Zilvetrigine dosage forms and dosing regimens for treating pain

Abstract

Disclosed herein are methods of treating pain, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof.

Description

Atorney Docket No, 67573-428431 (VPI / 24-009 WO)DOSAGE FORMS AND DOSING REGIMENS FOR TREATING PAINCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U .S. Provisional Application No. 63 / 677,665, filed July 31, 2024, 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 tire 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. Tire 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. Then 2018 40(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 agrowing awareness of the risks and relative ineffectiveness of the current 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 Navi .8 gene (SCN10A). (3) preclinical work in animal models, and (4) pharmacology of known Navl.8-modulating agents. In addition, because Navi.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., tire dorsal root ganglia), Navi.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 Navi.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, Painfiil Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nayl.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 Nav currents can prevent or reduce neural signaling and Nav channels 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 Nav channels. 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 tire voltage-gated ion channel super-family and comprises 9 isoforms, designated Navl.l - Navi.9. Tire tissue localizations of the nine isoforms vary. Nav 1.4 is the primary sodium channel of skeletal muscle, and Nav 1.5 is the primary sodium channel of cardiacmyocxtes. Navi.7, Navi.8 and Navi.9 are primarily localized to the peripheral nervous system, while Navl.l, Navi.2, Navi.3, and Navi.6 are neuronal channels found in both the central and peripheral nervous systems. Tire 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. XL VII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4). p. 397 (2005)).

[0007] Upon their discovery, Nav 1.8 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, Navi.8 has been shown to be a carrier of tire 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). Navi.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al.. The tetrodotoxin-resistant Na+channel Nav 1.8 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 Nav 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Set. U S A, 2007. 104(20): p. 8520-5; Joshi. S.K., et al.. Involvement of the TTX- resistant sodium channel Navi .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, NavL8. Pain, 2002. 95(1-2): p. 143-52; Dong, X.W., et al., Small interfering RNA-mediated selective knockdown ofNa(v)L8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21; Huang. H.L., et al., Proteomic profding 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. FEBSLett, 2000. 467(2-3): p. 249-52; Ruangsri, S.. et al.. Relationship of axonal voltage-gated sodium channel 1.8 (Navi .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 NavL8 is expressed include the nociceptors involved in pain signaling. Nav 1.8 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). Navi.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 Navi.7 and Navi.8 sodium channels: a computer simulation 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 Navi.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 chamrel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Set. USA, 2006. 103(21): p. 8245-50). In some animal pain models. Navi.8 mRNA expression levels have been shown to increase in tire 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 Navl.7, Navi.8 and Navi.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 Navi.8 and Navi.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 pain in a subject, comprising administering to the subject Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof, in amounts specified herein.

[0009] In another aspect, the disclosure relates to a pharmaceutical composition comprising Compound 1, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate in amounts specified herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 provides the X-ray powder diffraction (XRPD) pattern of Compound 1 Form A.

[0011] Figure 2 provides the13C solid-state NMR (SSNMR) spectrum of Compound 1 Form A.

[0012] Figure 3 provides the X-ray powder diffraction (XRPD) pattern of Compound 1 Methanol Solvate Form C.

[0013] Figure 4 provides the13C solid-state NMR (SSNMR) spectrum of Compound 1 Methanol Solvate Form C.

[0014] Figure 5 provides the X-ray powder diffraction (XRPD) pattern of Compound 1 2-MeTHF Solvate Form D.

[0015] Figure 6 provides the13C solid-state NMR (SSNMR) spectrum of Compound 1 2-MeTHF Solvate Form D.DETAILED DESCRIPTIONDefinitions

[0016] The chemical elements are identified herein in accordance with the Periodic Table of tire 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.

[0017] 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.

[0018] As used herein, the tenn “substantially crystalline" refers to a solid material having little or no amorphous molecules. For example, substantially crystalline materials have less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). It is also noted that the term "substantially crystalline" includes the descriptor "cry stalline." which refers to materials that are 100% crystalline form.

[0019] As used herein, a crystalline form is "substantially pure" when it accounts for an amount byweight equal to or greater than 90% of the sum of all solid fonn(s) in a sample as determined by a method in accordance with the art. such as quantitative XRPD. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum ofall solid form(s) in a sample. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.

[0020] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," "XRPD spectrum" interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate).

[0021] A "signal" or "peak" as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. An XRPD peak is identified by its angular value as measured in degrees 20 (°20), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed, for example, as "a signal at ... degrees two-theta," "a signal at [a] two-theta value(s) of ... " and / or "a signal at at least ... two-theta value(s) selected from .... "

[0022] The repeatability of the measured angular values is in the range of ±0.2° 20. i.e., tire angular value can be at the recited angular value +0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[0023] One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

[0024] The temis "signal intensities" and "peak intensities" interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0025] As used herein, an X-ray powder diffractogram is "substantially similar to that in [a particular] Figure" when at least 90%, such as at least 95%. at least 98%. or at least 99%. of the signals in the two diffractograms overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in XRPD diffractograms even for the same cry stalline form. Thus, those of ordinary' skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta) generally mean that value is identified as ±0.2 degrees two-theta of the reported value, an art-recognized variance.

[0026] 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 tire 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.

[0027] 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.

[0028] 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).

[0029] As used herein, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely H 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.

[0030] 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.

[0031] 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 tire invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H.13C,13N,18O,17O, and31P, respectively.

[0032] 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 thereol), any solvate, hydrate, or cocrystal form thereof, and any solution or suspension thereof.

[0033] As used herein, the term “about.” when used in relation to a specified amount, refers to a range encompassing that specified amount that provides a pharmacological effect equivalent to that obtained from the specified amount. The term “about” may refer to an acceptable error for the specified amount as determined by one of skill in the art, which may depend in part on how the amount is measured or determined. In some embodiments, the term “about” means within 20%, 15%, 10%, 5%, 4%, 3%, 2%,1% or 0.5% of the specified amount. In some embodiments, the term '‘about” means within 20% of the specified amount. In some embodiments, the term “about” means within 15% of the specified amount. In some embodiments, the term “about” means within 10% of the specified amount. In some embodiments, the term “about” means within 5% of the specified amount. In some embodiments, the temi “about” means within 1% of the specified amount. In some embodiments, the term “about” means within 0.5% of the specified amount.

[0034] 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).

[0035] As used herein, the term “subject” or “patient” means an animal, preferably a mammal, and most preferably a human.

[0036] 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 2-(4- / e / 7-biityl-5-chloro-2-mcthyl-phcnyl)-4-oxo- 1H- 1 ,6-naphthyridine-5-carboxamide, regardless of the actual mass of any salt, solvate, hydrate, or cocry stal form that may be administered.

[0037] 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.

[0038] As used herein, the tenn “dose,” when referring to the administration of Compound 1, or a pharmacally acceptable salt thereof, refers to an amount of the compound or salt administered in a 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.

[0039] As used herein, the term “first dose” refers to the first dose of Compound 1, or a pharmacally acceptable salt thereof, that is administered in a given course of treatment. When the “first dose” is larger than the “subsequent dose” (defined below) administered in a given course of treatment, the “first dose” is sometimes referred to as a “loading dose.”

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.Medical Uses of Compound 1 or a Pharmaceutically Acceptable Salt ThereofMethods of Treatment

[0044] In one aspect, the disclosure relates to a method of treating pain in a subject, comprising administering to the subject Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours; (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[0045] In another aspect, the disclosure relates to a method of treating pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours;wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours; (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[0046] In some embodiments, the pain treated in the foregoing method is 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 cardiac arrhythmia.

[0047] In some embodiments, the pain treated in the foregoing method is 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.

[0048] In some embodiments, the pain treated in the foregoing method is gut pain, 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.

[0049] In some embodiments, the pain treated in the foregoing method is neuropathic pain. 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 tenn “diabetic peripheral neuropathy” includes painful diabetic peripheral neuropathy.

[0050] In some embodiments, the pain treated in the foregoing method is neuropathic pain, 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; complexregional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, antiretroviral 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.

[0051] In some embodiments, the pain treated in the foregoing method is musculoskeletal pain. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0052] In some embodiments, the pain treated in the foregoing method is musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain.

[0053] In some embodiments, the pain treated in the foregoing method is inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia.

[0054] In some embodiments, the pain treated in the foregoing method is inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

[0055] In some embodiments, the pain treated in the foregoing method is idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0056] In some embodiments, the pain treated in the foregoing method is idiopathic pain, wherein idiopathic pain comprises reflex sympathetic dystrophy pain.

[0057] In some embodiments, the pain treated in the foregoing method is pathological cough.

[0058] In some embodiments, the pain treated in the foregoing method is acute pain. In some aspects, the acute pain comprises acute post-operative pain.

[0059] In some embodiments, the pain treated in the foregoing method is 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).

[0060] In some embodiments, the pain treated in the foregoing method is bunionectomy pain.

[0061] In some embodiments, the pain treated in the foregoing method is shoulder arthroplasty pain or shoulder arthroscopy pain.

[0062] In some embodiments, the pain treated in the foregoing method is herniorrhaphy pain.

[0063] In some embodiments, the pain treated in the foregoing method is abdominoplasty pain.

[0064] In some embodiments, the pain treated in the foregoing method is visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0065] In some embodiments, the pain treated in the foregoing method is neurodegenerative disease. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0066] In some embodiments, the pain treated in the foregoing method is acute pain, sub-acutc 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 / hemiation pain, radiculopathy, facet joint syndrome, failed back surgery' syndrome, bums, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytocytosis, 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.

[0067] In some embodiments, the pain treated in the foregoing method is femur cancer pain; non- malignant chronic bone pain; rheumatoid arthritis: osteoarthritis; spinal stenosis; neuropathic low back pain: myofascial pain symdrome: 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), postmastectomy 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, bum 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.

[0068] In some embodiments, the pain treated in the foregoing method is 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.

[0069] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg even- 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0070] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequentdoses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0071] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even’ 12 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0072] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0073] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[0074] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein tire subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, tire method comprises administering to the subject Compound1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0075] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0076] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg. followed by subsequent doses of 35 mg every 12 hours.

[0077] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0078] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in the subject: wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, tire method comprises administering to the subject Compound1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0079] 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 pharmacally acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0080] 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 pharmacally acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0081] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0082] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 (SP1D48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or apharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0083] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours: wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0084] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even’ 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain: wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0085] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0086] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) adifference 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0087] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0088] 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 an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0089] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every’ 12 hours; wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0090] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0091] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0092] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0093] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0094] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7. optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0095] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0096] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0097] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale, hi some embodiments, the methodcomprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0098] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0099] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0100] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) 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 (SP1D48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable saltthereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[0101] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0102] 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 an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0103] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to tire subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0104] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein thesubject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0105] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0106] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (b) a first dose of 70 mg. followed by subsequent doses of 35 mg every 12 hours.

[0107] 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 pharmacally acceptable salt thereof, in an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein thesubject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0108] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even' 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0109] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0110] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. Insome embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0111] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0112] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg even' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every' 12 hours.

[0113] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0114] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg every 12 hours.

[0115] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ’ 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0116] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject: wherein tire subject experiences (a) 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 (SP1D48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable saltthereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[0117] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0118] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0119] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0120] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0121] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0122] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0123] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0124] 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 pharmacally acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0125] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0126] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a firstdose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0127] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[0128] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3. optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[0129] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable saltthereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[0130] 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 pharmacally acceptable salt thereof, in an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) a difference from placebo in time-weighted sum of pain intensitydifference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[0131] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0132] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11 .2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0133] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0134] 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 pharmacally acceptable salt thereof, in an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0135] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0136] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0137] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0138] 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 pharmacally acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7. optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0139] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0140] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours: or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0141] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve - 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0142] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0143] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0144] 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 pharmacally acceptable salt thereof, in an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[0145] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0146] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein thesubject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0147] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0148] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0149] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In someembodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0150] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0151] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in tire subject. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0152] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or apharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0153] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute postoperative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0154] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute postoperative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every712 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every712 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0155] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subjectCompound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0156] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0157] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain): wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[0158] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy' pain, abdominoplasty' pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of:(a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0159] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0160] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31 .2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0161] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, orherniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0162] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty7pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally716.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:(b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0163] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every712 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every712 hours.

[0164] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty7pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0165] 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 an amount of: (c) a first dose of about 10 mg, follow ed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0166] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain): wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0. optionally 49.0 to 59.0 or about 54.0; and / or (b) a difference from placebo in time-w'eighted 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0167] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain ismoderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0168] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0169] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg even' 12 hours.

[0170] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve 12 hours; whereinthe acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every- 12 hours.

[0171] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every- 12 hours.

[0172] 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 an amount of: (a) a first dose of about 180 mg. folloyved by subsequent doses of about 90 mg every 12 hours; yvherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; yvherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) a difference from placebo in time-yveighted 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1. or apharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0173] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0174] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain): wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2. optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0175] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or apharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0176] 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 pharmacally acceptable salt thereof, in an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0177] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0178] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point NumericPain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0179] 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 an amount of: (c) a first dose of about 10 mg, follow ed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0180] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein tire acute pain is lessened in the subject; wherein the subject experiences (a) 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 29.0 to 79.0, optionally' 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[0181] 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 phannaccutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a firstdose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours: or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0182] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve - 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even- 12 hours; wherein the acute pain is lessened in the subject: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0183] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 w t % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[0184] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0185] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantiallycrystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0186] 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 an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0187] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg ofmagnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0188] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments.Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire pharmaceutical composition comprises about 35 mg of Compound 1: about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every' 12 hours.

[0189] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251 .3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0190] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0191] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0192] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceuticallyacceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0193] 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 pharmacally acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is lessened in the subject: wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0194] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg ofcroscarmellose sodium: and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0195] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0196] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even- 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0197] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[0198] 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 an amount of:(a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate: wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or(b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[0199] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0200] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0201] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of nncrocrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium: and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251 .3 mg of lactose: about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0202] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, thepharmaceutical composition comprises about 35 mg of Compound 1; about 251 .3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0203] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystallinc cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0204] 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 an amount of: (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:(b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0205] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0206] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmcllosc sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, asrecorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0207] 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 pharmacally acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875?t % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0208] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, tire pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0209] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; w herein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3 2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0210] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0211] 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 an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ' 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[0212] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0213] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0214] 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 an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0215] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg ofmagnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0216] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, tire pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0217] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain islessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmacal composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every’ 12 hours.

[0218] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmacal composition comprises about 6.25 w t % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg ofcroscarmellose sodium: and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 2 1.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0219] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0220] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose: 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-pointNumeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0221] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0222] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical compositioncomprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 \vt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 t % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, follow ed by subsequent doses of 5 mg even’ 12 hours.

[0223] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose: 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even’ 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0224] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[0225] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0226] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0227] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable saltthereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[0228] 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 pharmacally acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of:(a) a first dose of 180 mg, follow ed by subsequent doses of 90 mg every 12 hours.

[0229] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; w'herein the acute pain is moderate to severe acute pain; w'herein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the pharmacal composition is a tablet corecomposition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0230] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71 .5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmacal composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0231] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0232] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) a difference from placebo in time-weighted sum of pain intensitydifference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose: about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of:(b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0233] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0234] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical compositioncomprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 \vt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, follow ed by subsequent doses of 5 mg even’ 12 hours.

[0235] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; w herein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 w4 % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0236] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and / or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0237] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every’ 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3 2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcry stalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; andabout 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0238] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours: or (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[0239] 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 an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscanncllosc sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline(e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg ever}’ 12 hours.

[0240] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0241] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose: 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Fonn A). In someembodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0242] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:(a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0243] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium: and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1: about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the pharmacal composition is a tablet corecomposition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0244] 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 pharmacally acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystal I inc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmacal composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0245] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0246] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; w herein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein tire acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, tire pharmacalcomposition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose: about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:(b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0247] 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 an amount of:(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0248] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 to48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg even’ 12 hours.

[0249] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the pharmacal composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0250] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt% of magnesium stearate: wherein tire subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium: and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0251] 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 an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every' 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every’ 12 hours.

[0252] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmacally acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0253] 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 an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 w't % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[0254] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0255] 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 an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0256] 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 an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) a difference from placebo in time-w eighted 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 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0257] 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 an amount of:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg ofmagnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0258] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmacal composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmacal composition is a tablet core composition. In some embodiments, tire pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0259] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein theacute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmacal composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every’ 12 hours.

[0260] 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 an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcr stalline cellulose; about 502.6 mg of lactose; about 33.6 mgof croscarmellose sodium; and about 11 .2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 2 1.3 mg of rnicrocrystallinc cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0261] 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 an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical compo...

Claims

CLAIMSWhat is claimed is:

1. A method of treating pain in a subject, comprising administering to the subject Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof, in an amount of:(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours:(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours;(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every' 12 hours;(d) about 140 mg once per day;(e) about 70 mg once per day;(f) about 10 mg once per day; or(g) about 5 mg every 48 hours.

2. Tire method of claim 1, wherein said pain is acute pain, and wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of:(a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours;(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every' 12 hours.

3. Tire method of claim 2, wherein the acute pain is lessened in the subject.

4. The method of claim 2 or 3. wherein the first dose is about 180 mg, and the subsequent doses are about 90 mg.

5. The method of claim 4, wherein the subject experiences (a) 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 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and / or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-pointNumeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3.

6. Tire method of claim 2 or 3, wherein the first dose is about 70 mg, and the subsequent doses are about 35 mg.

7. The method of claim 6, wherein the subject experiences (a) 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 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and / or (b) 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 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2.

8. The method of claim 2 or 3, wherein the first dose is about 10 mg, and the subsequent doses are about 5 mg.

9. The method of claim 8, wherein the subject experiences (a) 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 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and / or (b) 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 1.7 to 5.7, optionally about 3.7.

10. The method of any one of claims 2-9, wherein the acute pain is moderate to severe acute pain.

11. The method of claim 10, wherein the subj ect 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.

12. The method of any one of claims 2-11, wherein the acute pain is acute post-operative pain or postsurgical pain.

13. The method of any one of claims 2-12, wherein the acute pain is bunionectomy pain.

14. The method of any one of claims 2-12, wherein the acute pain is abdominoplasty pain.

15. The method of claim 1, wherein said pain is chronic pain, and wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of:(d) about 140 mg once per day;(e) about 70 mg once per day;(f) about 10 mg once per day; or(g) about 5 mg every 48 hours.

16. Tire method of claim 15, wherein the chronic pain is lessened in tire subject.

17. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 140 mg once per day.

18. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 70 mg once per day.

19. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 10 mg once per day.

20. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 5 mg every 48 hours.

21. The method of any one of claims 15-20. wherein the chronic pain is moderate to severe chronic pain.

22. The method of claim 21, wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS).

23. The method of any one of claims 15-22. wherein the chronic pain is neuropathic pain, musculoskeletal pain, or visceral pain.

24. The method of any one of claims 15-23, wherein the chronic pain is diabetic peripheral neuropathy.

25. The method of any one of claims 1-24, wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate.

26. The method of claim 25, wherein Compound 1 is substantially cry stalline.

27. The method of claim 26, wherein Compound 1 is substantially pure Form A.

28. Tire method of any one of claims 25-27, wherein the pharmaceutical composition is a tablet core composition.

29. The method of any one of claims 25-28. wherein the pharmacal composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate.

30. The method of any one of claims 25-29, wherein the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium: and about 0.8 mg of magnesium stearate.

31. The method of any one of claims 25-29, wherein the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate.

32. The method of any one of claims 25-29. wherein the pharmacal composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose: about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate.

33. A pharmaceutical composition comprising:5-7 wt % of Compound 1:(Compound 1);44-46 wt % of microcrystalline cellulose:44-46 wt % of lactose;2.8-3.2 wt % of croscarmellose sodium; and0.9- 1.1 wt % of magnesium stearate.

34. The pharmaceutical composition of claim 33, wherein Compound 1 is substantially crystalline.

35. The pharmaceutical composition of claim 34, wherein less than 15% of Compound 1 is in amorphous form.

36. The pharmaceutical composition of claim 34, wherein Compound 1 is substantially pure Form A.

37. The pharmaceutical composition of claim 36, wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition.

38. The pharmaceutical composition of claim 36 or 37, wherein Fonn A is characterized by an X-ray powder diffractogram (XRPD).

39. The pharmaceutical composition of any one of claims 36-38, wherein Form A is characterized by13C solid-state nuclear magnetic resonance (13C SSNMR) spectrum.

40. The pharmaceutical composition of any one of claims 33-39, wherein the pharmaceutical composition is a tablet core composition.

41. The pharmaceutical composition of any one of claims 33-40, wherein the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate.

42. The pharmaceutical composition of any one of claims 33-41, wherein the pharmaceutical composition comprises about 5 mg of Compound 1.

43. The pharmaceutical composition of claim 42, wherein the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate.

44. The pharmaceutical composition of any one of claims 33-41, wherein the pharmaceutical composition comprises about 35 mg of Compound 1.

45. The pharmaceutical composition of claim 44, wherein the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate.

46. The pharmaceutical composition of any one of claims 33-41, wherein the pharmaceutical composition comprises about 70 mg of Compound 1.

47. Tire pharmaceutical composition of claim 46, wherein the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate.

48. The pharmaceutical composition of any one of claims 33-47 for use in treating pain in a subject.

49. Use of the pharmaceutical composition of any one of claims 33-47 in the manufacture of a medicament for treating pain in a subject.

50. A method of treating pain in a subject comprising administering the pharmaceutical composition of any one of claims 33-47 to the subject.

51. Tire pharmaceutical composition for use of claim 48, the use of claim 49, or tire method of claim 50, wherein said pain is acute pain.

52. The pharmaceutical composition for use, use, or method of claim 51, wherein the acute pain is bunionectomy pain.

53. Tire pharmaceutical composition for use, use, or method of claim 51, wherein the acute pain is abdominoplasty pain.

54. The pharmaceutical composition for use of claim 48, the use of claim 49, or the method of claim 50, wherein said pain is chronic pain.

55. The pharmaceutical composition for use, use, or method of claim 54, wherein the chronic pain is diabetic peripheral neuropathy.

56. A substantially crystalline Compound 1:(Compound 1); wherein the substantially crystalline Compound 1 is selected from Compound 1 Methanol Solvate Form C and Compound 1 2-MeTHF Solvate Fonn D.

57. The substantially crystalline Compound 1 according to claim 56, where the substantially crystalline Compound 1 is Compound 1 Methanol Solvate Form C, optionally wherein Compound 1 Methanol Solvate Fonn C is characterized by:(a) an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two- theta, 9.8 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta; and / or(b) an X-ray powder diffractogram substantially similar to FIG. 3; and / or(c) aljC SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 177.2 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.0 ± 0.2 ppm, 157.3 ± 0.2 ppm, 152.7 ± 0.2 ppm, 151.7 ± 0.2 ppm, 150.7 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.6 ± 0.2 ppm, 145.3 ± 0.2 ppm, 134.1 ± 0.2 ppm, 133.3 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.2 ± 0.2 ppm, 130.3 ± 0.2 ppm, 115.4 ± 0.2 ppm. 114.5 ± 0.2 ppm, 113.9 ± 0.2 ppm, 111.2 ± 0.2 ppm. 50.1 ± 0.2 ppm, 36.4 ± 0.2 ppm, 31.0 ± 0.2 ppm, 29.3 ± 0.2 ppm, 19.9 ± 0.2 ppm, and 18.3 ± 0.2 ppm; and / or(d) a ' ’C SSNMR spectrum substantially similar to FIG. 4.

58. The substantially crystalline Compound 1 according to claim 56, where the substantially crystalline Compound 1 is Compound 1 2-MeTHF Solvate Form D, optionally wherein Compound 1 2- MeTHF Solvate Form D is characterized by:(a) an X-ray powder diffractogram having one, two, or three signals selected from 5.4 ± 0.2 degrees two- theta, 8.6 ± 0.2 degrees two-theta, and 17.0 ± 0.2 degrees two-theta; and / or(b) an X-ray powder diffractogram substantially similar to FIG. 5; and / or(c) aljC SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.6 ± 0.2 ppm, 177.0 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.3 ± 0.2 ppm, 169.5 ± 0.2 ppm, 169.1 ± 0.2 ppm, 157.1 ± 0.2 ppm, 156.4 ± 0.2 ppm, 152.9 ± 0.2 ppm, 151.8 ± 0.2 ppm, 150.4 ± 0.2 ppm, 149.7± 0.2 ppm, 148.6 ± 0.2 ppm, 147.3 ± 0.2 ppm, 145.3 ± 0.2 ppm, 144.6 ± 0.2 ppm, 134.6 ± 0.2 ppm. 133.7± 0.2 ppm, 133.0 ± 0.2 ppm, 132.5 ± 0.2 ppm, 131.1 ± 0.2 ppm, 130.2 ± 0.2 ppm, 116.4 ± 0.2 ppm. 115.4± 0.2 ppm, 114.4 ± 0.2 ppm, 113.5 ± 0.2 ppm, 112.9 ± 0.2 ppm, 111.5 ± 0.2 ppm, 110.9 ± 0.2 ppm, 75.1 ±0.2 ppm, 68.9 ± 0.2 ppm, 36.3 ± 0.2 ppm, 32.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 29.2 ± 0.2 ppm, 25.0 ± 0.2 ppm, 23.2 ± 0.2 ppm, 19.4 ± 0.2 ppm, and 17.6 ± 0.2 ppm; and / or(d) a13C SSNMR spectrum substantially similar to FIG. 6.

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