and 0-0.2 wt % of a lubricant; and the extragranular blend comprises 20-25 wt % of a filler; 1-2 wt % of a disintegrant; and 0.8-1.0 wt % of a lubricant, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of microcrystalline cellulose; 1-2 wt % of croscarmellose sodium; and 0-0.2 wt % of magnesium stearate; and the extragranular blend comprises 20-25 wt % of microcrystalline cellulose; 1-2 wt % of croscarmellose sodium; and 0.8-1.0 wt % of magnesium stearate, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises about 50 wt % of a solid dispersion comprising a polymer and Compound 1, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; about 23.4 wt % of microcrystalline cellulose; about 1.5 wt % of croscarmellose sodium; and about 0.1 wt % of magnesium stearate; and the extragranular blend comprises about 22.6 wt % of microcrystalline cellulose; about 1.5 wt % of croscarmellose sodium; and about 0.9 wt % of magnesium stearate, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises 50 wt % of a solid dispersion comprising a polymer and Compound 1, wherein the solid dispersion comprises 75 wt % of the polymer (e.g., HPMCAS) and 25 wt % of Compound 1; 23.4 wt % of microcrystalline cellulose; 1.5 wt % of croscarmellose sodium; and 0.1 wt % of magnesium stearate; and the extragranular blend comprises 22.6 wt % of microcrystalline cellulose; 1.5 wt % of croscarmellose sodium; and 0.9 wt % of magnesium stearate, wherein such weight percentages are based on the combined weights of the intragranular and extragranular blends. In some embodiments, the intragranular blend comprises about 200 mg of the solid dispersion, about 93.6 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 0.4 mg of magnesium stearate; and the extragranular blend comprises about 90.4 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 3.6 mg of magnesiumstearate. In some embodiments, the intragranular blend comprises about 200 mg of the solid dispersion, wherein the solid dispersion comprises about 150 mg of the polymer (e.g., HPMCAS) and about 50 mg of Compound 1, about 93.6 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 0.4 mg of magnesium stearate; and the extragranular blend comprises about 90.4 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises 200 mg of the solid dispersion, wherein the solid dispersion comprises 150 mg of the polymer (e.g., HPMCAS) and 50 mg of Compound 1, 93.6 mg of microcrystalline cellulose, 6.0 mg of croscarmellose sodium, and 0.4 mg of magnesium stearate; and the extragranular blend comprises 90.4 mg of microcrystalline cellulose, 6.0 mg of croscarmellose sodium, and 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises about 0.4 mg of magnesium stearate, and the extragranular blend comprises about 3.6 mg of magnesium stearate. In some embodiments, the intragranular blend comprises 0.4 mg of magnesium stearate, and the extragranular blend comprises 3.6 mg of magnesium stearate.

[0209] In another aspect, the disclosure relates to a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; 0.5-1.5 wt % of a lubricant; and 0.05-0.8 wt % (e.g., 0.1-0.3 wt %) of a glidant. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant. In some embodiments, the one or more fillers comprise microcrystalline cellulose and mannitol. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of microcrystalline cellulose; 20-25 wt % of mannitol; 2-4 wt % of croscarmellose sodium; 0.5-1.5 wt % of magnesium stearate; and 0.1-0.3 wt % of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 20-25 wt % of microcrystalline cellulose; 20-25 wt % of mannitol; 2-4 wt % of croscarmellose sodium; and 0.5-1.5 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the tablet core composition is coated with a tablet coating (e.g., Opadry Blue). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1. In some embodiments, the polymer is HPMCAS. In some embodiments, the solid dispersion comprises 70-80 wt % of the polymer and 20-30 wt % of Compound 1 (e.g., about 75 wt % of the polymer and about 25 wt % of Compound 1). In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; about 1.0 wt % of magnesium stearate; and about 0.2 wt % ofcolloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 50 wt % of the solid dispersion; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 50 wt % of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 75 wt % of the polymer (e.g., HPMCAS) and about 25 wt % of Compound 1; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; about 1.0 wt % of magnesium stearate; and about 0.2 wt % of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 50 wt % of of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 75 wt % of the polymer (e.g., HPMCAS) and 25 wt % of Compound 1; 22.9 wt % of microcrystalline cellulose; 22.9 wt % of mannitol; 3 wt % of croscarmellose sodium; 1.0 wt % of magnesium stearate; and 0.2 wt % of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 127- 129 mg of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises 127-129 mg of mannitol. In some embodiments, the pharmaceutical composition comprises 16-18 mg of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises 5-6 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 1.0-1.2 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer and Compound 1. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer and Compound 1; 127-129 mg of microcrystalline cellulose; 127-129 mg of mannitol; 16-18 mg of croscarmellose sodium; 5-6 mg of magnesium stearate; and 1.0-1.2 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 210 mg of the polymer (e.g., HPMCAS) and about 70 mg of Compound 1; 127-129 mg of microcrystalline cellulose; 127-129 mg of mannitol; 16-18 mg of croscarmellose sodium; 5-6 mg of magnesium stearate; and 1.0-1.2 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 210 mg of the polymer (e.g., HPMCAS) and about 70 mg of Compound 1; about 128.2 mg of microcrystalline cellulose; about 128.2 mg of mannitol; about 16.8 mg of croscarmellose sodium; about 5.6 mg of magnesium stearate; and about 1.1 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises about 210 mg of the polymer (e.g., HPMCAS) and about 70 mg of Compound 1; about 128.24 mg of microcrystalline cellulose; about 128.24 mg of mannitol; about 16.8 mg of croscarmellose sodium; about 5.6 mg of magnesium stearate; and about 1.12 mg of colloidal silicon dioxide. In someembodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 210 mg of the polymer (e.g., HPMCAS) and 70 mg of Compound 1; 128.2 mg of microcrystalline cellulose; 128.2 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.1 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer (e.g., HPMCAS) and Compound 1, wherein the solid dispersion comprises 210 mg of the polymer (e.g., HPMCAS) and 70 mg of Compound 1; 128.24 mg of microcrystalline cellulose; 128.24 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.12 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer and Compound 1; 128.2 mg of microcrystalline cellulose; 128.2 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.1 mg of colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises 280 mg of a solid dispersion comprising a polymer and Compound 1; 128.24 mg of microcrystalline cellulose; 128.24 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.12 mg of colloidal silicon dioxide. In some embodiments the pharmaceutical composition is suitable for tableting by direct compression. Additional Therapeutic Agents

[0210] It will also be appreciated that Compound 1, pharmaceutically acceptable salts of Compound 1, and pharmaceutically acceptable compositions of Compound 1 can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin, naphthylalkanones such as Nabumetone, oxicams such as Piroxicam, para-aminophenol derivatives, such as Acetaminophen, propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin, salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal, fenamates such as meclofenamic acid, Mefenamic acid, and pyrazoles such as Phenylbutazone), or opioid (narcotic)agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0211] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[0212] (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[0213] (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[0214] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[0215] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[0216] (5) a histamine (H1) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[0217] (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[0218] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0219] (8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid,budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (- )-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)- quinolinone;

[0220] (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)- 5-(2-pyridyl) quinazoline;

[0221] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[0222] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0223] (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)- 7H-[l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4- triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0224] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0225] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0226] (15) a coal-tar analgesic, in particular paracetamol;

[0227] (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

[0228] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

[0229] (18) a beta-adrenergic such as propranolol;

[0230] (19) a local anesthetic such as mexiletine;

[0231] (20) a corticosteroid such as dexamethasone;

[0232] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0233] (22) a 5-HT2Areceptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0234] (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[0235] (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER (Nucynta®);

[0236] (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)- 2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4- b]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5- methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)- 3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2- propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6- dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2- (hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l- methyl-7- oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4- propoxybenzenesulfonamide;

[0237] (26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino- 5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]- methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5- methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino- 4,5-dimethyl-octanoic acid;

[0238] (27) a cannabinoid such as KHK-6188;

[0239] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[0240] (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

[0241] (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

[0242] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[0243] (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S- [2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l- iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S- chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4- chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5- (trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3- chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyldisulfide;

[0244] (33) an acetylcholinesterase inhibitor such as donepezil;

[0245] (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6- dimethyl- lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4- methylbenzenesulfonamide or 4- [(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl}amino)ethyl]benzoic acid;

[0246] (35) a leukotriene B4 antagonist; such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)- cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

[0247] (36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6- (3-pyridylmethyl)-l,4-benzoquinone (CV-6504);

[0248] (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate;

[0249] (38) a NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ- 00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), CN111217776, WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035 the entire contents of each application hereby incorporated by reference;

[0250] (38a) a NaV1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2- (trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4- benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy- phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2- methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl- phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl- spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5- isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl- spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxy- phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3- trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2- trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'- (5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3- methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone.

[0251] (39) a NaV1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 120815 (US2014228371) WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667(US2020140411), WO2020 / 144375, WO2020 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622 (CN112479996), WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, WO2023 / 138599, WO2023 / 211990, WO2023 / 211990, WO2023 / 238065, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each application hereby incorporated by reference;

[0252] (39a) a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)- 4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2- hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2- dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2- (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H- pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4- (trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2- (methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4- fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2- carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2- chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3- sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2- carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4- carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro- 2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2- methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4- fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4- difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2- (4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4- fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano- N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2- fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl- 4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4- trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3- fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4- [[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3- chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4- fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4- carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro- phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4- (difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]- 3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro- phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2- fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro- 6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

[0253] (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

[0254] (41) a 5-HT3 antagonist, such as ondansetron;

[0255] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[0256] (43) a nicotinic receptor antagonist, such as varenicline;

[0257] (44) an N-type calcium channel antagonist, such as Z-160;

[0258] (45) a nerve growth factor antagonist, such as tanezumab;

[0259] (46) an endopeptidase stimulant, such as senrebotase;

[0260] (47) an angiotensin II antagonist, such as EMA-401;

[0261] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

[0262] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

[0263] (50) bupivacaine and meloxicam combination (e.g., HTX-011 / Zynrelef™).

[0264] In one embodiment, the additional appropriate therapeutic agents are selected from V-116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

[0265] In another embodiment, the additional appropriate therapeutic agents are selected from N-(6- amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4- (trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0266] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 inhibitor such as Brivoglide(AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.

[0267] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0268] In another embodiment, the additional therapeutic ag...

Claims

CLAIMS What is claimed is:

1. A method of treating chronic pain in a subject, comprising administering to the subject Compound 1:or a pharmaceutically to about 80 mg per day.

2. The method of claim 1, wherein the chronic pain is lessened in the subject.

3. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 70 mg per day, optionally wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 70 mg per day.

4. The method of any one of claims 1-3, wherein the chronic pain is moderate to severe chronic pain; optionally: wherein the subject has a baseline weekly average pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS); or wherein the chronic pain is neuropathic pain, musculoskeletal pain, or visceral pain; or wherein the chronic pain is diabetic peripheral neuropathy; or wherein the chronic pain is lumbosacral radiculopathy.

5. The method of any one of claims 1-11, wherein the subject experiences a change of -1 to -4, optionally -2.0 to -2.5, in weekly average of daily pain on an 11-point Numeric Pain Rating Scale (NPRS) at week 12 of treatment, relative to baseline; and / or wherein the subject experiences an improvement in sleep, as determined by a change in Daily Sleep Interference Scale (DSIS) score at week 12 of treatment, relative to baseline.

6. The method of any one of claims 1-5, wherein Compound 1 is administered in a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; 0.5-1.5 wt % of a lubricant; and 0.05-0.8 wt % of a glidant.

7. The method of claim 6, wherein the one or more fillers comprise microcrystalline cellulose and mannitol; and / or the disintegrant is croscarmellose sodium; and / or the lubricant is magnesium stearate; and / or the glidant is colloidal silicon dioxide.

8. The method of any one of claims 1-5, wherein Compound 1 is administered in a pharmaceutical composition comprising: about 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 75 wt % of HPMCAS and about 25 wt % of Compound 1; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; about 1.0 wt % of magnesium stearate; and about 0.2 wt % of colloidal silicon dioxide.

9. The method of claim 8, wherein Compound 1 is administered in a pharmaceutical composition comprising: 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises 75 wt % of HPMCAS and 25 wt % of Compound 1; 22.9 wt % of microcrystalline cellulose; 22.9 wt % of mannitol; 3 wt % of croscarmellose sodium; 1.0 wt % of magnesium stearate; and 0.2 wt % of colloidal silicon dioxide.

10. The method of any one of claims 1-5, wherein Compound 1 is administered in a pharmaceutical composition comprising about 70 mg of Compound 1; and / or 127-129 mg of microcrystalline cellulose; and / or 127-129 mg of mannitol; and / or 16-18 mg of croscarmellose sodium; and / or 5-6 mg of magnesium stearate; and / or 1.0-1.2 mg of colloidal silicon dioxide.

11. The method of any one of claims 1-5, wherein Compound 1 is administered in a pharmaceutical composition comprising:about 280 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 210 mg of HPMCAS and about 70 mg of Compound 1; about 128.2 mg of microcrystalline cellulose; about 128.2 mg of mannitol; about 16.8 mg of croscarmellose sodium; about 5.6 mg of magnesium stearate; and about 1.1 mg of colloidal silicon dioxide.

12. The method of claim 11, wherein Compound 1 is administered in a pharmaceutical composition comprising: 280 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises 210 mg of HPMCAS and 70 mg of Compound 1; 128.2 mg of microcrystalline cellulose; 128.2 mg of mannitol; 16.8 mg of croscarmellose sodium; 5.6 mg of magnesium stearate; and 1.1 mg of colloidal silicon dioxide.

13. The method of any one of claims 6-12, wherein the pharmaceutical composition is a tablet core composition, optionally wherein the tablet core composition is coated with a tablet coating.

14. A method of treating acute pain in a subject, comprising administering to the subject Compound 1:or a pharmaceutically acceptable salt thereof, in a first dose of about 85 to about 115 mg, followed by subsequent doses of about 40 to about 60 mg every 12 hours.

15. The method of claim 14, wherein the acute pain is lessened in the subject.

16. The method of claim 14 or 15, wherein the first dose is about 100 mg, and the subsequent doses are about 50 mg; optionally wherein the first dose is 100 mg, and the subsequent doses are 50 mg.

17. The method of any one of claims 14-16, wherein the acute pain is moderate to severe acute pain; optionally wherein the subject has a baseline pain score of ≥4 on an 11-point Numeric Pain Rating Scale (NPRS) or wherein the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale.

18. The method of any one of claims 14-17, wherein the acute pain is acute post-operative pain or postsurgical pain, optionally wherein the acute pain is bunionectomy pain or abdominoplasty pain.

19. The method of any one of claims 14-18, wherein the subject experiences a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 75.0 to 125.0, optionally 95.0 to 105.0 or about 99.

9.

20. The method of any one of claims 14-19, wherein the subject experiences a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 10.0 to 50.0, optionally 25.0 to 35.0 or about 29.

3.

21. The method of any one of claims 14-20, wherein the subject experiences (a) a change of -2.5 to -4.5, optionally -3.0 to -4.0 or about -3.4, in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline; and / or (b) a 51% reduction in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline; and / or (c) a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 115 to 480 minutes after administration of the first dose; and / or (d) a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 210 to 270 minutes after administration of the first dose; and / or (e) a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), about 240 minutes after administration of the first dose; and / or (f) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 100.0 to 140.0, optionally 113.0 to 123.0 or about 118.4; and / or (g) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 30.0 to 65.0, optionally 43.0 to 53.0 or about 48.4; and / or (h) a change of -2.5 to -4.5, optionally -3.0 to -4.0 or about -3.4, in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours,relative to baseline; and / or (i) a 47% reduction in pain intensity on an 11-point Numeric Pain Rating Scale (NPRS) after 48 hours, relative to baseline; and / or (j) a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 90 to 180 minutes after administration of the first dose; and / or (k) a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), 100 to 140 minutes after administration of the first dose; and / or (l) a 2-point reduction in pain intensity, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), about 119 minutes after administration of the first dose.

22. The method of any one of claims 14-21, wherein Compound 1 is administered in a pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant.

23. The method of claim 22, wherein the one or more fillers comprise microcrystalline cellulose; and / or the disintegrant is croscarmellose sodium; and / or the lubricant is magnesium stearate.

24. The method of any one of claims 14-21, wherein Compound 1 is administered in a pharmaceutical composition comprising: about 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 75 wt % of HPMCAS and about 25 wt % of Compound 1; about 46 wt % of microcrystalline cellulose; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate.

25. The method of claim 24, wherein Compound 1 is administered in a pharmaceutical composition comprising: 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 75 wt % of HPMCAS and about 25 wt % of Compound 1; 46 wt % of microcrystalline cellulose; 3 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate.

26. The method of any one of claims 14-21, wherein Compound 1 is administered in a pharmaceutical composition comprising about 50 mg of Compound 1; and / or about 184 mg of microcrystalline cellulose; and / or about 12 mg of croscarmellose sodium; and / or about 4 mg ofmagnesium stearate; and / or about 200 mg of a solid dispersion comprising a polymer and Compound 1.

27. The method of claim 26, wherein Compound 1 is administered in a pharmaceutical composition comprising: about 200 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 150 mg of HPMCAS and about 50 mg of Compound 1; about 184 mg of microcrystalline cellulose; about 12 mg of croscarmellose sodium; and about 4 mg of magnesium stearate.

28. The method of claim 27, wherein Compound 1 is administered in a pharmaceutical composition comprising: 200 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises 150 mg of HPMCAS and 50 mg of Compound 1; 184 mg of microcrystalline cellulose; 12 mg of croscarmellose sodium; and 4 mg of magnesium stearate.

29. The method of any one of claims 14-28, wherein Compound 1 is administered in a pharmaceutical composition comprising an intragranular blend and extragranular blend, optionally wherein the intragranular blend comprises about 0.4 mg of magnesium stearate, optionally 0.4 mg of magnesium stearate, and the extragranular blend comprises about 3.6 mg of magnesium stearate, optionally 3.6 mg of magnesium stearate.

30. The method of any one of claims 22-29, wherein the pharmaceutical composition is a tablet core composition, optionally wherein the tablet core composition is coated with a tablet coating.

31. A pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 40-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; 0.5-1.5 wt % of a lubricant; and 0.05-0.8 wt % of a glidant.

32. The pharmaceutical composition of claim 31, wherein the one or more fillers comprise microcrystalline cellulose and mannitol; and / or the disintegrant is croscarmellose sodium; and / or the lubricant is magnesium stearate; and / or the glidant is colloidal silicon dioxide.

33. The pharmaceutical composition of claim 31 or 32, wherein the pharmaceutical composition comprises: about 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 75 wt % of HPMCAS and about 25 wt % of Compound 1; about 22.9 wt % of microcrystalline cellulose; about 22.9 wt % of mannitol; about 3 wt % of croscarmellose sodium; about 1.0 wt % of magnesium stearate; and about 0.2 wt % of colloidal silicon dioxide.

34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition comprises: 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises 75 wt % of HPMCAS and 25 wt % of Compound 1; 22.9 wt % of microcrystalline cellulose; 22.9 wt % of mannitol; 3 wt % of croscarmellose sodium; 1.0 wt % of magnesium stearate; and 0.2 wt % of colloidal silicon dioxide.

35. The pharmaceutical composition of claim 31 or 32, wherein the pharmaceutical composition comprises: about 280 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 210 mg of HPMCAS and about 70 mg of Compound 1; about 128.2 mg of microcrystalline cellulose; about 128.2 mg of mannitol; about 16.8 mg of croscarmellose sodium; about 5.6 mg of magnesium stearate; and about 1.1 mg of colloidal silicon dioxide.

36. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition comprises: 280 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises 210 mg of HPMCAS and 70 mg of Compound 1; 128.2 mg of microcrystalline cellulose; 128.2 mg of mannitol; 16.8 mg of croscarmellose sodium;5.6 mg of magnesium stearate; and 1.1 mg of colloidal silicon dioxide.

37. A pharmaceutical composition comprising: 45-55 wt % of a solid dispersion comprising a polymer and Compound 1; 42-50 wt % of one or more fillers; 2-4 wt % of a disintegrant; and 0.5-1.5 wt % of a lubricant.

38. The pharmaceutical composition of claim 37, wherein the one or more fillers comprise microcrystalline cellulose; and / or the disintegrant is croscarmellose sodium; and / or the lubricant is magnesium stearate.

39. The pharmaceutical composition of claim 37 or 38, wherein the pharmaceutical composition comprises: about 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 75 wt % of HPMCAS and about 25 wt % of Compound 1; about 46 wt % of microcrystalline cellulose; about 3 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate.

40. The pharmaceutical composition of claim 39, wherein the pharmaceutical composition comprises: 50 wt % of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 75 wt % of HPMCAS and about 25 wt % of Compound 1; 46 wt % of microcrystalline cellulose; 3 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate.

41. The pharmaceutical composition of claim 37 or 38, wherein the pharmaceutical composition comprises: about 200 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises about 150 mg of HPMCAS and about 50 mg of Compound 1; about 184 mg of microcrystalline cellulose; about 12 mg of croscarmellose sodium; and about 4 mg of magnesium stearate.

42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises:200 mg of a solid dispersion comprising HPMCAS and Compound 1, wherein the solid dispersion comprises 150 mg of HPMCAS and 50 mg of Compound 1; 184 mg of microcrystalline cellulose; 12 mg of croscarmellose sodium; and 4 mg of magnesium stearate.

43. A process for preparing Compound 1: comprising transforming ato Compound 1.

44. The process of claim 43, wherein said transforming a compound of formula 5 to Compound 1 comprises transforming the compound of formula 5 to a compound of formula 11: and transforming the compound of1.

45. The process of claim 43 or 44, wherein: (a) the compound of formula 5 is obtained by transforming a compound of formula 4:to the compound of formula 5, optionally wherein the compound of formula 4 is obtained by transforming a compound of formula 3: of formula 3 is obtained byto the compound of formula 3; or(b) the compound of formula 5 is a compound of formula 4’: to the compound of formula 5, optionallyof formula 4’ is obtained by transforming a compound of formula 3:of formula 3 is obtained by transforming a compound of formula: to the compound of formula 3.

46. A compound selected from:,

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