Treating pain associated with central sensitization

Abstract

The present invention features methods of treating pain, eg, pain associated with central sensitization, with modified NSAIDs, eg, phosphosulindac.

Description

Related Applications

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 384790, 63 / 384792, 63 / 384793, 63 / 384794, 63 / 384795, and 63 / 384796, all filed November 23, 2022, and U.S. Provisional Application No. 63 / 483353, filed February 6, 2023. The entire contents of these provisional applications are incorporated herein by reference for all purposes. [Technical Field]

[0002] The present invention relates to compounds and their use in the treatment of pain associated with central sensitization. The present invention also relates to compounds and their use in the treatment of neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN), neuropathic pain associated with diabetic peripheral neuropathy (DPN), neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), neuropathic pain associated with post-herpetic neuralgia (PHN), migraine pain, and corneal neuropathic pain. [Background technology]

[0003] Recent studies have shown that pain associated with central sensitization is relatively common, present in up to one in five patients with chronic pain from any cause. In fact, approximately 20% of the adult patient population reports widespread, whole-body pain associated with central sensitization.

[0004] Pain associated with central sensitization occurs when a subject's nervous system is in a persistently hyperactive state, resulting in a lowered threshold for firing action potentials. Therefore, in this situation, the central nervous system responds as if peripheral input were present, even though the peripheral nervous system is providing limited input (i.e., the central nervous system is hyperexcitable). This state of hypersensitivity is known as "windup" and manifests as pain sensations in response to innocuous stimuli (allodynia) and exaggerated responses to painful stimuli (hyperalgesia). Central sensitization results from changes in the properties of neurons in the CNS (i.e., central neuroplasticity), such that pain perception is no longer linked to the presence, intensity, or duration of a particular peripheral stimulus (noxious or not). Therefore, central sensitization is associated with the onset and maintenance of pain when pain signaling occurs centrally even in the absence of peripheral stimulation (i.e., due to hypersensitivity of central pain-signaling neurons).

[0005] Dynamic changes in central neurons (i.e., plasticity) that occur in the development and maintenance of pain associated with central sensitization are thought to be a major factor in many clinical pain syndromes. Pain associated with central sensitization, sometimes referred to as centralized pain or central pain, has both genetic and environmental influences that predispose patients, and occurs, for example, in fibromyalgia, chronic pain syndromes, and patients with nerve damage such as stroke or spinal cord injury. Although pain can be experienced as having a peripheral origin, pain onset occurs at a central site of action, resulting in symptoms of allodynia and hyperalgesia.

[0006] Central sensitization can be a component of neuropathic pain associated with neuropathy.Neuropathy is a disease or abnormality of nervous system, and affects more than 20 million Americans.According to recent research, about 1 in 10 adults suffer from neuropathic pain, and the economic burden of treating this pain increases.

[0007] Neuropathy is related to the development of neuropathic pain. Neuropathic pain can occur as a result of damage to the peripheral nervous system or central nervous system. Peripheral neuropathic pain is caused by damage to nerve structures, such as peripheral nerve endings or nociceptors, which make these nerve structures highly sensitive to stimuli and can generate pulses even in the absence of stimuli. Damage can occur for many reasons, such as traumatic injury (such as nerve compression, spinal cord injury, and post-operative nerve injury), chemotherapy treatment, diseases such as diabetes and advanced cancer, and viruses (such as shingles or HIV).

[0008] Peripheral nerve lesions can often result in pathological conditions characterized by the presence of persistent spontaneous pain, which is associated with hyperalgesia (increased response to noxious stimuli) and allodynia (pain induced by non-painful stimuli).Hyperalgesia and allodynia are associated with central sensitization, in which CNS nociceptive neurons exhibit increased excitability due to persistent input or a decrease in stimulus threshold induced by peripheral injury.As mentioned herein, central sensitization is associated with the development and maintenance of neuropathic pain associated with peripheral neuropathy.

[0009] In terms of symptoms, pain associated with central sensitization can cause sharp pain, dull pain, painful burning or cold sensations, paresthesia, loss of proprioception, numbness, or even loss of pain sensation.Similarly, peripheral neuropathy can cause sharp pain, dull pain, painful burning or cold sensations, paresthesia, loss of proprioception, numbness, or even loss of pain sensation.

[0010] Currently, there is a global need for additional pain therapies, and pain associated with central sensitization has become a major health problem in a wide range of populations. From a treatment perspective, pain associated with central sensitization often responds to neuromodulators, antiepileptics, or antidepressants, but not to nonsteroidal anti-inflammatory drugs (NSAIDs). Recommended therapies include tricyclic antidepressants (TCAs), such as amitriptyline, serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine or venlafaxine, and anticonvulsants, such as pregabalin and gabapentin.

[0011] Neuropathic pain is also a growing health problem in a wide range of populations. Treatment of neuropathic pain is often attempted with so-called non-traditional analgesics, for example, antidepressants such as duloxetine and amitriptyline, or antiepileptic drugs such as gabapentin or pregabalin. Additionally, local anesthetics (including lidocaine) are used to treat and manage neuropathic pain.

[0012] Despite evidence to the contrary, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to manage neuropathic pain. However, NSAIDs have been shown to be ineffective in treating neuropathic pain that may be related to central sensitization. In fact, a review of recent clinical trials found no evidence of significant pain reduction with NSAIDs in patients with neuropathic pain, and no clinical outcomes demonstrated statistically significant differences between NSAIDs and placebo (Moore et al. Cochrane Database of Systematic Reviews (2015); 10:1-25). The Cochrane Library concluded that NSAIDs should not be recommended for the treatment of neuropathic pain. Therefore, the anti-inflammatory activity of typical NSAIDs naturally does not produce analgesic effects when pain is mediated by central sensitization or is related to peripheral neuropathy.

[0013] Therefore, there is a great need for compounds that treat pain associated with central sensitization. Additionally, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, such as PTPN and PHN, and pain due to migraine. Summary of the Invention

[0014] The present inventors have surprisingly found that phosphosulindac (PS) is effective in treating pain associated with central sensitization. Indeed, data from several distinct animal models that develop central sensitization demonstrate the ability of PS to treat allodynia, i.e., the manifestation of central sensitization that occurs through signal amplification in centrally located neurons in response to typically innocuous stimuli. The observations regarding the treatment of allodynia in several distinct models, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, support a role for PS acting directly on neuronal signaling associated with central sensitization. Thus, the combined observations herein demonstrate the broadly applicable role of PS as a centrally acting analgesic in the treatment of pain associated with central sensitization (i.e., pain that occurs at a central site of action and manifests, for example, as allodynia).

[0015] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, as well as activity in the treatment of rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO 2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED) and suggests that PS reduces corneal sensitivity in the acute model. The observation of decreased sensitivity to acute stimuli that do not produce persistent pain does not demonstrate efficacy in treating pain associated with central sensitization (i.e., originating at a central site of action). Furthermore, in this acute model, the effects of PS were observed immediately, suggesting that the local activity of this atypical NSAID is similar to that observed with typical NSAIDs (e.g., ketorolac) in the same model. Again, such peripheral activity does not demonstrate efficacy of PS in treating pain originating at a central site of action. Indeed, clinical guidance in the field generally recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain associated with central sensitization, and ketorolac has been shown to have limited analgesic activity in such models of pain. Furthermore, in a DED model, PS was found to restore suppressed ocular sensitivity, suggesting a role for PS in increasing, rather than reducing, nociception. Thus, while these observations fall short of suggesting a role for PS in treating pain associated with central sensitization, the observations herein demonstrate the unprecedented activity of PS in reducing pain generated at a central site of action.

[0016] The present inventors have investigated the activity of PS in specific animal models in which central sensitization manifested as allodynia has been established, and have demonstrated surprising therapeutic efficacy comparable to that of direct-acting neuroleptic anesthetics, which can reduce pain associated with central sensitization. Specific animal models are important when developing therapies for treating pain associated with central sensitization. Indeed, given the pathogenesis of such pain, which involves changes in the sensitivity of centrally located neurons, observing the effectiveness of a particular compound in, for example, an acute pain model cannot indicate the compound's usefulness in treating pain associated with central sensitization. Therefore, the effectiveness of a compound in treating pain associated with central sensitization is demonstrated by observations showing the compound's ability to reverse the manifestations of central sensitization (e.g., allodynia) in a model system in which chronic pain has been established. Therefore, animal models used in early testing before further clinical development are essential. Based on specific animal models of pain (e.g., allodynia) generated through central neuronal sensitization, the observations herein demonstrate the unprecedented efficacy of PS in treating pain associated with central sensitization.

[0017] Therefore, in a first aspect, the present invention provides a method for treating pain associated with central sensitization, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, so that the pain associated with central sensitization is treated.In some embodiments, the pain associated with central sensitization is not the pain associated with central sensitization caused by chemotherapy-induced peripheral neuropathy (CIPN) or diabetic peripheral neuropathy (DPN).

[0018] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0019] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0020] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0021] As described above, pain associated with central sensitization occurs as a result of the hyperactivity of centrally located neurons, which exhibit a decreased stimulation threshold and can depolarize even in the absence of peripheral stimuli. Indeed, the perception of pain is no longer associated with the presence, intensity, or duration of a specific peripheral stimulus (noxious or not). Therefore, a subject with pain associated with central sensitization may experience pain induced by non-painful stimuli (allodynia) or experience increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Therefore, PS may reduce pain signaling originating centrally. PS may reduce pain signaling originating in the dorsal root ganglion. PS may reduce pain signaling originating in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS may reduce pain signaling originating in the CNS. In some embodiments, the pain associated with central sensitization is allodynia. Allodynia can be in response to mechanical and / or thermal stimuli. Additionally, in some embodiments, pain associated with central sensitization is hyperalgesia.

[0022] In some embodiments, the pain associated with central sensitization is pain associated with post-traumatic peripheral neuropathy. In some embodiments, the pain associated with central sensitization is pain associated with postherpetic neuralgia. In some embodiments, the pain associated with central sensitization is pain from migraine (or pain from other headache disorders). In some embodiments, the pain associated with central sensitization is corneal neuropathic pain.

[0023] Furthermore, in vivo evidence indicates the efficacy of PS in treating neuropathic pain associated with PTPN, migraine pain, neuropathic pain associated with PHN, and corneal neuropathic pain. Further experiments in specific animal models will confirm these preliminary observations.

[0024] Accordingly, in another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PTPN is treated and / or prevented.

[0025] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is treated and / or prevented.

[0026] In another aspect, the present invention provides a method for treating and / or preventing migraine pain, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is treated and / or prevented.

[0027] In a further aspect, the present invention provides a method for treating and / or preventing pain, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that pain is treated and / or prevented.

[0028] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS is particularly preferred as a formulation for local administration. PS can be administered, for example, topically, to the area where pain sensation occurs. In some embodiments, PS is formulated for oral administration. Thus, PS can be administered orally. Thus, in some embodiments, the present invention provides a method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that pain associated with central sensitization is treated, wherein the PS is administered orally. In some embodiments, the PS is administered both orally and topically.

[0029] The observations herein regarding the treatment of allodynia in several distinct models, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, support the role of PS in directly affecting neuronal signaling associated with central sensitization. Because these activities are not shared by sulindac (PS's parent compound), the observations herein demonstrate that modifying sulindac not only confers surprising analgesic activity to PS that acts directly on neuronal signaling, but also makes PS more capable of traversing toward its primary central site of action, thereby enabling it to exert its analgesic activity on neuronal signaling even more effectively. Thus, without wishing to be bound by theory, the observations herein suggest that modifying NSAIDs so that they can act directly on neuronal signaling by traversing peripheral neurons that project to the central nervous system and more easily access their primary site of action may overcome the apparent failure of NSAIDs in treating pain associated with central sensitization. Thus, as an alternative to PS, the methods of the present invention can be practiced using one or more modified NSAIDs disclosed herein. As used herein, a "modified NSAID" refers to a compound that results from the modification of an NSAID molecule (ie, the parent compound).

[0030] Thus, in a further aspect, the present invention provides a method for treating pain associated with central sensitization, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the pain associated with central sensitization is treated.

[0031] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with CIPN is treated and / or prevented. In certain embodiments, the modified NSAID is not PS.

[0032] In a further aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented. In certain embodiments, the modified NSAID is not PS.

[0033] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with PTPN is treated and / or prevented.

[0034] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with PHN is treated and / or prevented.

[0035] In another aspect, the present invention provides a method for treating and / or preventing migraine pain, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that migraine pain is treated and / or prevented.

[0036] In a further aspect, the present invention provides a method for treating and / or preventing corneal neuropathic pain, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that corneal neuropathic pain is treated and / or prevented.

[0037] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). Modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib or modified celecoxib.In certain embodiments, the NSAID of modified NSAID can be sulindac, ibuprofen, aspirin or naproxen.Therefore, modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac or NOSH-sulindac. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofenamide.

[0038] In certain embodiments, the modified NSAID does not have the formula LXIX and / or LXX.

[0039] In certain embodiments, the modified NSAID can be selected from phospho-naproxen, such as Formula VIII; phospho-ibuprofen, such as Formula III; phospho-glycerol ibuprofen, such as Formula LXXI; glycerol-phospho-aspirin II, such as Formula V; phosphosulindac amide, such as Formula X; phospho-ibuprofen amide, such as Formula XI; phospho-glycerol-ibuprofen-amide, such as Formula XII; NO-sulindac, such as Formula XLIV; platinum sulindac, such as Formula LXVII; NO-aspirin, such as Formula XLIX; HS-sulindac, such as Formula XXXIV; or NOSH-aspirin, such as Formula LIX.

[0040] In certain embodiments, the modified NSAID is a modified sulindac, such as an NO-releasing sulindac (e.g., NO-sulindac, such as that of Formula XLIV), an HS-releasing sulindac (e.g., HS-sulindac, such as that of Formula XXXIV), a phosphoramido-modified sulindac (e.g., phosphosulindac amide, such as that of Formula X), or a metal-chelated sulindac (e.g., platinum sulindac, such as that of Formula LXVII). In certain embodiments, the modified NSAID is a modified sulindac, such as an NO-releasing sulindac (e.g., NO-sulindac, such as that of Formula XLIV), an HS-releasing sulindac (e.g., HS-sulindac, such as that of Formula XXXIV), or preferably a phosphoramido-modified sulindac (e.g., phosphosulindac amide, such as that of Formula X). In certain embodiments, the modified NSAID is a phospho-NSAID, such as phospho-naproxen, such as that of Formula VIII; phospho-ibuprofen, such as that of Formula III; phospho-glycerol ibuprofen, such as that of Formula LXXI; or glycerol-phospho-aspirin II, such as that of Formula V. In certain embodiments, the modified NSAID is a phosphoroamide NSAID, such as phospho-glycerol ibuprofen amide, such as that of Formula XII; phospho-ibuprofen-amide, such as that of Formula XI; or phosphosulindacamide, such as that of Formula X. In certain embodiments, the modified NSAID is a modified ibuprofen, such as phospho-ibuprofen, such as that of Formula III; phospho-glycerol ibuprofen, such as that of Formula LXXI; or phospho-ibuprofen-amide, such as that of Formula XI.

[0041] In some embodiments, the modified NSAID is formulated for oral administration.Therefore, the modified NSAID can be orally administered.In certain embodiments, the orally administered modified NSAID is a phosphoroamide NSAID, for example, phosphosulindacamide such as formula X; or phospho-ibuprofenamide such as formula XI.In some embodiments, the orally administered modified NSAID is phospho-ibuprofen such as formula III; phospho-glycerol-ibuprofen such as formula LXXI; NO-sulindac such as formula XLIV; or HS-sulindac such as formula XXXIV.In certain embodiments, the orally administered modified NSAID is a modified sulindac, for example, PS such as formula I or II, NO-sulindac such as formula XLIV; or HS-sulindac such as formula XXXIV; or phosphosulindacamide such as formula X. In certain embodiments, the orally administered modified NSAID is a modified ibuprofen, for example, phospho-ibuprofen, such as that of Formula III; phospho-glycerol-ibuprofen, such as that of Formula LXXI; or phospho-ibuprofen-amide, such as that of Formula XI, particularly phospho-ibuprofen-amide, such as that of Formula XI. [Brief explanation of the drawings]

[0042] [Figure 1] Schematic of a therapeutic study of pain associated with central sensitization. [Figure 2] Effect of PS on the treatment of pain associated with central sensitization. [Figure 3] Effect of PS on the treatment of pain associated with central sensitization induced by paclitaxel. The effect of PS compared to vehicle control was significant from day 5 and increased thereafter (†, p<0.002; ‡, p=4.9×10-5; &, p=1.7×10-7; *, p=2.2×10-7). [Figure 4] Effect of PS on the treatment of pain associated with central sensitization caused by vincristine. The effect of PS compared to vehicle control was significant at day 16 (*p=8.6×10-6). [Figure 5]Effect of PS on the treatment of pain associated with central sensitization caused by oxaliplatin. The effect of PS compared to vehicle control was significant at day 22 (*p=0.004). [Figure 6] Effect of PS compared with sulindac, lidocaine, and pregabalin on the treatment of pain associated with central sensitization. A. Mechanical allodynia (*, statistically significant difference; NS, statistically not significant). B. Cold allodynia (values: mean ± SEM; *, p<0.0001). [Figure 7] Schematic of therapeutic studies on pain associated with central sensitization. STZ is streptozotocin. PWT is the paw withdrawal threshold test. [Figure 8] Effect of PS on pain associated with central sensitization caused by STZ compared with vehicle. [Figure 9] Effects of sulindac, lidocaine, and pregabalin on pain associated with central sensitization. [Figure 10] A) Confirmation of the validity of the model system. B) Effect of PS on PTPN-associated pain compared to sulindac and pregabalin. The effect of PS compared to vehicle control was significant at 14 days (p<0.005). [Figure 11] Schematic diagram of PS metabolism. [Figure 12] Biodistribution of PS in various tissues after local administration. SN = sciatic nerve. DRG = dorsal root ganglion. [Figure 13-1] Distribution of PS metabolites in various tissues after local administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion. [Figure 13-2] (Figure 13 continued) Distribution of PS metabolites in various tissues following local administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion. [Figure 14] A) Biodistribution of PS in ocular tissues upon topical administration of PS to the outer surface of the eyelid; B) Levels of sulindac detected in ocular tissues as a result of hydrolysis of PS upon administration to the outer surface of the eyelid. [Figure 15] Schematic of the prevention study of neuropathic pain associated with CIPN. PWT is the paw withdrawal threshold test. [Figure 16] Effect of PS on preventing neuropathic pain associated with CIPN compared with vehicle. [Figure 17] Effect of PS on preventing neuropathic pain associated with paclitaxel-induced CIPN. The effect of PS compared to vehicle control was significant (*, p=3.0×10-8; **, p=2.3×10-6). [Figure 18] Schematic of the study of prevention of neuropathic pain associated with DPN. STZ is streptozotocin. PWT is paw withdrawal threshold test. [Figure 19] Effect of PS on preventing neuropathic pain associated with DPN. *, p<0.0001 (STZ vs. naive); **, p<0.004 (PS vs. vehicle); ***, p<0.001 (lidocaine vs. vehicle). [Figure 20] Effect of glycero-phospho-aspirin II, phosphonaproxen, and phosphoibuprofen on the treatment of neuropathic pain associated with CIPN. Compared to vehicle control: *, p<0.0001, †, p<0.001, &, p<0.02. DETAILED DESCRIPTION OF THE INVENTION

[0043] definition The following definitions of pain types follow those of the International Association for the Study of Pain (IASP). "Pain" is an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage. "Central sensitization" refers to increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. "Peripheral sensitization" refers to increased responsiveness and decreased threshold of nociceptive neurons in the periphery to stimulation of their receptive fields. The exact etiology of central and peripheral sensitization differs between neuropathic pain and other forms of pain, such as inflammatory pain. "Allodynia" is pain caused by stimuli that normally do not elicit pain. "Hyperalgesia" is increased pain from stimuli that normally elicit pain. Pain associated with central sensitization can be either systemic or at multiple locations within the body. Given the involvement of the relevant nervous systems, pain associated with central sensitization exhibits symptoms corresponding to those observed in neuropathic pain. Therefore, patients with pain associated with central sensitization may experience one or more sensations described as hot, burning, throbbing, electric shock, stabbing, sharp pain, cramping, tingling, numbness, or tingling.Pain associated with central sensitization is also associated with mood swings, fatigue, cognitive impairment, sleep changes, and pain-catastrophizing.In addition, patients with pain associated with central sensitization may have multifocal pain, memory complaints, and comorbid conditions, including major depressive disorder or generalized anxiety disorder.

[0044] "Neuropathic pain" is caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain is a clinical description (and not a diagnosis) that requires a demonstrable lesion or disease that meets established neurological diagnostic criteria. Patients with neuropathic pain may experience one or more sensations described as heating, burning, throbbing, electric shocks, stabbing, sharp pain, cramping, aching, tingling, numbness, or tingling. The term "lesion of the somatosensory nervous system" is generally used when diagnostic testing (e.g., imaging, neurophysiological testing, biopsy, clinical examination) reveals an abnormality or there has been obvious trauma. The term "disease of the somatosensory nervous system" is generally used when the underlying cause of the lesion (e.g., stroke, vasculitis, diabetes, genetic abnormality) is known. "Peripheral neuropathic pain" is pain caused by a lesion or disease of the peripheral somatosensory nervous system. "Central neuropathic pain" is pain caused by a lesion or disease of the central somatosensory nervous system.

[0045] The following definitions of headache types follow the International Classification of Headache Disorders (ICHD), Third Edition (ICHD-3). There are two major types of migraine: "migraine without aura," a clinical syndrome characterized by headache with specific characteristics and associated symptoms, and "migraine with aura," characterized primarily by transient focal neurological symptoms that usually precede or sometimes accompany the headache. "Migraine without aura" (i.e., common migraine; simple hemicrania) is a recurrent headache disorder that begins episodically and lasts 4 to 72 hours. The headache typically has a unilateral location, a pulsatile quality, moderate or severe intensity, worsens with everyday physical activity, and is associated with nausea and / or photophobia and phonophobia. "Migraine with aura" (i.e., typical or classic migraine) usually develops gradually and involves recurrent attacks of unilateral, fully reversible visual, sensory, or other CNS symptoms lasting several minutes, usually followed by headache and associated migraine symptoms. "Episodic migraine" generally involves approximately 1-2 migraines / headaches per month. "Chronic migraine" is headaches occurring 15 or more days per month for more than 3 months, with at least 8 of those days per month having migraine characteristics.

[0046] Generally, the term "disease" refers to a physical condition or state of health of a patient or subject that can be treated using the methods provided herein.

[0047] The term "therapeutically effective amount" refers to an amount of a compound or a combination of compounds described herein that is sufficient to produce the effect of the intended application. Thus, if the intended application is to treat a disease, the "therapeutically effective amount" refers to an amount of a compound or a combination of compounds described herein that is sufficient to treat the disease. If the intended application is to treat and / or prevent a disease, the "therapeutically effective amount" refers to an amount of a compound or a combination of compounds described herein that is sufficient to treat and / or prevent the disease.

[0048] "Pharmaceutically acceptable excipients" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inactive ingredients contained in pharmaceutical compositions. The use of such pharmaceutically acceptable excipients to formulate active pharmaceutical ingredients is well known in the art. To the extent that any conventional pharmaceutically acceptable excipient is incompatible with PS, its use in the therapeutic compositions of the present invention is contemplated.

[0049] Use of the term "about" when referring to a numerical value is optional and means that the number referred to is an approximation within typical experimental variation (or within statistical experimental error), and therefore the number may vary accordingly.

[0050] The term "comprising" encompasses both "including" and "consisting," e.g., a composition "comprising" X may consist exclusively of X, or may include something additional (e.g., X+Y).

[0051] Qualified NSAID As used herein, a "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., the parent compound). Exemplary modified NSAIDs are discussed in Ramos-Inza et al. (J. Med. Chem. (2021); 64: 16380-16421) and WO2009 / 023631, which are incorporated herein by reference in their entireties.

[0052] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs (metal-NSAIDs), HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs).

[0053] Phospho-NSAIDs The phospho-NSAID can be PS, for example, having formula I or II.

[0054] Phospho-NSAIDs can be, for example, compounds of formula III: [ka] The compound may be phospho-ibuprofen, having the formula:

[0055] Phospho-NSAIDs can be represented, for example, by formula IV: [ka] The compound may be phospho-ibuprofen-PEG having the formula:

[0056] The PEG can have a molecular weight (g / mol) ranging from about 200 to about 15,000, e.g., from about 200 to 3,000, or from about 200 to 1,000. The phospho-ibuprofen-PEG can be in its anionic form as shown in Formula IV and / or in its protonated form.

[0057] Phospho-NSAIDs can be represented, for example, by formula V, VI, or VII: [ka] It may be phospho-aspirin, having the formula:

[0058] Thus, the phospho-aspirin can be glycero-phospho-aspirin I (e.g., having formula VI), or, in particular, glycero-phospho-aspirin II (e.g., having formula V). The phospho-aspirin can be 2-acetoxy-benzoic acid 4-(diethoxy-phosphoryloxymethyl)-phenyl ester or 2-acetoxybenzoic acid 3-(diethoxy-phosphoryloxymethyl)-phenyl ester.

[0059] Phospho-NSAIDs can be represented, for example, by formula VIII: [ka] It may be phospho-naproxen, having the formula:

[0060] Phospho-NSAIDs can be represented, for example, by formula IX: [ka] The compound may be phospho-flurbiprofen, having the formula:

[0061] Phosphoramide-NSAIDs Phosphoramido-NSAIDs can be, for example, compounds of formula X: [ka] It may be a phosphosulindac amide having the formula:

[0062] Phosphoramido-NSAIDs can be represented, for example, by formula XI: [ka] The compound may be a phosphoibuprofen-amide having the formula:

[0063] Phosphoramido-NSAIDs can be represented, for example, by formula XII: [ka] The compound may be a phospho-glycerol-ibuprofen-amide having the formula:

[0064] Selenium-modified NSAIDs In the case of Se-NSAIDs, Se can be incorporated as a selenocyanate, sulfur selenide, selenazolidine, or selenoester.

[0065] Se-NSAIDs can be represented, for example, by formula XIII: [ka] It can be Se-sulindac, having the formula:

[0066] Se-NSAIDs can be represented, for example, by formula XIV or XV: [ka] Se-ibuprofen, having the formula where R is SeCN or SeCF3.

[0067] Se-NSAIDs can be represented, for example, by formula XVI, XVII, or XVIII: [ka] may be Se-aspirin having the formula where R is SeCN or SeCF3.

[0068] Se-NSAIDs can be represented, for example, by formula XIX or XX: [ka] It may be Se-celecoxib, having the formula:

[0069] Se-NSAIDs can be represented, for example, by formula XXI: [ka] It may be Se-naproxen, having the formula:

[0070] Se-NSAIDs can be represented, for example, by formula XXII: [ka] The compound may be Se-flurbiprofen, having the formula:

[0071] Se-NSAIDs can be represented, for example, by formula XXIII: [ka] It may be Se-ketoprofen, having the formula:

[0072] Metal-NSAID Metal-NSAIDs may be coordinated with copper (Cu), cobalt (Co), platinum (Pt), zinc (Zn), iridium (Ir), ruthenium (Ru), nickel (Ni), silver (Ag), manganese (Mn), or organotin. Cu complexes may be tetra- or hexa-coordinate. Co complexes may be hexa-coordinate. The organotin may be tetrabutyltin, tributyltin oxide, triphenyltin acetate, triphenyltin chloride, trimethyltin chloride, triphenyltin hydroxide, azocyclotin, cyhexatin, hexamethylditin, or tetraethyltin.

[0073] Metal-NSAIDs can be, for example, those of formula XXIV: [ka] The compound may be Cu(II)-naproxen having the formula:

[0074] Metal-NSAIDs can be, for example, those of formula XXV: [ka] The compound may be Cu(II)-flufenamic acid, having the formula:

[0075] Metal-NSAIDs can be, for example, those of formula XXVI, XXVII, XXVIII, or XXIX: [ka] [ka] The compound may be Cu(II)-indomethacin having the formula:

[0076] Metal-NSAIDs can be, for example, compounds of the formula XXX: [ka] The compound may be Co(II)-diflunisal, having the formula:

[0077] Metal-NSAIDs can be, for example, those of formula XXXI: [ka] The compound may be Co(II)-naproxen having the formula:

[0078] Metal-NSAIDs can be, for example, those of formula XXXII: [ka] The compound may be Co(II)-ibuprofen, having the formula:

[0079] Metal-NSAIDs can be, for example, those of formula XXXIII: [ka] The compound may be Co(II)-aspirin, having the formula:

[0080] H2S-releasing NSAID H2S-releasing NSAIDs can be represented, for example, by formula XXXIV: [ka] It may be HS-sulindac, having the formula:

[0081] H2S-releasing NSAIDs can be represented, for example, by formula XXXV: [ka] The compound may be HS-ibuprofen having the formula:

[0082] H2S-releasing NSAIDs can be represented, for example, by formula XXXVI: [ka] It may be HS-aspirin, having the formula:

[0083] The H2S-releasing NSAID can be, for example, of formula XXXVII, XXXVIII, XXXIX, or XL: [ka] It may be HS-naproxen, having the formula:

[0084] H2S-releasing NSAIDs can be represented, for example, by formula XLI: [ka] The compound may be HS-ketoprofen having the formula:

[0085] The H2S-releasing NSAID can be, for example, represented by formula XLII, or XLIII: [ka] It may be HS-diclofenac having the formula:

[0086] NO-releasing NSAID NO-releasing NSAIDs can be represented, for example, by formula XLIV or XLV: [ka] may be NO-sulindac having the formula wherein R is of formula XLVI or XLVII: [ka] It has.

[0087] NO-releasing NSAIDs can be represented, for example, by formula XLVIII or XLIX: [ka] It may be NO-aspirin, having the formula:

[0088] NO-releasing NSAIDs can be represented, for example, by formula L: [ka] It may be NO-naproxen, having the formula:

[0089] NO-releasing NSAIDs can be, for example, those of formula LI: [ka] The compound may be NO-flurbiprofen, having the formula:

[0090] NO-releasing NSAIDs can be represented, for example, by formula LII: [ka] It may be NO-indomethacin, having the formula:

[0091] NO-releasing NSAIDs can be represented, for example, by formula LIII, LIV, or LV: [ka] It may be NONO-aspirin, having the formula:

[0092] NO-releasing NSAIDs can be represented, for example, by formula LVI: [ka] It may be NONO-naproxen, having the formula:

[0093] NOSH-releasing NSAID NOSH-releasing NSAIDs can be represented, for example, by formula LVII: [ka] It can be NOSH-sulindac, having the formula:

[0094] NOSH-releasing NSAIDs can be represented, for example, by formula LVIII: [ka] It may be NOSH-naproxen, having the formula:

[0095] NOSH-releasing NSAIDs can be represented, for example, by formula LIX, LX, LXI, or LXII: [ka] It may be NOSH-aspirin, having the formula:

[0096] As is apparent from the formula of NOSH-releasing NSAIDs herein, NOSH-releasing NSAIDs release both NO and H2S. Therefore, NOSH-NSAIDs are NO- and H2S-releasing NSAIDs. This terminology is well established in the art.

[0097] Other modified NSAIDs The modified NSAID may be a modified NSAID that does not fall into one of the classes disclosed above.

[0098] For example, a modified NSAID may be, for example, of formula LXIII: [ka] The compound may be a nitroxide-aspirin having the formula:

[0099] Modified NSAIDs can be, for example, those of formula LXIV: [ka] The compound may be a triazole-thioether-naproxen having the formula:

[0100] Modified NSAIDs can be, for example, those of formula LXV: [ka] The compound may be an anthraquinone-aspirin having the formula:

[0101] Modified NSAIDs can be, for example, those of formula LXVI: [ka] The compound may be a diclofenac-N derivative having the formula:

[0102] The modified NSAID can be an NSAID drug hybrid, for example, an erlotinib-NSAID conjugate, a riboflavin-NSAID conjugate, a podophyllotoxin-NSAID conjugate, a chalcone-NSAID conjugate, an ursolic acid-NSAID conjugate, or a camptothecin-NSAID conjugate.

[0103] The modified NSAID can be, for example, of formula LXVII: [ka] It may be platinum-sulindac, having the formula:

[0104] Modified NSAIDs can be, for example, those of formula LXVIII: [ka] It may be Q922, having the formula:

[0105] In another aspect, the present invention provides a modified NSAID, or a pharmaceutical composition comprising the modified NSAID, having formula LXVIII.

[0106] The modified NSAID has the formula LXIX: [ka] may have:

[0107] The modified NSAIDs have the formula LXX: [ka] may have:

[0108] In some embodiments, the modified NSAID is a phospho-NSAID, such as that of formula LXXI: [ka] For example, phospho-glycerol-ibuprofen.

[0109] Generation of modified NSAIDs One of ordinary skill in the art would be able to use routine methods to produce the modified NSAIDs disclosed herein, for example, via modification of the carboxylic acid group.

[0110] Pain associated with chemotherapy-induced peripheral neuropathy (CIPN) or diabetic peripheral neuropathy (DPN) CIPN and associated neuropathic pain are frequent, dose-dependent side effects of commonly used chemotherapy. Peripheral nerve damage accounts for the majority of neurological damage associated with chemotherapy toxicity and is the most frequent limiting factor of chemotherapy, second only to hematologic toxicity. This pain is thought to result from direct toxic effects on sensory axons, demyelination, or impaired calcium metabolism. CIPN-associated neuropathic pain is particularly difficult to treat. Currently, CIPN-associated neuropathic pain is managed with antidepressants (e.g., duloxetine) and / or antiepileptic drugs (e.g., gabapentin and pregabalin). Unfortunately, pain management is not very satisfactory, and these systemic treatments induce significant side effects that lead to poor treatment adherence. In fact, to date, no satisfactory means exists for preventing or even treating CIPN-associated pain. The only approved drug, duloxetine, is generally considered ineffective.

[0111] DPN is peripheral neuropathy caused by diabetes and represents one of the most serious complications of diabetes. Approximately half of all people with diabetes have some form of nerve damage, and hyperglycemia is the primary cause of peripheral neuropathy in DPN. DPN can affect both small and large nerves. These nerves protect the body by sending signals to the brain regarding pain and temperature changes, detect touch and pressure, and help maintain balance. Clinical guidelines recommend pain relief in painful diabetic neuropathy with the use of antidepressants (e.g., duloxetine) and / or antiepileptic drugs (e.g., gabapentin and pregabalin), as well as opioids and topical agents such as capsaicin. Current treatments for DPN-related pain have limited effectiveness and can cause significant side effects.

[0112] Thus, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly CIPN or DPN.

[0113] The present inventors have surprisingly found that phosphosulindac (PS) is effective in treating and preventing pain associated with CIPN or DPN, as well as pain associated with other neuropathic pain disorders and central sensitization.

[0114] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, as well as activity in the treatment of rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore depressed ocular sensitivity in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as mentioned above, it showed similar activity to NSAIDs when administered to normal eyes in a DED model. However, these observations do not suggest a role for PS in the treatment of neuropathic pain associated with CIPN or DPN. Furthermore, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and therefore, anti-inflammatory activity alone is considered insufficient for therapeutic benefit.

[0115] Nevertheless, the present inventors have investigated the activity of PS in specific animal models of neuropathic pain and demonstrated surprising therapeutic efficacy comparable to that of direct-acting neuroleptic anesthetics, such as lidocaine and pregabalin. Specific animal models are important when developing therapies for treating neuropathic pain. Indeed, given the pathogenesis of pain associated with peripheral neuropathy, observing the efficacy of a particular compound in an alternative pain model, such as an inflammatory pain model, may not demonstrate the compound's usefulness in treating neuropathic pain. Therefore, animal models used in early testing prior to further clinical development are essential. Based on specific animal models of neuropathic pain associated with CIPN or DPN, the observations herein demonstrate the unprecedented efficacy of PS in the treatment and / or prevention of neuropathic pain associated with CIPN or DPN, respectively.

[0116] The present inventors surprisingly demonstrate analgesic activity of PS similar to that of centrally acting analgesics in treating neuropathic pain associated with CIPN or DPN. These observations correlate with the findings herein that locally administered PS can reach the primary site of action (e.g., the dorsal root ganglion (DRG)) known to be involved in the generation of neuropathic pain associated with CIPN or DPN. Furthermore, PS has been shown to be particularly stable in peripheral neurons and toward more central sites of action. While not wishing to be bound by this, these observations support the theory that PS exerts its analgesic activity directly on neurons and presumably within more central sites of action, consistent with the activity of PS comparable to that of centrally acting analgesics. In contrast, the non-phosphorylated "parent compound" of PS (i.e., sulindac, a typical NSAID) does not treat and / or prevent neuropathic pain associated with CIPN or DPN. Further observations by the inventors herein surprisingly demonstrate the analgesic efficacy of PS, but not its parent compound, sulindac, in other forms of neuropathic pain, supporting the theory that PS has direct activity on neural signaling from centrally located neurons and suggesting the versatility of PS in treating pain associated with central sensitization.

[0117] Therefore, based on the inventors' observations, modifying sulindac results in compounds that can exhibit analgesic activity not only directly on neuronal signaling, but also by traversing to the primary central site of action, allowing the modified NSAID to exert its analgesic activity on central neuronal signaling even more effectively.

[0118] These observations represent the first indication that compounds within the broader class of modified NSAIDs have direct analgesic effects on pain-sensing mechanisms and may treat or prevent neuropathic pain associated with CIPN or DPN. Therefore, based on these observations, similar to PS, these modified NSAIDs, in contrast to their parent compounds, are expected to exert analgesic activity directly on neural signaling, traversing the primary central site of action.

[0119] Thus, in certain aspects, the present invention provides methods for treating and / or preventing neuropathic pain associated with CIPN, the methods comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with CIPN is treated and / or prevented, wherein the modified NSAID is not a PS. In further aspects, the present invention provides methods for treating and / or preventing neuropathic pain associated with DPN, the methods comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, wherein the modified NSAID is not a PS, such that neuropathic pain associated with DPN is treated and / or prevented.

[0120] The modified NSAID for treating and / or preventing CIPN or DPN via topical administration is not a PS. In some embodiments, the modified NSAID is not a PS as disclosed in WO2022 / 251805 or WO2022 / 251806. In some embodiments, the modified NSAID is not a PS, or a solvate, derivative, or prodrug of PS, as disclosed in WO2022 / 251805 or WO2022 / 251806. In some embodiments, the modified NSAID is not any form of PS as disclosed in WO2022 / 251805 or WO2022 / 251806. Accordingly, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with CIPN is treated and / or prevented, provided that the contents of WO2022 / 251805 and WO2022 / 251806 are disclaimed. In a further aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented, provided that the contents of WO2022 / 251805 and WO2022 / 251806 are disclaimed. In some embodiments, reference to "PS" or "phosphosulindac" encompasses both PS-I and PS-II, as well as solvates, derivatives, and prodrugs of PS, including solvates, derivatives, and prodrugs of PS-I and PS-II. Compounds of Formulas I and II are described in U.S. Patent No. 8,236,820, which is incorporated herein by reference in its entirety. For purposes of this application, the term PS does not include phosphosulindac-amide, e.g., having Formula IX.

[0121] Thus, modified NSAIDs for treating and / or preventing CIPN or DPN have the formula I (PS-I): [ka] The sulfoxide form of PS, or a solvate thereof, may also have the formula: Formula II (PS-II): [ka] The sulfide form of PS, or a solvate thereof, is also not.

[0122] The modified NSAID can be any one of the modified NSAIDs disclosed herein other than PS. For example, the modified NSAID can be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). The modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib, or modified celecoxib.In certain embodiments, the NSAID of the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen.Therefore, the modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac.In certain embodiments, the modified NSAID can be phospho-NSAID. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofen amide. In certain embodiments, the modified NSAID can be phosphonaproxen, phosphoibuprofen, and / or glycero-phospho-aspirin II.

[0123] In certain embodiments, the modified NSAID for treating and / or preventing pain associated with CIPN or DPN can be one or more of the following: phospho-naproxen, such as Formula VIII; phospho-ibuprofen, such as Formula III; phospho-glycerol ibuprofen, such as Formula LXXI; glycerol-phospho-aspirin II, such as Formula V; NO-sulindac, such as Formula XLIV; NO-aspirin, such as Formula XLIX; HS-sulindac, such as Formula XXXIV; Pt-sulindac, such as Formula LXVII; NOSH-aspirin, such as Formula LIX; phosphosulindac amide, such as Formula X; phospho-ibuprofen amide, such as Formula XI; phospho-glycerol-ibuprofen-amide, such as Formula XII; or a compound having Formula LXVIII or LXIX.

[0124] In certain embodiments, the modified NSAID can be a phospho-NSAID, such as phospho-naproxen, such as that represented by Formula VIII; phospho-ibuprofen, such as that represented by Formula III; phospho-glycerol ibuprofen, such as that represented by Formula LXXI; or glycerol-phospho-aspirin II, such as that represented by Formula V. In certain embodiments, the modified NSAID can be an NO-releasing NSAID, such as NO-sulindac, such as that represented by Formula XLIV, or NO-aspirin, such as that represented by Formula XLIX. In certain embodiments, the modified NSAID can be an HS-releasing NSAID, such as HS-sulindac, such as that represented by Formula XXXIV. In certain embodiments, the modified NSAID can be an NOSH-releasing NSAID, such as NOSH-aspirin, such as that represented by Formula LIX. In particularly preferred embodiments, the modified NSAID can be a phosphoroamide NSAID, such as phosphosulindac amide, such as that represented by Formula X; phospho-ibuprofen amide, such as that represented by Formula XI; or phospho-glycerol-ibuprofen amide, such as that represented by Formula XII.

[0125] In certain embodiments, the modified NSAID is a modified sulindac other than PS, such as an NO-releasing sulindac (e.g., NO-sulindac, such as that of Formula XLIV); an HS-releasing sulindac (e.g., HS-sulindac, such as that of Formula XXXIV); or a phosphoramido-modified sulindac (e.g., a phosphosulindacamide, such as that of Formula X).

[0126] In certain embodiments, the modified NSAID is a modified ibuprofen, for example, phospho-ibuprofen, such as that of formula III, phospho-glycerol-ibuprofen, such as that of formula LXXI, or phospho-ibuprofen-amide, such as that of formula XI, particularly phospho-ibuprofen-amide, such as that of formula XI.

[0127] As described above, nerve damage associated with CIPN or DPN can result in overactivation of pain signaling pathways, leading to sensitization of peripheral and / or central neurons, and these neurons exhibit a decreased stimulation threshold. Therefore, subjects with CIPN or DPN may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, modified NSAIDs can have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Furthermore, modified NSAIDs can reduce pain generated through peripheral sensitization or through central sensitization that occurs as a result of neuropathy. Therefore, modified NSAIDs can reduce pain signaling generated centrally. Modified NSAIDs can reduce pain signaling generated in the sciatic nerve. Modified NSAIDs can reduce pain signaling generated in the dorsal root ganglion. Considering the observation that modified NSAID PS has been shown to ascend peripheral neurons to the spinal cord, modified NSAIDs can reduce pain signaling that occurs in the spinal cord. In some embodiments, the neuropathic pain is allodynia. Allodynia can be in response to mechanical and / or thermal stimuli. Furthermore, in some embodiments, the neuropathic pain is hyperalgesia.

[0128] The modified NSAID can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises the modified NSAID and one or more pharmaceutically acceptable excipients. The modified NSAID can be formulated for topical administration, particularly for topical administration to the upper and lower extremities of a subject (i.e., to achieve a stocking-glove distribution).

[0129] In some embodiments, the modified NSAID is formulated for oral administration. Thus, the modified NSAID can be administered orally. Accordingly, in some embodiments, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with CIPN is treated and / or prevented, wherein the modified NSAID is administered orally. Accordingly, in some embodiments, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with DPN is treated and / or prevented, wherein the modified NSAID is administered orally. In such embodiments, the modified NSAID can be PS.

[0130] Accordingly, in some aspects, the present invention provides methods for treating and / or preventing neuropathic pain associated with CIPN, the methods comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with CIPN is treated and / or prevented, wherein the PS is administered orally.

[0131] Accordingly, in another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented, wherein the PS is administered orally.

[0132] In certain embodiments for treating and / or preventing CIPN or DPN when administered orally, the modified NSAID can be one or more of the following: PS, such as formula I or II; phospho-naproxen, such as formula VIII; phospho-ibuprofen, such as formula III; phospho-glycerol ibuprofen, such as formula LXXI; phospho-ibuprofen amide, such as formula XI; NO-sulindac, such as formula XLIV; phosphosulindac amide, such as formula X; HS-sulindac, such as formula XXXIV; Pt-sulindac, such as formula LXVII; NOSH-aspirin, such as formula LIX; or a compound having formula LXIX.

[0133] In certain embodiments for treating and / or preventing CIPN or DPN when administered orally, the modified NSAID can be a phospho-NSAID, e.g., a PS such as that of Formula I or II; a phospho-naproxen such as that of Formula VIII; a phospho-ibuprofen such as that of Formula III; or a phospho-glycerol ibuprofen such as that of Formula LXXI.

[0134] In certain embodiments for treating and / or preventing CIPN or DPN when administered orally, the modified NSAID can be a phosphoroamide NSAID, for example, phospho-ibuprofenamide, such as that of Formula XI; or phosphosulindacamide, such as that of Formula X.

[0135] In certain embodiments for treating and / or preventing CIPN or DPN when administered orally, the modified NSAID can be an NO-releasing NSAID, e.g., NO-sulindac, such as that of Formula XLIV; an HS-releasing NSAID, e.g., HS-sulindac, such as that of Formula XXXIV, or an NOSH-releasing NSAID, such as NOSH-aspirin, such as that of Formula LIX.

[0136] In certain embodiments for treating and / or preventing CIPN or DPN when administered orally, the modified NSAID can be a modified sulindac, e.g., a PS such as that of Formula I or II; an NO-sulindac such as that of Formula XLIV; an HS-sulindac such as that of Formula XXXIV; a Pt-sulindac such as that of Formula LXVII; or a phosphosulindacamide such as that of Formula X.

[0137] In certain embodiments for treating and / or preventing CIPN or DPN when administered orally, the modified NSAID can be a modified ibuprofen, for example, phospho-ibuprofen, such as that of Formula III; phospho-glycerol-ibuprofen, such as that of Formula LXXI; or phospho-ibuprofen-amide, such as that of Formula XI, particularly phospho-ibuprofen-amide, such as that of Formula XI.

[0138] Further Embodiments of Pain Associated with CIPN As outlined above, chemotherapy can cause damage to neurons, resulting in peripheral neuropathy and associated neuropathic pain. Pain can occur during or after a patient receives chemotherapy, and can manifest as, for example, shooting, burning, or stabbing pain associated with other sensory symptoms. Thus, in some embodiments, the present invention provides a method for preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, so that the neuropathic pain associated with CIPN is prevented. In other embodiments, the present invention provides a method for treating neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, so that the neuropathic pain associated with CIPN is treated. A subject may experience neuropathic pain caused by one or more previous doses of chemotherapy prior to one or more subsequent doses, and therefore, the subject would benefit from an analgesic that can treat existing neuropathic pain and prevent the development of further neuropathic pain. Thus, in some embodiments, the modified NSAIDs can be used for the treatment and prevention of neuropathic pain associated with CIPN. In accordance with the above, the present invention provides modified NSAIDs for use in the treatment and / or prevention of neuropathic pain associated with CIPN. Furthermore, the present invention provides use of the modified NSAIDs for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with CIPN.

[0139] Because CIPN develops in the context of chemotherapy, the subject may be a human patient with cancer who is about to undergo, is undergoing, or has previously undergone treatment with one or more chemotherapy compounds. Chemotherapeutic compounds generally refer to drugs with antitumor properties or the ability to inhibit cell growth or proliferation. The prevalence of CIPN is drug-dependent, with reported rates ranging from 19% to over 85% in patients receiving different drug treatments. This prevalence is highest with platinum-based drugs, taxanes, immunomodulators, and epothilones, but is also observed in patients receiving other common cancer chemotherapy drugs, including vinca alkaloids and proteasome inhibitors. Thus, the one or more chemotherapeutic compounds can be a platinum-based anti-tumor drug (e.g., oxaliplatin, cisplatin, or carboplatin), a taxane (e.g., paclitaxel, docetaxel, or cabazitaxel), a vinca alkaloid (e.g., vincristine, vinblastine, vinorelbine, or vindesine), or a proteasome inhibitor (e.g., bortezomib). The one or more chemotherapeutic compounds can be one or more immunomodulatory agents, including thalidomide and / or analogs thereof. The one or more chemotherapeutic compounds can be a platinum-based anti-tumor drug, such as oxaliplatin, a taxane, such as paclitaxel, and a vinca alkaloid, such as vincristine. The subject can have any cancer that is treated with a chemotherapeutic compound associated with the development of CIPN and associated neuropathic pain. In some embodiments, the subject with CIPN has a solid tumor cancer. The subject may have ovarian cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer), Kaposi's sarcoma, and / or pancreatic cancer. Alternatively, the subject may have melanoma, esophageal cancer, prostate cancer (e.g., hormone-refractory prostate cancer), head and neck cancer, gastric cancer, and / or cervical cancer.

[0140] Based on the observations herein, modified NSAIDs may have a direct analgesic effect on CIPN-associated neuropathic pain. CIPN-associated neuropathic pain may be burning pain. Subjects undergoing or after chemotherapy may experience constant symmetric neuropathic pain in the lower and upper limbs. In the treatment of CIPN-associated neuropathic pain, modified NSAIDs may reduce neuropathic pain. In some cases, the reduction is so complete that neuropathic pain disappears. In the treatment of CIPN-associated neuropathic pain, modified NSAIDs may also reduce one or more of the sensory symptoms associated with CIPN. In the prevention of CIPN-associated neuropathic pain, modified NSAIDs may reduce the incidence of neuropathic pain. In the prevention of CIPN-associated neuropathic pain, modified NSAIDs may also reduce the incidence of one or more of the sensory symptoms associated with CIPN.

[0141] Patients with CIPN describe various bilateral sensory symptoms, for example, in the hands and feet (also described as a "stocking-glove" distribution). Sensory symptoms include paresthesia (e.g., numbness, tingling, tingling, and / or formication), burning, or electric shocks (i.e., a sensation like an electric shock). Even if the sensory symptoms experienced by a subject undergoing or after chemotherapy are not considered painful (or do not reach the threshold required to be considered pain in themselves), modified NSAIDs can reduce any one or more of the sensory symptoms experienced by a subject undergoing or after chemotherapy, including those listed above. Modified NSAIDs can be used to reduce the stocking-glove distribution in subjects undergoing or after chemotherapy. In some cases, the reduction is complete, such that one or more sensory symptoms disappear.

[0142] As mentioned above, neuropathic pain associated with CIPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. Modified NSAIDs may reduce the neuronal signaling involved in pain sensation in subjects undergoing or after chemotherapy. Modified NSAIDs may reduce pain that occurs through peripheral sensitization or central sensitization. In some cases, the reduction may be so complete that pain generation disappears. Thus, modified NSAIDs may reduce centrally generated pain signaling. Modified NSAIDs may reduce pain signaling that occurs in the sciatic nerve. Modified NSAIDs may reduce pain signaling that occurs in the dorsal root ganglion. Considering that PS has been shown to ascend peripheral neurons toward the spinal cord, without wishing to be bound by theory, modified NSAIDs may reduce pain signaling that occurs in the spinal cord. In some cases, the reduction may be so complete that pain signaling is eliminated. Neuropathic pain CIPN in a subject undergoing or after chemotherapy can be allodynia (e.g., mechanical allodynia or thermal allodynia). Additionally or alternatively, neuropathic pain CIPN in a subject undergoing or after chemotherapy can be hyperalgesia.

[0143] Neuropathic pain in patients undergoing or following chemotherapy can be measured using a visual analog pain scale or other suitable methods in the art.

[0144] Further embodiments of pain associated with DPN Conditions that occur in diabetic patients, particularly hyperglycemia, can cause damage to neurons, resulting in peripheral neuropathy and associated neuropathic pain. Neuropathic pain in these patients develops over time and often worsens in patients with long-standing disease, and can include stabbing, burning, and / or shooting pain. In some embodiments, the present invention provides a method for preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with DPN is prevented. In other embodiments, the present invention provides a method for treating neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with DPN is treated. Because DPN develops over time in diabetic patients, subjects may experience worsening neuropathic pain over time; therefore, subjects would benefit from an analgesic that can treat ongoing neuropathic pain and prevent the development of further neuropathic pain. Thus, in some embodiments, the modified NSAIDs can be used for the treatment and prevention of neuropathic pain associated with DPN. In accordance with the above, the present invention provides modified NSAIDs for use in the treatment and / or prevention of neuropathic pain associated with DPN. Furthermore, the present invention provides use of the modified NSAIDs for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with DPN.

[0145] Based on the observations herein, modified NSAIDs may have a direct analgesic effect on DPN-associated neuropathic pain. DPN-associated neuropathic pain may be stabbing, burning, and / or shooting pain. Subjects with DPN may experience constant, symmetric neuropathic pain in the lower and upper limbs. In treating DPN-associated neuropathic pain, modified NSAIDs may reduce neuropathic pain. In some cases, the reduction is so complete that neuropathic pain disappears. In treating DPN-associated neuropathic pain, modified NSAIDs may also reduce one or more of the sensory symptoms associated with DPN. In preventing DPN-associated neuropathic pain, modified NSAIDs may reduce the incidence of neuropathic pain. In preventing DPN-associated neuropathic pain, modified NSAIDs may also reduce the incidence of one or more of the sensory symptoms associated with DPN.

[0146] Sensory symptoms of DPN include paresthesia (e.g., numbness, tingling, tingling, or formication), burning, or electric shock sensations (i.e., electric shock-like sensations). DPN usually affects the extremities, such as the feet, hands, legs, and arms, where nerve fibers are the longest and most numerous, and patients often have a "stocking-glove" distribution. Even if the sensory symptoms experienced by a subject with DPN are not considered painful (or do not reach the threshold required to be considered pain in themselves), modified NSAIDs may be used to reduce any one or more of the sensory symptoms experienced by a subject with DPN, including those listed above. Modified NSAIDs may be used to reduce the stocking-glove distribution in a subject with DPN. In some cases, the reduction is complete, such that one or more sensory symptoms disappear.

[0147] As mentioned above, neuropathic pain associated with DPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. Modified NSAIDs may reduce the neuronal signaling involved in pain sensation in subjects with DPN. Modified NSAIDs may reduce pain generated through peripheral sensitization or central sensitization. In some cases, the reduction may be complete, such that pain generation disappears. Thus, modified NSAIDs may reduce centrally generated pain signaling. Modified NSAIDs may reduce pain signaling generated in the sciatic nerve. Modified NSAIDs may reduce pain signaling generated in the dorsal root ganglion. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, without wishing to be bound by theory, modified NSAIDs may reduce pain signaling generated in the spinal cord. In some cases, the reduction may be complete, such that pain signaling is eliminated. Neuropathic pain in subjects with DPN may be allodynia (e.g., mechanical allodynia or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject with DPN can be hyperalgesia.

[0148] Neuropathic pain in subjects with DPN can be measured using a visual analog pain scale or other suitable methods in the art.

[0149] Pain related to central sensitization As outlined above, pain associated with central sensitization occurs when centrally located neurons exhibit reduced sensitivity to firing action potentials (i.e., neurons are sensitized). This occurs in the context of persistent nociceptive signaling from the periphery, resulting in peripheral sensitization, which ultimately leads to hyperexcitability of central neurons, which ultimately manifests as pain sensations even in the absence of ongoing peripheral input. In fact, central sensitization is associated with spontaneous pain, but typically manifests as allodynia (pain induced by non-painful stimuli) or hyperalgesia (enhanced pain sensation in response to noxious stimuli). Central sensitization is associated with chronic pain states in which pain is generated or amplified by hyperexcitability of higher-order neurons. Pain can manifest as widespread pain or radiating pain, sometimes localized near the original site of nociception. In some embodiments, the present invention provides a method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that pain associated with central sensitization is treated. Subjects experiencing pain associated with central sensitization would benefit from an analgesic that can reduce the pain caused by central sensitization and prevent further pain associated with central sensitization. Thus, in some embodiments, PS can be used to treat and prevent pain associated with central sensitization. In accordance with the above, the present invention provides PS for use in treating pain associated with central sensitization. Furthermore, the present invention provides use of PS for the manufacture of a medicament for treating pain associated with central sensitization.

[0150] Pain associated with central sensitization is not acute nociceptive pain (i.e., pain that subsides when the noxious stimulus is removed). Thus, in some embodiments, pain associated with central sensitization is chronic pain (i.e., pain that persists or recurs for more than three months). In certain embodiments, pain is perceived in the absence of peripheral nociceptor input, for example, to noxious or innocuous stimuli. The pathogenesis of central sensitization can vary depending on the initial pathology that triggers peripheral input and contributes to central sensitization. For example, central sensitization can be the result of an inflammatory pain mechanism, i.e., the initial trigger was an inflammatory response, but the resulting central sensitization causes pain even in the absence of ongoing inflammation. In certain cases, central sensitization is the result of a neuropathic pain mechanism. Central sensitization is a characteristic of some chronic pain conditions. Pain associated with central sensitization can be pain associated with one or more of the following: inflammatory pain, neuropathic pain, fibromyalgia, chronic pain, chronic regional pain syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, spondyloarthritis, lupus, temporomandibular disorders, and / or idiopathic low back pain. Pain associated with central sensitization resulting from inflammatory pain is not due to an ongoing peripheral inflammatory response. In certain embodiments, pain associated with central sensitization can be pain associated with one or more of the following: neuropathic pain, fibromyalgia, chronic pain, chronic regional pain syndrome, osteoarthritis, temporomandibular disorders, and / or idiopathic low back pain. In some embodiments, pain associated with central sensitization occurs after a stroke or spinal cord injury or in subjects with multiple sclerosis. In some embodiments, pain associated with central sensitization can be pain associated with post-traumatic peripheral neuropathy. In some embodiments, pain associated with central sensitization can be pain associated with postherpetic neuralgia. In some embodiments, the pain associated with central sensitization can be pain from a migraine. In some embodiments, the pain associated with central sensitization can be pain from other headache disorders. In some embodiments, the pain associated with central sensitization can be pain associated with corneal neuropathic pain.

[0151] Based on the observations herein, PS has a direct analgesic effect on pain associated with central sensitization. In treating pain associated with central sensitization, PS can reduce pain. In some cases, the reduction is complete, such that the pain disappears. In treating pain associated with central sensitization, PS can also reduce one or more symptoms associated with central sensitization. In treating and preventing pain associated with central sensitization, PS can reduce the incidence of pain. In treating and preventing pain associated with central sensitization, PS can also reduce the incidence of one or more symptoms associated with central sensitization.

[0152] Pain associated with central sensitization may be radiating pain. The pain may be widespread. In some embodiments, the pain may be radiating around the area of ​​the initial injury. In some embodiments, pain associated with central sensitization may have characteristics of neuropathic pain and thus may result in one or more sensations described as heating, burning, throbbing, electric shocks, stabbing, sharp pain, cramping, aching, tingling, numbness, or tingling. Patients suffering from pain associated with central sensitization may experience a variety of symptoms. Symptoms include mood swings, fatigue, cognitive impairment, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia, and / or phonophobia. Even if the symptoms experienced by a subject experiencing pain associated with central sensitization are not considered painful (or do not reach the threshold required to be considered painful per se), PS may reduce any one or more of the symptoms experienced by the subject. In some cases, the reduction is complete, such that one or more of the symptoms experienced by the subject disappears. Indeed, elimination of the underlying pain associated with central sensitization will result in an improvement in many of the associated symptoms.

[0153] As described above, pain associated with central sensitization can be allodynia and / or hyperalgesia. In certain embodiments, pain associated with central sensitization is allodynia (e.g., mechanical or thermal allodynia). PS can reduce neuronal signaling involved in pain sensation generated through central sensitization. In some cases, the reduction can be complete, such that pain generation disappears. Thus, PS can reduce pain signaling generated centrally. PS can reduce pain signaling generated in the dorsal root ganglion. PS can reduce pain signaling generated in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce pain signaling generated in the CNS. In some cases, the reduction can be complete, such that pain signaling is eliminated. Pain associated with central sensitization in a subject can be neuropathic pain. In certain embodiments, pain associated with central sensitization, such as neuropathic pain, is not pain associated with central sensitization caused by CIPN or DPN. In some embodiments, PS does not prevent the development of central sensitization.

[0154] Pain associated with central sensitization in a patient can be measured using a visual analog pain scale or other suitable method in the art.

[0155] The observations herein regarding the treatment of allodynia in several distinct models, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, support the role of PS in directly affecting neuronal signaling associated with central sensitization. Because these activities are not shared by sulindac (PS's parent compound), the observations herein demonstrate that modifying sulindac not only confers surprising analgesic activity to PS that acts directly on neuronal signaling, but also makes PS more capable of traversing toward its primary central site of action, thereby enabling it to exert its analgesic activity on neuronal signaling even more effectively. Thus, without wishing to be bound by theory, the observations herein suggest that modifying NSAIDs so that they can act directly on neuronal signaling by traversing peripheral neurons that project to the central nervous system and more easily access their primary site of action may overcome the apparent failure of NSAIDs in treating pain associated with central sensitization. Thus, as an alternative to PS, the methods of the present invention can be practiced using one or more modified NSAIDs disclosed herein. Thus, the present invention provides a method of treating pain associated with central sensitization, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the pain associated with central sensitization is treated. As used herein, "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., the parent compound).

[0156] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). Modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib or modified celecoxib.In certain embodiments, the NSAID of modified NSAID can be sulindac, ibuprofen, aspirin or naproxen.Therefore, modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac or NOSH-sulindac. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofenamide.

[0157] In certain embodiments, the modified NSAID for treating pain associated with central sensitization is selected from one or more of the following: phospho-naproxen, such as Formula VIII; phospho-ibuprofen, such as Formula III; phospho-glycerol ibuprofen, such as Formula LXXI; glycerol-phospho-aspirin II, such as Formula V; phosphosulindac amide, such as Formula X; phospho-ibuprofen amide, such as Formula XI; phospho-glycerol-ibuprofen-amide, such as Formula XII; NO-sulindac, such as Formula XLIV; platinum sulindac, such as Formula LXVII; NO-aspirin, such as Formula XLIX; HS-sulindac, such as Formula XXXIV; or NOSH-aspirin, such as Formula LIX.

[0158] In certain embodiments, the modified NSAID for treating pain associated with central sensitization is a modified sulindac other than PS, such as NO-releasing sulindac (e.g., NO-sulindac, such as Formula XLIV), HS-releasing sulindac (e.g., HS-sulindac, such as Formula XXXIV), phosphoramido-modified sulindac (e.g., phosphosulindac amide, such as Formula X), or metal-chelated sulindac (e.g., platinum sulindac, such as Formula LXVII). In certain embodiments, the modified NSAID for treating pain associated with central sensitization is a modified sulindac other than PS, such as NO-releasing sulindac (e.g., NO-sulindac, such as Formula XLIV), HS-releasing sulindac (e.g., HS-sulindac, such as Formula XXXIV), or preferably phosphoramido-modified sulindac (e.g., phosphosulindac amide, such as Formula X).

[0159] In certain embodiments, the modified NSAID for treating pain associated with central sensitization is a phospho-NSAID other than PS, for example, phospho-naproxen, such as that of Formula VIII; phospho-ibuprofen, such as that of Formula III; phospho-glycerol ibuprofen, such as that of Formula LXXI; or glycerol-phospho-aspirin II, such as that of Formula V.

[0160] In certain embodiments, the modified NSAID for treating pain associated with central sensitization is a phosphoroamide NSAID, for example, a phospho-glycerol ibuprofen amide, such as that of Formula XII; a phospho-ibuprofen-amide, such as that of Formula XI; or a phosphosulindacamide, such as that of Formula X.

[0161] In certain embodiments, the modified NSAID for treating pain associated with central sensitization is a modified ibuprofen, for example, phospho-ibuprofen, such as that of Formula III; phospho-glycerol-ibuprofen, such as that of Formula LXXI; or phospho-ibuprofen-amide, such as that of Formula XI.

[0162] In certain embodiments for treating pain associated with central sensitization, the modified NSAID is a modified form of sulindac, such as an NO-releasing sulindac (e.g., NO-sulindac, such as of Formula XLIV), an HS-releasing sulindac (e.g., HS-sulindac, such as of Formula XXXIV), or a phosphoramido-modified sulindac (e.g., phosphosulindacamide, such as of Formula X).

[0163] In some embodiments for treating pain associated with central sensitization, the modified NSAID is administered orally.

[0164] In certain embodiments, the orally administered modified NSAID can be one or more of the following: PS, such as of Formula I or II; phosphosulindac amide, such as of Formula X; phospho-ibuprofen amide, such as of Formula XI; phospho-ibuprofen, such as of Formula III; phospho-glycerol-ibuprofen, such as of Formula LXXI; NO-sulindac, such as of Formula XLIV; or HS-sulindac, such as of Formula XXXIV; Pt-sulindac, such as of Formula LXVIII; or phosphonaproxen, such as of Formula VIII.

[0165] In some embodiments, the orally administered modified NSAID is a phospho-NSAID, e.g., PS, such as those of Formula I or II; phospho-naproxen, such as those of Formula VIII; phospho-ibuprofen, such as those of Formula III; or phospho-glycerol-ibuprofen, such as those of Formula LXXI. In certain embodiments, the orally administered modified NSAID is a phosphoroamide NSAID, e.g., phosphosulindacamide, such as those of Formula X; or phospho-ibuprofenamide, such as those of Formula XI.

[0166] In some embodiments, the orally administered modified NSAID is a modified sulindac, e.g., a PS such as that of Formula I or II; an NO-sulindac such as that of Formula XLIV; an HS-sulindac such as that of Formula XXXIV; or a phosphosulindac amide such as that of Formula X.

[0167] In certain embodiments, the orally administered modified NSAID is a modified ibuprofen, for example, phospho-ibuprofen, such as that of Formula III; phospho-glycerol-ibuprofen, such as that of Formula LXXI; or phospho-ibuprofen-amide, such as that of Formula XI, particularly phospho-ibuprofen-amide, such as that of Formula XI.

[0168] In certain embodiments for treating pain associated with central sensitization, the orally administered modified NSAID is a phosphosulindacamide, such as of Formula X.

[0169] Pain associated with post-traumatic peripheral neuropathy Posttraumatic peripheral neuropathy (PTPN) can result from a variety of traumatic peripheral nerve injuries and is associated with neuropathic pain that can cause anything from mild discomfort to lifelong disability. Traumatic nerve injuries can be classified into categories (Seddon and Sunderland Grades I to VI) based on the presence of demyelination and the degree of damage to the nerve's axons and connective tissue (see Menorca et al., Hand Clin. (2013); 29(3):317-330). The main classifications, in order of severity, are transient nerve conduction disturbances (Grade I), axonotmesis (including Grades II to IV), and neurectomy (Grade V). Grade VI (later added to the Seddon and Sunderland classification) involves damage at different levels along the nerve (Grades III to V).

[0170] Naturally, such peripheral nerve trauma can be associated with chronic neuropathic pain. Trauma can result in tangles of nerve fibers and connective tissue (traumatic neuroma) that develop after nerve injury, and this area is associated with paresthesia. The damaged nerve and any surrounding nerves can show changes in gene expression, which makes them hypersensitive due to the occurrence of spontaneous discharges. Thus, trauma results in painful hypersensitivity to innocuous stimuli (allodynia) or exaggerated pain response to noxious stimuli (hyperalgesia), which reflects central sensitization. Traumatic neuropathic pain can cause patients to experience burning, stabbing, burning, pins and needles, or nauseous sensations, as well as numbness, tingling, and pricking.

[0171] Neuropathic pain associated with PTPN is particularly difficult to treat. It is currently managed with secondary amine tricyclic antidepressants (e.g., nortriptyline, desipramine), calcium channel α-2-δ ligand anticonvulsants (e.g., pregabalin, gabapentin), opioids, ketamine, and topical lidocaine. Additionally, techniques including nerve blocks, ablation, and nerve stimulation designed to disrupt, block, or modulate pain pathways are available. Unfortunately, pain management is not very satisfactory, and many systemic treatments induce significant side effects that lead to poor treatment adherence.

[0172] Therefore, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly PTPN.

[0173] The present inventors have surprisingly found that PS is effective in treating and preventing pain associated with PTPN.

[0174] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and to be active in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore the ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as mentioned above, it exhibited similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in the treatment of PTPN-associated neuropathic pain. Furthermore, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and therefore, anti-inflammatory activity alone is considered insufficient for therapeutic benefit.

[0175] Nevertheless, preliminary in vivo evidence indicates the efficacy of PS in treating neuropathic pain associated with PTPN. Further experiments in specific animal models of PTPN-associated neuropathic pain will confirm these preliminary observations.

[0176] Thus, the present invention provides a method for treating and / or preventing neuropathic pain associated with PTPN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PTPN is treated and / or prevented.

[0177] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0178] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0179] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0180] Neuropathic pain associated with PTPN can result from traumatic nerve injury that meets any one or more of the Seddon and Sunderland classifications (i.e., grades I to VI). For example, traumatic nerve injury can be a transient nerve conduction disorder (grade I, defined by focal demyelination (causing asynchronous conduction or even conduction block) without damage to the axon or connective tissue). Transient nerve conduction disorders can be caused by mild compression or traction of the nerve. Compression injuries can occur where the nerve passes through narrow anatomical gaps, such as in the upper extremity, including the carpal tunnel and cubital tunnel. Nerves can also be compressed by displaced fracture fragments, joint dislocations, or expanding hematomas.

[0181] Traumatic nerve injury can be axonotmesis (Grades II-IV, in increasing order of severity: with intact endoneurium and axonal damage (Grade II); with intact perineurium and axonal and endoneurial damage (Grade III); and with intact epineurium and axonal, endoneurial, and perineurial damage (Grade IV)). Axonotmesis can be caused by a crush injury that does not result in complete severance of the nerve. Such crush injuries, with varying degrees of nerve damage, can result from acute traumatic compression of the nerve with a blunt body such as a bat, surgical clamp, or other crushable object.

[0182] In some cases, traumatic nerve injury can be a nerve transection (Grade V, where complete transection of the nerve is observed, defined by complete severance of the axon and connective tissue layer). Injuries involving complete transection of the nerve can occur due to a knife, gunshot, laceration with glass, or as a result of a car accident or surgical complications.

[0183] Finally, traumatic nerve injury can be a combination of any one of these classes (Grade VI).

[0184] In some embodiments, the traumatic nerve injury is a compression injury. In certain embodiments, the traumatic nerve injury is a crush injury. In certain embodiments, the neuropathic pain associated with PTPN is pain caused by nerve compression injury and / or nerve crush injury. Nerve compression injuries can be caused by accidents and trauma, joint sprains (e.g., ankle, knee, or wrist), arthritis, fractures, bone spurs, joint dislocations (e.g., elbow or shoulder), herniated discs, hypothyroidism, surgical complications, tumors, and / or cysts.

[0185] Traumatic nerve injury can affect one or more of the following nerves: median nerve, radial nerve, suprascapular nerve, ulnar nerve, lateral femoral cutaneous nerve, peroneal nerve, pudendal nerve, sciatic nerve, tibial nerve, and / or spinal nerve. Spinal nerves can be one or more of the following: cervical nerve, thoracic nerve, lumbar nerve, sacral nerve, and / or coccygeal nerve. Thus, neuropathic pain associated with PTPN can be pain caused by one or more of the following: carpal tunnel syndrome, pronator teres syndrome, radial tunnel syndrome, suprascapular nerve entrapment, thoracic outlet syndrome, ulnar nerve entrapment (cubital tunnel syndrome or Guyon tunnel syndrome), dysesthesias of femoral neuralgia, peroneal nerve compression, pudendal nerve entrapment syndrome, sciatica, tarsal tunnel syndrome, cervical disc herniation, thoracic disc herniation, and / or lumbar disc herniation. In certain embodiments, the neuropathic pain associated with PTPN can be pain caused by a herniated disc.

[0186] Neuropathic pain associated with PTPN can be caused by a herniated disc in the vertebrae of the spine. A herniated disc (disc prolapse or disc slippage) occurs when the fibrous outer portion of the disc ruptures or tears, causing the disc to bulge out of the vertebrae of the spine. Such a herniated disc can cause compression of the nerves located between the adjacent vertebrae, or even the spinal cord itself. This can cause pain, numbness, tingling, or weakness in the arms or legs. Long-term compression of the disc can result in symptoms associated with neuropathic pain (e.g., allodynia and hyperalgesia). Although disc bulging is less severe than a herniated disc, it is also a cause of neuropathic pain associated with PTPN. A herniated (or bulging) disc can be a cervical disc, causing pain in the neck, shoulder, or arm, for example. The herniated (or bulging) disc can be, for example, a herniated (or bulging) thoracic disc, causing pain in the mid-back around the level of the herniated (or bulging) disc. The herniated (or bulging) disc can be, for example, a lumbar herniated (or bulging) disc, causing intermittent or continuous back pain and / or sciatica.

[0187] Neuropathic pain associated with post-traumatic peripheral neuropathy, for example, due to traumatic injury to peripheral neurons, can occur immediately after injury and can manifest as, for example, a poorly localized, sometimes diffuse burning, stinging, tingling, pins and needles, or nausea, and is associated with other sensory symptoms. Thus, in some embodiments, the present invention provides a method for treating neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that neuropathic pain associated with PTPN is treated. Pain can also occur delayed after injury. Thus, the present invention provides a method for preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that neuropathic pain associated with PTPN is prevented. Considering that pain can be experienced both immediately and delayed, a subject may experience pain immediately upon injury, which may develop into a different pain sensation that occurs later. Thus, in some embodiments, PS can be used for the treatment and prevention of neuropathic pain associated with PTPN. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of neuropathic pain associated with PTPN. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PTPN.

[0188] Based on the observations herein, PS has a direct analgesic effect on PTPN-associated neuropathic pain. PTPN-associated neuropathic pain can be stabbing or burning pain. In treating PTPN-associated neuropathic pain, PS can reduce neuropathic pain. In some cases, the reduction can be complete, such that PTPN-associated neuropathic pain disappears. In treating PTPN-associated neuropathic pain, PS can also reduce one or more of the sensory symptoms associated with PTPN. In preventing PTPN-associated neuropathic pain, PS can reduce the incidence of neuropathic pain. In preventing PTPN-associated neuropathic pain, PS can also reduce the incidence of one or more of the sensory symptoms associated with PTPN.

[0189] Patients with PTPN describe a variety of sensory symptoms. Sensory symptoms include paresthesia (e.g., numbness, tingling, prickling, and / or crawling), burning, or pricking sensations. Even if the sensory symptoms experienced by a subject with traumatic nerve injury are not considered painful (or do not reach the threshold required to be considered pain in themselves), PS can reduce any one or more of the sensory symptoms experienced by the subject, including those listed above. In some cases, the reduction can be complete, such that one or more of the sensory symptoms associated with PTPN disappear.

[0190] As described above, nerve injury associated with PTPN can result in overactivation of pain signaling pathways, leading to sensitization of peripheral and / or central neurons, which exhibit a decreased stimulation threshold. Therefore, subjects with PTPN may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Thus, neuropathic pain associated with PTPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. PS may reduce neuronal signaling involved in pain sensation in subjects with traumatic peripheral nerve injury. PS may reduce pain generated via peripheral sensitization or central sensitization. In particular, given the ability of PS to traverse toward the primary pain-generating site, PS may reduce pain generated via central sensitization. In some cases, the reduction can be complete, such that pain generation is eliminated. Thus, PS can reduce pain signaling originating centrally. PS can reduce pain signaling originating in peripheral nerves. PS can reduce pain signaling originating in the dorsal root ganglion. PS can reduce pain signaling originating in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce pain signaling originating in the CNS. In some cases, the reduction can be complete, such that pain signaling is eliminated. Neuropathic pain in a subject with PTPN can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, neuropathic pain in a subject with PTPN can be hyperalgesia.

[0191] Neuropathic pain in patients can be measured using a visual analog pain scale or other suitable methods in the art.

[0192] PS can be formulated into pharmaceutical compositions for use in the present invention.In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients.PS can be formulated for local administration, particularly for local administration near or to the area of ​​trauma on the subject's body.

[0193] In certain embodiments for treating and / or preventing pain associated with PTPN, PS may be administered orally.

[0194] The observation herein that PS achieves significant analgesic effects on PTPN-associated neuropathic pain, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, supports a role for PS in directly affecting neuronal signaling generated by traumatic injury to peripheral nerves, for example, by reducing the pain caused by central sensitization. Because these activities are not shared by sulindac (PS's parent compound), the observation herein suggests that modifying sulindac not only confers surprising analgesic activity to PS that acts directly on neuronal signaling, but also makes PS more capable of traversing toward the central site of action, thereby enabling it to exert its analgesic activity on neuronal signaling even more effectively. Thus, without wishing to be bound by theory, the observation herein suggests that it may be possible to overcome the apparent failure of NSAIDs to achieve meaningful analgesic effects on PTPN-associated neuropathic pain by modifying NSAIDs so that they can act directly on neuronal signaling by traversing peripheral neurons that project to the central nervous system and more easily access their primary site of action. Therefore, as an alternative to PS, the method of the present invention can be carried out using one or more modified NSAIDs disclosed herein. Accordingly, the present invention also provides a method for treating and / or preventing neuropathic pain associated with PTPN, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with PTPN is treated and / or prevented. As used herein, "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., a parent compound).

[0195] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). Modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib or modified celecoxib.In certain embodiments, the NSAID of modified NSAID can be sulindac, ibuprofen, aspirin or naproxen.Therefore, modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac or NOSH-sulindac. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofenamide.

[0196] In certain embodiments, the modified NSAID does not have the formula LXIX and / or LXX.

[0197] In certain embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PTPN is one or more of the following: PS, such as formula I or II; phospho-naproxen, such as formula VIII; phospho-ibuprofen, such as formula III; phosphosulindac amide, such as formula X; phospho-ibuprofen amide, such as formula XI; NO-sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; Q922, such as formula LXVIII; NOSH-1, such as formula LIX; or a compound having formula LXIX or LXX.

[0198] In certain embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PTPN is a phospho-NSAID, e.g., PS, such as that of Formula I or II; phospho-naproxen, such as that of Formula VIII; or phospho-ibuprofen, such as that of Formula III. In other embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PTPN is an NO-releasing NSAID, e.g., NO-sulindac, such as that of Formula XLIV; or an HS-releasing NSAID, e.g., HS-sulindac, such as that of Formula XXXIV.

[0199] In certain embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PTPN is a phosphoroamide NSAID, for example, phosphosulindacamide, such as that of Formula X; or phospho-ibuprofenamide, such as that of Formula XI.

[0200] In certain embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PTPN is a modified sulindac, e.g., a PS, such as that of Formula I or II; NO-sulindac, such as that of Formula XLIV; HS-sulindac, such as that of Formula XXXIV; or a phosphosulindacamide, such as that of Formula X. In other embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PTPN is a modified ibuprofen, e.g., a phospho-ibuprofen, such as that of Formula III; or a phospho-ibuprofenamide, such as that of Formula XI.

[0201] In some embodiments for treating and / or preventing neuropathic pain associated with PTPN, the modified NSAID is administered orally. In certain embodiments for treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is selected from one or more of the following: PS, such as of Formula I or II; phospho-ibuprofen, such as of Formula III; phosphosulindacamide, such as of Formula X; or phospho-ibuprofenamide, such as of Formula XI.

[0202] In certain embodiments, the orally administered modified NSAID is a phospho-NSAID, e.g., phosphosulindac (PS), such as those of Formula I or II; or phospho-ibuprofen, such as those of Formula III. In certain embodiments for treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is a phosphoroamide NSAID, e.g., a phosphosulindac amide, such as those of Formula X; or a phospho-ibuprofen amide, such as those of Formula XI.

[0203] In certain embodiments, the orally administered modified NSAID is a modified sulindac, e.g., phosphosulindac (PS), such as that of Formula I or II; or a phosphosulindac amide, such as that of Formula X. In certain embodiments for treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is a modified ibuprofen, e.g., phospho-ibuprofen, such as that of Formula III; or preferably, a phospho-ibuprofen amide, such as that of Formula XI.

[0204] Pain associated with postherpetic neuralgia PHN is a common complication of shingles caused by reactivation of the varicella-zoster virus (VZV). VZV is a highly virulent neurotropic virus that can cause chickenpox (varicella) as a primary infection in susceptible individuals. The virus can be retrogradely transported from the skin along the axons of sensory neurons to establish latent infections within sensory ganglia of the peripheral nervous system. If a previously infected subject becomes immunosuppressed, the virus can reactivate and manifest as acute herpes zoster (AHZ, "shingles"). Recovery from AHZ is often accompanied by the development of postherpetic neuralgia, a neuropathic pain syndrome characterized by persistent pain in the area affected by shingles. PHN is typically defined as pain that persists for more than 90 days after the initial appearance of the rash or at least 3 months after healing of the skin lesions. AHZ is diagnosed more than 1 million times annually in the United States alone. Approximately 20% of patients with AHZ will experience PHN and continue to suffer from intermittent neuropathic symptoms, including itching and pain. The pain is characterized by sharp, stabbing, throbbing, or burning sensations, often localized to the original rash site. Long-lasting pain is associated with painful hypersensitivity to innocuous stimuli (allodynia) or exaggerated pain responses to noxious stimuli (hyperalgesia), reflecting central sensitization. Without treatment, the incidence of pain persisting 3 months after rash onset is reported to be approximately 8–15%, with this figure increasing rapidly in the elderly.

[0205] Pain associated with PHN is associated with peripheral and particularly central sensitization (Hadley et al., Curr Pain Headache Rep. (2016); 20:17). During VZV reactivation, the virus replicates and spreads from the dorsal root ganglia to the periphery. Viral spread causes nerve damage (e.g., due to an immune response against neurons), which leads to more frequent depolarization of nociceptors. A decrease in the threshold for nociceptor signaling leads to peripheral sensitization. Ongoing peripheral signaling leads to central sensitization, characterized by a state of heightened activation of centrally located neurons (e.g., in the dorsal root horn and higher-order neurons). Additional pathogenesis mechanisms resulting in altered gene expression in centrally located neurons, loss of co-inhibitory signaling, or alterations in neuronal signaling networks (e.g., deafferentation) all contribute to the hypersensitivity experienced in subjects with PHN-associated pain. Persistent pain associated with central sensitization manifests as hyperalgesia (increased response to noxious stimuli) and / or allodynia (pain induced by non-painful stimuli).

[0206] Neuropathic pain associated with PHN is particularly difficult to treat. Current treatments for PHN-associated neuropathic pain include systemic tricyclic antidepressants, anticonvulsants, and opioids, as well as topical lidocaine and capsaicin. Additionally, interventional therapies exist, including subcutaneous botulinum toxin injections, nerve blocks, and nerve stimulation. However, these therapies are not always effective. In fact, even with the most effective medications, only 30–50% of patients achieve greater than 50% pain relief, often with significant side effects. PHN-associated neuropathic pain causes significant suffering and economic burden, manifested in both medical costs and lost quality-adjusted life years. Given the lack of effectiveness of current treatments, PHN-associated pain represents an area of ​​largely unmet medical need.

[0207] Thus, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly PHN.

[0208] The present inventors have surprisingly found that PS is effective in treating and preventing pain associated with PHN.

[0209] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and to be active in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as noted above, it exhibited similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in the treatment of neuropathic pain associated with PHN. Furthermore, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and therefore, anti-inflammatory activity alone is considered insufficient for therapeutic benefit. Indeed, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1-25) concluded that NSAIDs did not achieve pain reduction in PHN.

[0210] Nevertheless, preliminary in vivo evidence indicates the effectiveness of PS in treating neuropathic pain associated with PHN.

[0211] Accordingly, the present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is treated and / or prevented.

[0212] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0213] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0214] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0215] As outlined above, reactivation of the varicella-zoster virus can cause acute shingles, which manifests as a rash, followed by neuropathic pain associated with postherpetic neuralgia (PHN). As described above, neuropathic pain associated with PHN persists for 90 days or more after the initial appearance of the rash or for at least 3 months after the resolution of skin lesions. The pain can manifest as, for example, sharp, burning, throbbing, or stabbing pain. Because neuropathic pain associated with PHN typically occurs after the reactivation of shingles and the resolution of the rash, subjects can take preventative measures to avoid the development of neuropathic pain after the resolution of the rash and skin lesions. Thus, in some embodiments, the present invention provides a method for preventing neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is prevented. In another embodiment, the present invention provides a method for treating neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the neuropathic pain associated with PHN is treated. Because pain associated with PHN develops during the rash episode and persists after the rash has resolved, the subject would benefit from an analgesic that can both treat existing neuropathic pain and prevent the development of further neuropathic pain associated with PHN. Thus, in some embodiments, PS can be used for the treatment and prevention of neuropathic pain associated with PHN. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of neuropathic pain associated with PHN. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PHN.

[0216] As described herein, pain associated with PHN is typically localized to the rash site. The rash (e.g., a maculopapular rash) may develop in one or more adjacent dermatomes (areas of the skin primarily innervated by a single spinal nerve). The spinal nerve may be a cervical nerve, a thoracic nerve, a lumbar nerve, and / or a sacral nerve. Thus, neuropathic pain associated with PHN may be experienced in one or more adjacent dermatomes. Neuropathic pain associated with PHN may be experienced in one or more dermatomes, where each dermatome is innervated by a cervical nerve, a thoracic nerve, a lumbar nerve, or a sacral nerve. Typically, neuropathic pain associated with PHN develops along the thoracic dermatome on the subject's trunk. In certain cases, for example, in immunocompromised individuals, the rash, and therefore the associated neuropathic pain, may be more widespread, affecting three or more dermatomes (i.e., due to disseminated herpes zoster).

[0217] Based on the observations herein, PS has a direct analgesic effect on the neuropathic pain associated with PHN. The neuropathic pain associated with PHN can be sharp, throbbing, stabbing, or burning pain. In the treatment of neuropathic pain associated with PHN, PS can reduce neuropathic pain. In some cases, the reduction is so complete that neuropathic pain disappears. In the treatment of neuropathic pain associated with PHN, PS can also reduce one or more of the sensory symptoms associated with PHN. In the prevention of neuropathic pain associated with PHN, PS can reduce the incidence of neuropathic pain. In the prevention of neuropathic pain associated with PHN, PS can also reduce the incidence of one or more of the sensory symptoms associated with PHN.

[0218] Patients with PHN describe a variety of sensory symptoms. These include itching and numbness. Even if the sensory symptoms experienced by a subject with PHN are not considered painful (or do not reach the threshold required to be considered pain in themselves), PS can reduce any one or more of the sensory symptoms experienced by the subject. In some cases, the reduction is so complete that one or more of the sensory symptoms experienced by the subject disappear.

[0219] As described above, nerve damage associated with PHN can result in overactivation of pain signaling pathways, leading to sensitization of peripheral and / or central neurons, and these neurons exhibit a decreased stimulation threshold. Therefore, subjects with PHN may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS can have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Therefore, neuropathic pain associated with PHN can be the result of central sensitization leading to allodynia and / or hyperalgesia. PS can reduce neuronal signaling involved in pain sensation in subjects with PHN. In some cases, the reduction can be complete, such that pain disappears. PS can reduce pain that occurs through peripheral sensitization or central sensitization. In some cases, the reduction can be complete, such that pain disappears. In particular, given PS's ability to travel longitudinally toward central pain-generating sites, PS can reduce pain generated through central sensitization. Therefore, PS can reduce centrally generated pain signaling. PS can reduce pain signaling in peripheral nerves, such as nerves innervating one or more dermatomes. PS can reduce pain signaling in one or more spinal nerves, such as one or more cervical nerves, one or more thoracic nerves, one or more lumbar nerves, and / or one or more sacral nerves. In particular, PS can reduce pain signaling in one or more thoracic nerves. PS can reduce pain signaling in the dorsal root ganglia. PS can reduce pain signaling in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce pain signaling in the CNS. In some cases, the reduction can be so complete that pain signaling is eliminated. Neuropathic pain in subjects with PHN can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject with PHN can be hyperalgesia.

[0220] Neuropathic pain in patients can be measured using a visual analog pain scale or other suitable methods in the art.

[0221] In another embodiment, PS may also be useful for treating other herpes zoster-related pain, such as prodromal pain (preceding the onset of rash symptoms) or acute herpes zoster pain (occurring simultaneously with the onset of rash symptoms). Damage to peripheral neurons caused by viral translocation leads to increased signaling from centrally located neurons. This may drive neuronal sensitization prior to the onset of persistent pain characteristic of PHN-associated neuropathic pain. Therefore, PS may be useful for treating pain during these stages of the pathology of infectious diseases. Therefore, the present invention also provides a method for treating pain experienced by a subject as a result of herpes zoster, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the pain is treated. The present invention also provides a method for treating acute herpes zoster pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the acute herpes zoster pain is treated. The present invention also provides a method for treating prodromal pain of shingles, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the prodromal pain of shingles is treated.

[0222] The PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises the PS and one or more pharmaceutically acceptable excipients. The PS can be formulated for topical administration, particularly to the area of ​​the skin (e.g., a dermatome) affected by the rash, for example, to the trunk of a subject.

[0223] In certain embodiments for treating and / or preventing pain associated with PHN, PS may be administered orally.

[0224] The observation herein that PS achieves significant analgesic effects on neuropathic pain associated with PHN, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, supports a role for PS in directly affecting neuronal signaling involved in the development of neuropathic pain associated with PHN, for example, by reducing pain caused by central sensitization. Because these activities are not shared by sulindac (PS's parent compound), the observation herein suggests that modifying sulindac not only confers surprising analgesic activity to PS that acts directly on neuronal signaling, but also makes PS more capable of traversing toward its primary central site of action, thereby enabling it to exert its analgesic activity on neuronal signaling even more effectively. Thus, without wishing to be bound by theory, the observation herein suggests that it may be possible to overcome the apparent failure of NSAIDs to achieve meaningful analgesic effects on neuropathic pain associated with PHN by modifying NSAIDs so that they can act directly on neuronal signaling by traversing peripheral neurons that project to the central nervous system and more easily access their primary site of action. Therefore, as an alternative to PS, the method of the present invention can be carried out using one or more modified NSAIDs disclosed herein. Thus, the present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, the method comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with PHN is treated and / or prevented. As used herein, "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., a parent compound).

[0225] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). Modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib or modified celecoxib.In certain embodiments, the NSAID of modified NSAID can be sulindac, ibuprofen, aspirin or naproxen.Therefore, modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac or NOSH-sulindac. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofenamide.

[0226] In certain embodiments, the modified NSAID for treating and / or preventing neuropathic pain associated with PHN is a PS, such as of Formula I or II; or NO-sulindac, such as of Formula XLIV.

[0227] In some embodiments, the modified NSAID is a phospho-NSAID, eg, PS, such as of Formula I or II; or an NO-releasing NSAID, eg, NO-sulindac, such as of Formula XLIV.

[0228] In certain embodiments, the modified NSAID is a modified sulindac, e.g., a PS such as that of Formula I or II; a NO-sulindac such as that of Formula XLIV; a HS-sulindac such as that of Formula XXXIV; or a phosphosulindac-amide such as that of Formula X. Preferably, the modified sulindac is a NO-sulindac such as that of Formula XLIV.

[0229] In some embodiments for treating and / or preventing neuropathic pain associated with PHN, the modified NSAID is administered orally.

[0230] In certain embodiments, the oral modified NSAID is a PS, such as of Formula I or II; or an NO-sulindac, such as of Formula XLIV.

[0231] Migraine pain Migraine is a disabling neurological disorder that affects over 1 billion people worldwide, with a 1-year prevalence of 15%. Its prevalence peaks in people aged 35-39 years and is the leading cause of disability in people under 50 years of age, thus representing a significant socioeconomic burden. Migraine is typically characterized by recurrent, unilateral, throbbing headaches of moderate to severe intensity, accompanied by symptoms of nausea, vomiting, and hyperesthesia.

[0232] The pathophysiology of migraine continues to be debated and is now classified as a neuronal disorder (Goadsby et al., Physiol Rev (2017); 97:553-622). The previous theory of pain generation via dilation of cranial arteries lost ground following the failure of effective therapies (e.g., sumatriptan) to reverse the slight dilation of these arteries observed during migraine attacks. Furthermore, the suggestion that migraine is triggered by so-called neurogenic inflammation (local release of endogenous inflammatory mediators in the dura) has also been deemed impractical, especially in light of the clinical failure of compounds designed to inhibit this process. Indeed, evidence of an inflammatory pathology in migraine patients is lacking. Therefore, migraine is considered a purely neuronal disorder resulting from alterations or dysfunction in the brainstem and hypothalamic regions, which contribute to altered cellular and vascular function in many areas of the brain. These changes result in neurons being unable to normally modulate or gate sensory input. Dysfunction in these areas may lead to the perception of headache due to normal vascular pulsation, and continued dysfunction may lead to central sensitization of trigeminovascular neurons, exacerbation of pain with normal physical activity, and cutaneous allodynia. Indeed, peripheral and central sensitization of trigeminal neurons, as observed clinically in migraine patients, is considered a fundamental component of this pathophysiology. This neuronal mechanism may explain the prolonged duration of migraine attacks and the transition to chronic migraine and certain associated symptoms (e.g., cutaneous allodynia).

[0233] Central sensitization occurs when the function of neural circuits in sensory pathways is enhanced or inappropriately regulated, resulting in abnormal sensitivity, manifested, for example, as the presence of persistent spontaneous pain often associated with hyperalgesia (increased response to noxious stimuli) and allodynia (pain induced by non-painful stimuli). Central sensitization results from changes in the properties of neurons in the CNS, such that the perception of pain is no longer associated with the presence, intensity, or duration of a specific peripheral stimulus (noxious or not). Thus, central sensitization is associated with the generation and maintenance of pain when pain signaling occurs centrally even in the absence of peripheral stimuli (i.e., due to hypersensitivity of central pain-signaling neurons).

[0234] As alluded to above, sensitization in migraine develops as a result of the failure of sensory signaling integration and filtering, ultimately resulting in the perception of activation of the sensory system under normal conditions, such as the cutaneous allodynia experienced by migraine sufferers. Such symptoms are experienced in both episodic and chronic migraines, although pain amplification is thought to be more involved in chronic migraines.

[0235] There is currently a global need for additional pain therapies for the treatment of migraine and other headache disorders.

[0236] Reflecting the diverse nature of this disorder, various pharmacological interventions for treating migraine have been proposed. Indeed, relatively nonselective drugs such as ergot alkaloids have been used for decades. Other treatments include opiates (e.g., oxycodone), beta-blockers (e.g., propranolol), anticonvulsants (e.g., topiramate), or serotonin receptor agonists (e.g., sumatriptan). Patients with milder symptoms may be able to manage their symptoms with nonsteroidal anti-inflammatory drugs (NSAIDs), but as noted above, the inflammatory response is considered of limited relevance when considering the pathophysiology of migraine. Indeed, studies have demonstrated that certain NSAIDs, such as naproxen, are not clinically useful for treating migraine (see, e.g., Law et al., Cochrane Database of Systematic Reviews (2013);10:1-45).

[0237] Thus, there is a great need for compounds that treat and / or prevent migraine pain and pain from other headache disorders, particularly pain associated with central sensitization.

[0238] The present inventors have surprisingly found that PS is effective in treating and preventing pain caused by migraine headaches.

[0239] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and to be active in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as noted above, it exhibited similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in treating migraine pain, which develops as a result of dysfunctional sensory neuron signaling rather than an inflammatory response. Indeed, certain typical NSAIDs (e.g., naproxen) have been shown to be clinically ineffective as analgesics for migraine headaches, suggesting that anti-inflammatory activity alone is insufficient to treat migraine pain.

[0240] Nevertheless, preliminary in vivo evidence indicates the efficacy of PS in the treatment of migraine pain. Further experiments in specific animal models of migraine pain will confirm these preliminary observations.

[0241] Accordingly, the present invention provides a method for treating and / or preventing migraine pain, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is treated and / or prevented.

[0242] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0243] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0244] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0245] As outlined above, migraine is characterized by moderate to severe attacks of unilateral, throbbing headache associated with photophobia, phonophobia, nausea, and / or vomiting. Accordingly, in some embodiments, the present invention provides a method for treating migraine pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is treated. Typically, a migraine attack consists of three phases: the prodromal phase, the migraine itself, and the postaural phase. The prodromal phase occurs approximately 24-48 hours before the headache phase and is typically characterized by symptoms such as mood changes, fatigue, and neck discomfort. Some individuals also experience aura, a transient, focal neurological symptom of visual, sensory, or motor disturbances. Subjects in the prodromal phase, prior to the onset of the headache phase, may be administered a therapeutic agent to prevent the onset of the headache phase. Accordingly, in other embodiments, the present invention provides a method for preventing migraine pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is prevented. A subject may experience recurrent migraine attacks, particularly if there are short interictal periods between attacks, and thus administration of a therapeutic agent may treat the pain of ongoing attacks and prevent the pain of subsequent attacks. Thus, in some embodiments, PS can be used to treat and prevent migraine pain. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of migraine pain. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment and / or prevention of migraine pain.

[0246] In some embodiments, when treating and / or preventing migraine pain, PS can be administered during the aura phase, headache phase, and / or aura phase. In particular, to prevent migraine pain, PS can be administered during the aura phase. To treat migraine pain, PS can be administered during the headache phase.

[0247] The migraine may be an episodic migraine. In certain cases, the migraine may be a chronic migraine. The migraine may be a migraine without aura or a migraine with aura.

[0248] Based on the observations herein, PS has a direct analgesic effect on migraine pain. Migraine pain can be a pulsating headache. Subjects with migraine, especially chronic migraine, may experience persistent migraine and / or aura-like periods with limited neurological recovery and baseline return between attacks. Subjects suffering from migraine may experience several associated symptoms, including aura, nausea, vomiting, photophobia, and / or phonophobia. Sensory disturbances associated with aura may include visual symptoms, tingling, and / or numbness. In addition, subjects may experience cranial autonomic symptoms, such as bloodshot or tearing eyes. In addition, subjects may experience cutaneous allodynia.

[0249] Migraine with aura can be typical migraine with aura or migraine with brainstem aura. Migraine can be hemiplegic migraine (e.g., familial hemiplegic migraine or sporadic hemiplegic migraine), retinal migraine, chronic migraine, or suspected migraine (with or without aura).

[0250] In treating migraine pain, PS can reduce pain. In some cases, the reduction can be complete, such that the migraine pain disappears. In treating migraine pain, PS can also reduce one or more of the symptoms associated with migraine. In preventing migraine pain, PS can reduce the incidence of pain. In preventing migraine pain, PS can also reduce the incidence of one or more of the symptoms associated with migraine. PS can reduce cutaneous allodynia. In certain embodiments, PS can reduce chronic migraine pain. As described above, the reduction can be complete, such that the pain disappears.

[0251] In treating and / or preventing pain from migraine, PS may reduce any one or more of the symptoms experienced by a subject with migraine, even if the symptoms experienced by the subject with migraine, such as aura or cranial autonomic symptoms, are not considered painful (or do not reach the threshold required to be considered painful in themselves). In some cases, the reduction may be complete, such that one or more of the symptoms experienced by a subject with migraine disappear.

[0252] Peripheral and central sensitization are characteristic of migraine pain. Migraine pain can be the result of central sensitization, which leads to allodynia, e.g., cutaneous allodynia, and / or hyperalgesia. Thus, a subject with migraine may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Thus, PS may reduce neuronal signaling involved in pain sensation in a subject with migraine. In some cases, the reduction may be complete, such that pain disappears. Furthermore, PS may reduce pain generated via peripheral sensitization or, particularly, via central sensitization. In particular, given the ability of PS to traverse to the central pain-generating site, PS may reduce pain generated via central sensitization. The reduction may be complete, such that pain generation disappears. Thus, PS can reduce pain signaling originating centrally. PS can reduce pain signaling originating in the trigeminal nerve. PS can reduce pain signaling originating in the trigeminal ganglion. PS can reduce pain signaling originating in the trigeminal nucleus caudalis within the trigeminocervical complex (TCC). Given that PS has been shown herein to ascend through peripheral neurons toward the CNS, preliminary observations of the analgesic activity of PS in migraine indicate that PS can reduce pain signaling originating in higher neurons and / or pain-sensing areas of the brain (e.g., trigeminothalamic neurons). The reduction can be complete, such that pain signaling is abolished. In some embodiments, the pain is allodynia, e.g., cutaneous allodynia. The allodynia can be in response to mechanical and / or thermal stimuli. Furthermore, in some embodiments, the pain is hyperalgesia. The pain due to migraine can be neuropathic pain.

[0253] Patients with migraine headaches can be diagnosed using the well-known ICHD-3 guidelines. Migraine pain can be measured using a visual analog pain scale or other suitable methods in the art.

[0254] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS is preferred as a formulation for topical administration. PS can be administered near the sensory branches of the trigeminal nerve (i.e., the ophthalmic nerve, maxillary nerve, and / or mandibular nerve). PS can be administered locally to the face and / or neck of a subject. PS can be administered locally to one or both temples of a subject. In certain cases, PS can be administered locally behind one or both ears of a subject.

[0255] In certain embodiments, PS may be administered orally to treat and / or prevent migraine pain.

[0256] The observation herein that PS reduces allodynia, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, supports a role for PS in directly affecting neuronal signaling, particularly that associated with central sensitization, occurring during migraine pathophysiology. Indeed, the observation herein demonstrates the efficacy of PS in a migraine model utilizing NTG, which is known to establish central sensitization corresponding to that occurring in migraine patients. Because these activities are not shared by sulindac (PS's parent compound), the observation herein suggests that modifications of sulindac not only confer remarkable analgesic activity to PS through direct effects on neuronal signaling, but also allow PS to more effectively traverse to its primary central site of action, thereby exerting its analgesic activity on neuronal signaling even more effectively. Therefore, without wishing to be bound by theory, the observations herein suggest that it may be possible to overcome the apparent failure of NSAIDs to achieve meaningful analgesic effects on the neuronal signal transduction generated by the pathophysiology of migraine by modifying NSAIDs so that they can act directly on neuronal signal transduction by traversing peripheral neurons projecting to the central nervous system and more easily access their primary site of action.Therefore, as an alternative to PS, the method of the present invention can be carried out using one or more modified NSAIDs disclosed herein.Therefore, the present invention provides a method for treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof so that migraine pain is treated and / or prevented.As used herein, "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., parent compound).

[0257] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). Modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib or modified celecoxib.In certain embodiments, the NSAID of modified NSAID can be sulindac, ibuprofen, aspirin or naproxen.Therefore, modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac or NOSH-sulindac. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofenamide.

[0258] In certain embodiments, the modified NSAID does not have the formula LXIX and / or LXX.

[0259] In certain embodiments, the modified NSAID for treating and / or preventing migraine pain is selected from one or more of the following: PS, such as of Formula I or II; or phosphonaproxen, such as of Formula VIII.

[0260] Thus, a modified NSAID for treating and / or preventing migraine pain can be a modified sulindac, e.g., a PS such as Formula I or II; an NO-releasing sulindac such as NO-sulindac (e.g., Formula XLIV); an HS-releasing sulindac such as HS-sulindac (e.g., Formula XXXIV); or a metal-chelated sulindac such as platinum sulindac (e.g., Formula LXVII).

[0261] In some embodiments, the modified NSAID for treating and / or preventing migraine pain is a phospho-NSAID, for example, PS, such as of Formula I or II; or phospho-naproxen, such as of Formula VIII.

[0262] In some embodiments for treating and / or preventing migraine pain, the modified NSAID is administered orally. In certain embodiments, the orally administered modified NSAID for treating and / or preventing migraine pain is selected from one or more of the following: PS, such as of Formula I or II; or phosphonaproxen, such as of Formula VIII.

[0263] In some embodiments for treating and / or preventing migraine pain, the orally administered modified NSAID can be a phospho NSAID, e.g., PS, such as those of Formula I or II; or phosphonaproxen, such as those of Formula VIII. In other embodiments for treating and / or preventing migraine pain, the orally administered modified NSAID can be a phosphoroamide NSAID, e.g., phosphosulindacamide, such as those of Formula X; or phospho-ibuprofenamide, such as those of Formula XI.

[0264] Pain from other headache disorders In light of the observations herein regarding the effectiveness of PS in treating migraine pain, PS may also treat and / or prevent pain in other headache disorders, particularly headache disorders whose pathophysiology manifests as trigeminal dysfunction.

[0265] For example, PS may treat and / or prevent chronic headache, tension-type headache, and / or trigeminal-autonomic headache. Trigeminal-autonomic headache may be cluster headache, hemicrania continua, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms. In some embodiments, PS may treat and / or prevent trigeminal neuralgia, e.g., head-facial pain.

[0266] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS is preferred as a formulation for topical administration. PS can be administered near the sensory branches of the trigeminal nerve (i.e., the ophthalmic nerve, maxillary nerve, and / or mandibular nerve). PS can be administered locally to the face and / or neck of a subject. PS can be administered locally to one or both temples of a subject. In certain cases, PS can be administered locally behind one or both ears of a subject.

[0267] In certain embodiments, PS may be administered orally to treat and / or prevent pain from other headache disorders.

[0268] In line with the above, pain from other headache disorders may be treated and / or prevented upon administration of one or more modified NSAIDs disclosed herein. The one or more modified NSAIDs may be administered orally.

[0269] Corneal neuropathic pain Corneal discomfort affects 5-30% of the population over the age of 50. Corneal neuropathic pain is a condition in which corneal pain is experienced in response to normally non-painful stimuli (e.g., wind or drafts). It reflects the sensitization of centrally acting neurons after prolonged and repeated nociceptive signaling from peripheral neurons in response to direct injury to the corneal nerve. Any mechanical or chemical injury to corneal nerve endings can result in ectopic sprouting and neuroma formation, which exhibit spontaneous activity. Central sensitization, manifested as painful hypersensitivity to innocuous stimuli (allodynia) or exaggerated pain responses to noxious stimuli (hyperalgesia), or even spontaneous signaling, leads to chronic corneal pain that persists even in the absence of peripheral stimuli or clinical signs. Thus, corneal neuropathic pain has a distinctly different pain-generating mechanism compared to, for example, inflammatory eye disorders, which induce acute peripheral pain signaling from the cornea in response to ongoing inflammation.

[0270] Patients with corneal neuropathic pain experience severe corneal pain, as well as irritation such as burning, photophobia, and gritty sensations, even in the absence of peripheral symptoms. Therefore, this indication inevitably negatively impacts the patient's quality of life. Chronic pain accompanied by photosensitivity and irritation leads to functional impairment and an inability to perform normal daily activities.

[0271] Corneal neuropathic pain is particularly difficult to treat. For patients with corneal neuropathic pain who experience corneal pain in the absence of any ongoing corneal pathology, anti-inflammatory medications are ineffective. Instead, centrally acting neuromodulators are often recommended. For example, anticonvulsants (e.g., gabapentin and pregabalin) may be considered first-line treatments, serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine) second-line treatments, and tricyclic antidepressants (e.g., nortriptyline, amitriptyline) third-line treatments. Combination therapy or weak opioids (tramadol) may also be used in a wide range of neuropathic pain settings when treatment is resistant.

[0272] Unfortunately, pain management is not very satisfactory and many systemic treatments induce significant side effects that lead to poor treatment adherence.

[0273] Therefore, there is a great need for compounds that treat and / or prevent corneal neuropathic pain.

[0274] The present inventors have surprisingly found that phosphosulindac (PS) is effective in treating corneal neuropathic pain.

[0275] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, as well as activity in the treatment of rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED) and suggests that PS reduces corneal sensitivity in an acute model of pain development in normal eyes. The observation of decreased sensitivity in healthy eyes to acute stimuli that do not produce persistent pain does not demonstrate efficacy in treating corneal neuropathic pain, which may be related to central sensitization and therefore originate at a central site of action. Furthermore, in this acute model, the effects of PS were observed immediately, suggesting a local action of PS, an atypical NSAID, similar to the activity observed with typical NSAIDs (e.g., ketorolac) in the same model. Again, such peripheral activity does not demonstrate the efficacy of PS in treating pain originating at a central site of action. Indeed, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and ketorolac has been shown to have limited analgesic activity in this model. Therefore, observations in acute pain models cannot be extrapolated to the treatment of corneal neuropathic pain. Furthermore, in a DED model, PS was observed to restore suppressed corneal sensitivity, suggesting a role for PS in increasing, rather than reducing, nociception.Therefore, while these observations fall short of suggesting a role for PS in the treatment of corneal neuropathic pain, the observations herein demonstrate unprecedented activity of PS in reducing pain generated at a central site of action.

[0276] Indeed, preliminary in vivo evidence indicates the effectiveness of PS in treating corneal neuropathic pain.

[0277] Thus, the present invention provides a method for treating corneal neuropathic pain, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the corneal neuropathic pain is treated.

[0278] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0279] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0280] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0281] Corneal neuropathic pain is also known as ophthalmic neuropathic pain. Therefore, in this specification, the terms "corneal neuropathic pain" and "ophthalmic neuropathic pain" can be used interchangeably. As explained above, corneal neuropathic pain is persistent chronic pain that occurs in light of neuroplastic changes in centrally located neurons due to persistent nociceptive signaling from the periphery. Such changes lead to hyperexcitability of nociceptors in the CNS, so-called central sensitization, which manifests as, for example, allodynia. Pain persists even in the absence of ongoing peripheral triggers, and like other neuropathic pain, the resolution of peripheral pathology does not affect pain sensation, making corneal neuropathic pain particularly difficult to treat. Thus, corneal neuropathic pain can be chronic corneal pain.

[0282] Corneal neuropathic pain can develop as a result of several peripheral drivers of nociception. Typically, corneal neuropathic pain develops in the context of consistent pain signaling originating from the cornea (one of the most densely innervated tissues). As mentioned above, persistent peripheral signaling via the corneal nerves ultimately leads to central sensitization, a key feature of corneal neuropathic pain, which can result in pain sensation even in the absence of peripheral triggers. Therefore, corneal neuropathic pain can be caused by any peripheral stimulus that causes chronic stimulation of the corneal nerves. For example, corneal neuropathic pain can be caused by chronic corneal surface diseases or conditions, such as recurrent corneal erosions, corneal surface neoplasms, and / or inflammatory ocular conditions. Corneal neuropathic pain can be caused by surgical interventions, such as corneal refractive surgery (e.g., photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), and corneal inlay procedures), cataract surgery (e.g., laser cataract surgery), corneal transplant surgery, and / or laser retinopexy. Corneal neuropathic pain can also be caused by laser surgery for the treatment of retinal conditions (e.g., diabetic macular edema; proliferative diabetic retinopathy; macular edema due to retinal vein occlusion; neovascularization secondary to retinal vein occlusion; peripheral retinal degeneration, holes, and / or tears; Eales' disease and other retinal vasculitides; central serous retinopathy; retinopathy of prematurity; and extrafoveal polyps of polypoidal choroidal vasculopathy (PCV)). Corneal neuropathic pain can be caused by infectious diseases, such as herpes simplex keratitis and / or herpes zoster keratitis.Corneal neuropathic pain can be caused by toxic keratopathy, such as caused by topical or systemic drugs (e.g., antiseptics containing benzalkonium chloride or isotretinoin, respectively).Corneal neuropathic pain can be caused by radiation or ultraviolet light exposure.Corneal neuropathic pain can be the result of systemic neuropathy, such as small fiber neuropathy or multiple sclerosis.In addition, corneal neuropathic pain can be caused by trauma, such as chemical burns, which cause damage to corneal nerves.The initial trigger for pain may be air pollution or dry weather, which induces persistent corneal inflammation and ultimately corneal neuropathic pain. Therefore, corneal neuropathic pain can be caused by allergens, such as allergic conjunctivitis. Corneal neuropathic pain can be caused by one or more chalazions, resulting from persistent corneal irritation caused by chalazions during blinking. Persistent peripheral nociceptor signaling in response to these peripheral triggers leads to increased sensitivity of centrally located neurons, resulting in the development of pain even after the initial clinical symptoms have resolved. In fact, even local anesthesia cannot alleviate pain, given the dysregulation of central neuronal signaling.

[0283] Furthermore, in some embodiments, corneal neuropathic pain is caused by direct damage to centrally located neurons, for example, due to ischemia, hemorrhage, mechanical compression, infection, and / or degenerative processes. Additionally, corneal neuropathic pain can be the result of damage to adjacent tissues or nerves, such as the conjunctiva, ocular muscles, the eye, the optic nerve, and / or autonomic or sympathetic nerves.

[0284] Corneal neuropathic pain occurs as a result of persistent peripheral nociceptive signaling, resulting in neuronal sensitization, which manifests as hypersensitivity to innocuous peripheral triggers and associated long-lasting pain. Thus, central sensitization is a hallmark of corneal neuropathic pain. Pain can manifest, for example, as shooting, burning, or stabbing pain associated with other sensory symptoms. Thus, in some embodiments, the present invention provides a method for treating corneal neuropathic pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal neuropathic pain is treated. Subjects experiencing corneal neuropathic pain would benefit from an analgesic that can treat existing corneal neuropathic pain and prevent the development of further corneal neuropathic pain (i.e., prevent further central sensitization). Thus, in some embodiments, PS can be used for the treatment and prevention of corneal neuropathic pain. In accordance with the above, the present invention provides a PS for use in treating corneal neuropathic pain. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment of corneal neuropathic pain.

[0285] Based on the observations herein, PS has a direct analgesic effect on corneal neuropathic pain.Corneal neuropathic pain can be stabbing pain or burning pain.In treating corneal neuropathic pain, PS can reduce corneal neuropathic pain.In some cases, the reduction can be complete, such that corneal neuropathic pain disappears.In treating corneal neuropathic pain, PS can also reduce one or more of the associated sensory symptoms.

[0286] Patients suffering from corneal neuropathic pain describe a variety of sensory symptoms. These include paresthesia (e.g., numbness, tingling, prickling, and / or crawling), photosensitivity, or photoallodynia. Even if the sensory symptoms experienced by the subject are not considered painful (or do not reach the threshold required to be considered painful in themselves), PS can reduce any one or more of the sensory symptoms experienced by the subject, including those listed above. In some cases, the reduction can be complete, such that one or more of the associated sensory symptoms disappear. Furthermore, in treating corneal neuropathic pain, PS can improve other associated symptoms in the subject, such as anxiety, depression, and / or apathy.

[0287] As described above, corneal neuropathic pain occurs as a result of the overactivity of centrally located neurons, which exhibit a decreased stimulus threshold and can depolarize even in the absence of peripheral stimuli. Indeed, the perception of pain is no longer linked to the presence, intensity, or duration of a specific peripheral stimulus (noxious or not). Therefore, corneal neuropathic pain may be the result of central sensitization. Accordingly, subjects with corneal neuropathic pain may experience pain induced by non-painful stimuli (allodynia) and / or increased pain in response to noxious stimuli (hyperalgesia). Based on preliminary observations, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Therefore, PS may reduce neuronal signaling involved in pain sensation in subjects with corneal neuropathic pain. Given the ability of PS to traverse to the central pain-generating site, PS may reduce pain generated through central sensitization. Therefore, PS may reduce centrally generated pain signaling. Corneal nociceptors constitute the first branch of the trigeminal nerve and transmit to the trigeminal ganglion and trigeminal nucleus caudalis. PS can reduce pain signaling originating in the trigeminal ganglion. PS can reduce pain signaling originating in the trigeminal nucleus caudalis within the trigeminocervical complex (TCC). Given that PS is shown herein to ascend peripheral neurons toward the CNS, PS can reduce pain signaling originating in higher neurons and / or pain-sensing areas of the brain (e.g., trigeminothalamic neurons). In some cases, the reduction can be complete, such that pain signaling is eliminated. In some embodiments, the corneal neuropathic pain is allodynia. The allodynia can be in response to mechanical and / or thermal stimuli. Additionally or alternatively, the corneal neuropathic pain in a subject can be hyperalgesia. In some embodiments, the corneal neuropathic pain is chronic corneal neuropathic pain. In some embodiments, the corneal neuropathic pain is not acute corneal pain.

[0288] Corneal neuropathic pain in patients can be measured using a visual analog pain scale or other suitable methods in the art.

[0289] Considering the observations herein, PS exhibits direct activity on neurons involved in the generation of pain caused by central sensitization. Therefore, PS may also be useful for treating certain forms of corneal pain. Corneal pain is also known as ocular pain, and therefore these terms may be used interchangeably herein. For example, PS can treat corneal pain caused by central sensitization. Therefore, the present invention also provides a method for treating corneal pain caused by central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the corneal pain caused by central sensitization is treated. In fact, PS can treat corneal pain manifested as allodynia. PS can treat corneal pain manifested as hyperalgesia. Because pain is caused by central sensitization, it is experienced in the absence of ongoing harmful peripheral triggers (e.g., corneal inflammation). Corneal pain can be chronic pain (i.e., pain lasting for more than 3 months). In certain embodiments, the corneal pain is not acute pain, such as acute pain associated with DED (ie, pain experienced as a result of ongoing corneal inflammation).

[0290] PS can be useful for treating corneal pain that occurs at the central site of action (i.e., the site responsible for central pain signaling in the absence of ongoing peripheral triggers). Therefore, the present invention provides a method for treating corneal pain that occurs at the central site of action, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal pain that occurs at the central site of action is treated. Indeed, given the observations herein, PS may treat corneal pain in light of its ability to traverse to the central site of action. For example, PS may reduce corneal pain by accumulating in the trigeminal nucleus caudalis or higher-order neurons in the CNS. Therefore, PS may act directly on the pain-generating center in the trigeminal nucleus caudalis or higher-order neurons in the CNS. Therefore, the present invention provides a method for treating corneal pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal pain is treated, wherein PS reduces pain signaling that occurs in the trigeminal nucleus caudalis or higher-order neurons in the CNS. In some cases, the reduction can be complete, such that pain signaling is eliminated.

[0291] The observations herein demonstrate the ability of PS, when topically administered to the outer surface of the eyelid, to penetrate the eyelid tissue and reach the cornea in therapeutically significant amounts. Administration to the outer surface of the eyelid avoids the need for eye drops, which can cause a stinging sensation, thereby reducing patient compliance and, therefore, therapeutic success. Furthermore, administration to the outer surface of the eyelid is preferable for patients with reduced motor function or lost fine motor skills, who may have difficulty administering eye drops. Naturally, such administration to the outer surface of the eyelid requires that the therapeutic agent effectively penetrate the eyelid to reach the ocular surface in therapeutically significant amounts. Thus, the observations herein confirm the efficacy of administration of PS to the outer surface of the eyelid as a suitable topical administration route for treating various ocular diseases and conditions, particularly in cases where the therapeutic agent must reach the ocular surface in therapeutically significant amounts to achieve therapeutic efficacy. Without wishing to be bound by theory, the ability of PS to reach corneal nerves in therapeutically significant amounts may enable PS to traverse along peripheral corneal neurons toward its central site of action, thus providing a pathway by which PS can reach the pain-generating centers associated with corneal pain, even when administered topically to the outer surface of the eyelid.

[0292] Therefore, in a further aspect, the present invention provides PS for use in therapy, wherein PS is topically administered to the outer surface of one or more eyelids.The present invention also provides a method for treating and / or preventing an eye disease or eye condition, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the eye disease or eye condition is treated and / or prevented, wherein PS is topically administered to the outer surface of one or more eyelids.The eye disease or eye condition can be corneal pain, such as corneal pain described herein, for example, corneal neuropathic pain.Therefore, the present invention also provides a method for treating and / or preventing corneal pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the corneal pain is treated and / or prevented, wherein PS is topically administered to the outer surface of one or more eyelids.The one or more eyelids can be one or both upper eyelids and / or one or both lower eyelids.

[0293] Corneal pain can be caused by central sensitization. Corneal pain can occur at a central site of action. As shown herein, corneal pain can be caused by one or more surgical interventions, such as corneal refractive surgery (including PRK, LASIK, SMILE, and / or corneal inlay procedures), laser retinopexy, cataract surgery (e.g., laser cataract surgery), and / or corneal transplant surgery. Also, as discussed herein, corneal pain can be caused by laser surgery for the treatment of retinal pathologies (e.g., diabetic macular edema; proliferative diabetic retinopathy; macular edema due to retinal vein occlusion; neovascularization secondary to retinal vein occlusion; peripheral retinal degeneration, holes, and / or tears; Eales' disease and other retinal vasculitis; central serous retinopathy; retinopathy of prematurity; extrafoveal polyps of polypoidal choroidal vasculopathy (PCV)). Corneal pain can be caused by intravitreal injection (e.g., for the treatment of wet age-related macular degeneration (AMD)). Corneal pain can be experienced during or after a surgical intervention or procedure. Thus, PS can be administered before, during, or after a surgical intervention or procedure. In certain cases, corneal pain is experienced during a surgical intervention or procedure. Thus, PS can be administered before or during a surgical intervention or procedure. As described herein, corneal pain can be caused by an inflammatory eye disease or ocular condition. The inflammatory eye disease or ocular condition can be dry eye disease (DED). The inflammatory eye disease or ocular condition can be allergic conjunctivitis. Corneal pain can be caused by one or more chalazions, for example, due to persistent irritation of the cornea caused by the chalazions during blinking. Corneal pain can be pain caused by one or more of the following: chronic corneal surface disease or condition (e.g., recurrent corneal erosions, corneal surface neoplasms, and / or inflammatory ocular conditions, such as dry eye disease (DED), or inflammatory ocular conditions caused by allergens, such as allergic conjunctivitis); infection (e.g., herpes simplex keratitis and / or herpes zoster keratitis); toxic keratopathy (e.g., to topical or systemic agents); radiation or ultraviolet light exposure; trauma (e.g., chemical burns).

[0294] The eye disease or eye condition can be an inflammatory eye disease or eye condition.The inflammatory eye disease or eye condition can be dry eye disease (DED), conjunctivitis (e.g., allergic conjunctivitis), keratitis, scleritis, or uveitis.In certain embodiments, the eye disease or eye condition is dry eye disease (DED).

[0295] In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of an ocular disease or condition, wherein the PS is topically administered to the outer surface of one or more eyelids. Further, the present invention provides use of PS for the manufacture of a medicament for treating and / or preventing an ocular disease or condition, wherein the PS is topically administered to the outer surface of one or more eyelids.

[0296] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS can be formulated for topical administration.

[0297] The preparation disclosed herein for topical administration of PS to the outer surface of eyelid can be used in the method disclosed herein.Eyelid can be upper eyelid or lower eyelid.When topical administration to the outer surface of eyelid, PS is applied substantially entirely to the outer surface of eyelid.

[0298] The observation herein that PS achieves significant analgesic effects on corneal neuropathic pain, together with the observation that PS can reach its primary site of action by traversing peripheral neurons toward the CNS, supports a role for PS in directly affecting neuronal signaling involved in the generation of corneal neuropathic pain, for example, in reducing the occurrence of pain caused by central sensitization. Because these activities are not shared by sulindac (PS's parent compound), the observation herein suggests that modifying sulindac not only confers surprising analgesic activity on PS that acts directly on neuronal signaling, but also makes PS more capable of traversing toward its primary central site of action, thereby enabling it to exert its analgesic activity on neuronal signaling even more effectively. Thus, without wishing to be bound by theory, the observation herein suggests that it may be possible to overcome the apparent failure of NSAIDs to achieve meaningful analgesic effects on corneal neuropathic pain by modifying NSAIDs so that they can act directly on neuronal signaling by traversing peripheral neurons that project to the central nervous system and more easily access their primary site of action. Therefore, as an alternative to PS, the method of the present invention can be carried out using one or more modified NSAIDs disclosed herein.Therefore, the present invention provides a method for treating corneal neuropathic pain, the method comprises administering a therapeutically effective amount of modified NSAID to a subject in need thereof, so that corneal neuropathic pain is treated.In this specification, " modified NSAID " refers to the compound that results from the modification of NSAID molecule (i.e., parent compound).

[0299] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramido-modified NSAIDs (phosphoamido-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, HS-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs), and NOSH-releasing NSAIDs (NOSH-NSAIDs). Modified NSAID can be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib or modified celecoxib.In certain embodiments, the NSAID of modified NSAID can be sulindac, ibuprofen, aspirin or naproxen.Therefore, modified NSAID can be phosphosulindacamide, Se-sulindac, HS-sulindac, NO-sulindac or NOSH-sulindac. The modified NSAID can be phosphoaspirin, phosphonaproxen, phosphoflurbiprofen, or phosphoibuprofen. The modified NSAID can be phosphoibuprofenamide.

[0300] Pharmaceutical compositions of PS The PS for use in the methods of the present invention can be formulated into a pharmaceutical composition suitable for administration to a subject in need thereof, such as a subject suffering from pain associated with central sensitization, a subject suffering from PTPN, a subject suffering from PHN, a subject suffering from migraine pain (and pain from other headache disorders), or a subject suffering from corneal neuropathic pain. The pharmaceutical composition is typically formulated to provide a therapeutically effective amount of PS and may further comprise a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprising PS can be formulated for topical use in the present invention.

[0301] Pain associated with central sensitization can be systemic or occur in various parts of the body. Pain can be diffuse and widespread, or localized to the area where the initial pain signaling occurs. Pain typically manifests in peripheral areas. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral area where pain is experienced. Therefore, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration.

[0302] Neuropathic pain associated with PTPN is sensed within the injured tissue, but pain can also radiate proximal to the injury site. In either case, pain is sensed from peripheral regions. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral area where neuropathic pain is experienced. Furthermore, pharmaceutical compositions containing PS can be applied to the area where one or more sensory symptoms of PTPN are experienced. Therefore, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration. A single application to the affected area may require less than about 5 ml of pharmaceutical composition, for example, about 3 ml of pharmaceutical composition.

[0303] Neuropathic pain associated with PHN most commonly manifests on the subject's torso. As outlined above, PHN tends to affect one or two adjacent dermatomes and generally does not cross the midline of the body. Less frequently, PHN can affect three or more dermatomes, resulting in a more widespread condition. Typically, neuropathic pain associated with PHN manifests in one or more thoracic dermatomes (i.e., the subject's torso). Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to peripheral locations experiencing neuropathic pain, such as thoracic dermatomes on the subject's torso. Furthermore, pharmaceutical compositions containing PS can be applied to locations experiencing one or more sensory symptoms of PHN. Therefore, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration, particularly to the skin of a subject's thoracic dermatomes. A single application to one or more thoracic dermatomes may require up to about 15 ml of pharmaceutical composition. A single application to both areas (i.e., three or more dermatomes) affected by neuropathic pain associated with disseminated shingles may require up to about 30 ml of pharmaceutical composition.

[0304] Migraine pain (and the pain of other headache disorders) is perceived as headache and facial pain. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral location where pain is experienced, such as the head and / or neck of a subject. Thus, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration, particularly to the skin near the sensory branches of the trigeminal nerve. PS can be administered to the skin of a subject's head and / or neck. PS can be administered locally where the neck meets the base of the skull. PS can be administered locally to one or both of a subject's temples. PS can be administered locally behind one or both of a subject's ears. For example, a single application to a temple or behind an ear may require less than about 2 ml of pharmaceutical composition, for example, about 1 ml of pharmaceutical composition (i.e., about 0.5 ml of pharmaceutical composition per temple or behind each ear).

[0305] Corneal neuropathic pain, such as corneal pain, is sensed by the eye. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied so that they reach the eyeball of a subject experiencing corneal neuropathic pain in a therapeutically significant amount. Thus, a pharmaceutical composition containing PS can be directly applied to one or both eyes of a subject experiencing corneal neuropathic pain. Thus, a pharmaceutical composition containing PS can be formulated for topical administration to the ocular surface (i.e., to the eyeball), for example, onto the cornea or the canthus. In a preferred embodiment, a pharmaceutical composition containing PS can be topically applied to the outer surface of one or more eyelids of a subject. Thus, a pharmaceutical composition containing PS can be formulated for transdermal administration, particularly to the skin of one or more eyelids of a subject (i.e., the outer surface of one or more eyelids of a subject). The one or more eyelids can be one or both upper eyelids. The one or more eyelids can be one or both lower eyelids. In the case of topical administration to the outer surface of the eyelid, substantially all of the PS is applied to the outer surface of the eyelid. In certain cases, the lower eyelid may be preferred because the outer surface of the lower eyelid is less damaged by the blinking process than the outer surface of the upper eyelid (i.e., when the eye is open, the outer surface of the upper eyelid is parallel to the skin of the orbit).In certain cases, the upper eyelid may be preferred because the surface area of ​​the outer surface for topical administration is typically larger.A single application to one eyelid may require less than about 1 ml of pharmaceutical composition, for example, about 0.5 ml of pharmaceutical composition.

[0306] In some embodiments, pharmaceutical compositions containing PS can be formulated as semisolids or liquids. Thus, pharmaceutical compositions containing PS can be formulated as creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. These compositions vary in the relative concentrations of oil and water, resulting in different densities. Altering the density of the formulation is a means by which the exposure of the affected area to the pharmaceutical composition can be controlled. For example, a less dense formulation that requires rubbing until absorbed may result in a shorter exposure time. Alternatively, a denser formulation that is not easily absorbed may allow for prolonged exposure of the affected area to the pharmaceutical ingredient. Those skilled in the art will recognize the formulation of topical pharmaceutical compositions to alter the relative exposure of the affected area to the active pharmaceutical ingredient.

[0307] For the treatment of corneal neuropathic pain, pharmaceutical compositions containing PS for topical administration to the ocular surface and / or the outer surface of the eyelid can be formulated as a gel (e.g., hydrogel) or ointment. For topical administration to the ocular surface, pharmaceutical compositions containing PS can be formulated as a gel (e.g., hydrogel), ointment, and / or eye drops. For topical administration to the outer surface of the eyelid, pharmaceutical compositions containing PS can be formulated as a cream, gel (e.g., hydrogel), lotion, ointment, foam, and / or spray.

[0308] In other embodiments, pharmaceutical compositions containing PS can be formulated as patches that can be applied to the skin, which can be manufactured in a manner that ensures controlled release of PS to the affected area.

[0309] In some embodiments for treating corneal neuropathic pain, a pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin of one or more eyelids (e.g., one or both lower eyelids) of a subject. The patch can be manufactured in a manner that ensures controlled release of PS through the outer surface of the eyelid so that a therapeutically appropriate amount of PS reaches the ocular surface.

[0310] In certain embodiments for treating corneal neuropathic pain, a pharmaceutical composition comprising PS can be formulated as an eye drop. Such eye drop formulations can include liquid or semisolid pharmaceutical compositions adapted for administration to the eye. A typical example of an eye drop composition is an eye drop solution administered dropwise to the eye. In some embodiments, the eye drop composition is an eye drop emulsion administered dropwise to the eye. In some embodiments, the drop volume is about 10 to about 100 μL. The drop volume can be greater than about 10 μL, greater than about 20 μL, greater than about 30 μL, greater than about 40 μL, greater than about 50 μL, greater than about 60 μL, greater than about 70 μL, greater than about 80 μL, greater than about 90 μL, or greater than about 100 μL. The drop volume can be less than about 10 μL, less than about 20 μL, less than about 30 μL, less than about 40 μL, less than about 50 μL, less than about 60 μL, less than about 70 μL, less than about 80 μL, less than about 90 μL, or less than about 100 μL.

[0311] Formulations suitable for topical administration and suitable pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO2019 / 067919, which is incorporated herein by reference in its entirety.

[0312] In some embodiments, formulations of PS suitable for topical administration may contain PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, PS may be present in concentrations of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, PS can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0313] In some embodiments for treating corneal neuropathic pain, formulations of PS suitable for topical administration to the ocular surface and / or the outer surface of the eyelid may contain PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, PS may be present in concentrations of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, PS can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0314] Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating pain associated with central sensitization. Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating and / or preventing neuropathic pain associated with PTPN. Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating and / or preventing migraine pain (or pain from other headache disorders). Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating and / or preventing neuropathic pain associated with PHN. For example, the composition may be formulated for transdermal administration or injection, for example, subcutaneous injection.

[0315] In certain embodiments for treating corneal neuropathic pain, the composition may be formulated for intravitreal injection.

[0316] The formulations disclosed herein are also suitable for treating corneal pain, for example, corneal pain caused by central sensitization and / or corneal pain that occurs at a central site of action.

[0317] As previously disclosed herein, in a further aspect, the present invention provides PS for use in therapy, wherein the PS is topically administered to one or more outer surfaces of the eyelid. The present invention also provides a method for treating and / or preventing an ocular disease or condition, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the ocular disease or condition is treated and / or prevented, wherein the PS is topically administered to one or more outer surfaces of the eyelid.

[0318] In some embodiments of topical administration of PS to the outer surface of one or more eyelids, the pharmaceutical composition comprising PS can be formulated as a gel (e.g., a hydrogel) or an ointment. For topical administration to the outer surface of the eyelid, the pharmaceutical composition comprising PS can be formulated as a cream, gel (e.g., a hydrogel), lotion, ointment, foam, and / or spray.

[0319] In some embodiments of topical administration of PS to the outer surface of one or more eyelids, a pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin of one or more eyelids (e.g., one or both lower eyelids) of a subject. The patch can be manufactured in a manner that ensures controlled release of PS through the outer surface of the eyelid so that a therapeutically appropriate amount of PS reaches the ocular surface.

[0320] In some embodiments of topical administration of PS to the outer surface of one or more eyelids, the PS formulation may contain PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, PS may be present in concentrations of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, PS can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0321] A single application to one eyelid may require less than about 1 ml of the pharmaceutical composition, for example, about 0.5 ml of the pharmaceutical composition.

[0322] The observations herein surprisingly demonstrate that PS, even when administered orally, has a direct effect on neuronal pain signaling that originates centrally (e.g., via central sensitization). Previous observations have shown that when administered locally, PS traverses peripheral neurons toward central sites, thus enabling PS to directly act on neurons involved in pain generation. Local administration of PS is administered to areas of high peripheral sensory neuron concentration, allowing for uptake and transport to the central site of action in amounts high enough to achieve analgesic effects. It was unexpected that oral administration of PS would also achieve analgesic effects for indications known to have central pain generation sites, such as pain associated with central sensitization, pain associated with PTPN, pain associated with postherpetic neuralgia (PHN), and pain due to migraine. Indeed, typical NSAIDs have been shown to be ineffective in treating neuropathic pain, regardless of the route of administration (Moore et al., Cochrane Database of Systematic Reviews (2015); 10:1-25). The Cochrane Library concluded that NSAIDs should not be recommended for the treatment of neuropathic pain.

[0323] The observations herein demonstrate that upon oral administration, PS is found in therapeutically significant amounts in pain-sensing regions of the brain (e.g., the medulla oblongata and cerebellum). The evidence herein demonstrates that PS is taken up by neurons innervating the stomach wall and traverses along the vagus nerve to reach central sites in the brain. These observations are supported by observations demonstrating the translocation of PS along the sciatic nerve and the absence of therapeutic levels of PS in the blood. Thus, without wishing to be bound by theory, PS may exert its direct analgesic effect on neurons in centrally located pain-sensing regions of the brain, providing an elegant mechanism by which centrally generated pain may be relieved regardless of its original etiology.

[0324] Thus, PS can be administered orally. In some embodiments, pharmaceutical compositions comprising PS for use in the present invention can be formulated for oral administration.

[0325] Thus, the present invention provides a method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that pain associated with central sensitization is treated, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with CIPN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PTPN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing migraine pain (or pain associated with other headache disorders), comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain (or pain associated with other headache disorders) is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing corneal neuropathic pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal neuropathic pain is treated and / or prevented, wherein the PS is administered orally.

[0326] PS for oral administration can be formulated as a liquid or solid dosage form.

[0327] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.

[0328] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, or granules. Tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation field. Capsules, tablets, and pills can be designed to release PS only or preferentially in a specific part of the intestinal tract, such as the stomach, optionally in a delayed manner.

[0329] In some embodiments, formulations for oral administration include one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-static agents.

[0330] Formulations suitable for oral administration may contain PS at a concentration of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0331] Even when administered orally, PS reduces pain signaling occurring in the CNS, particularly pain-sensing regions of the brain. In some embodiments, oral administration of PS reduces pain signaling occurring in the brain. Upon oral administration, PS can accumulate (via the vagus nerve) at therapeutically significant levels in the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray (PAG). In certain embodiments, upon oral administration, PS accumulates at therapeutically significant levels in the medulla oblongata and / or cerebellum. PS, for example, upon oral administration, can reduce pain signaling in the somatosensory cortex, for example, the primary somatosensory cortex. Orally administered PS can reduce pain signaling in one or more of the following brain regions: the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray. In certain embodiments, orally administered PS can reduce pain signaling in the medulla oblongata and / or cerebellum.

[0332] In some embodiments, the PS is administered both orally and topically.

[0333] Pharmaceutical Compositions of Modified NSAIDs The modified NSAID for use in the methods of the present invention can be formulated into a pharmaceutical composition suitable for administration to a subject in need thereof, such as a subject with CIPN or DPN, or pain associated with central sensitization, a subject with PTPN, a subject with PHN, a subject with migraine pain (and pain from other headache disorders), or a subject with corneal neuropathic pain.The pharmaceutical composition is typically formulated to provide a therapeutically effective amount of the modified NSAID and may further include a pharmaceutically acceptable excipient.In certain embodiments, the pharmaceutical composition comprising the modified NSAID can be formulated for topical use in the present invention.

[0334] Neuropathic pain associated with CIPN can occur in various parts of the body. However, as outlined above, CIPN and DPN tend to affect the peripheral nerves of the upper and lower limbs, thus the extremities, which explains the "stocking-glove" distribution experienced by these patients. Therefore, a particularly useful pharmaceutical composition containing a modified NSAID is one that can be directly applied to the peripheral location experiencing neuropathic pain, such as the upper and lower limbs of a subject. Furthermore, a pharmaceutical composition containing a modified NSAID PS can be applied to the location experiencing one or more sensory symptoms of CIPN or DPN. Therefore, a pharmaceutical composition containing a modified NSAID can be formulated for topical administration. In particular, a pharmaceutical composition containing a modified NSAID can be formulated for transdermal administration, particularly to the skin of the upper and / or lower limbs of a subject.

[0335] In some embodiments, pharmaceutical compositions containing modified NSAIDs can be formulated as semisolids or liquids. Thus, pharmaceutical compositions containing modified NSAIDs can be formulated as creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. These compositions vary in the relative concentrations of oil and water, resulting in compositions with different densities. Altering the density of the formulation is a means of controlling the exposure of affected areas to the pharmaceutical composition. For example, a less dense formulation that requires rubbing until absorbed may result in a shorter exposure time. Alternatively, a denser formulation that is not easily absorbed may allow for prolonged exposure of affected areas to the pharmaceutical crude. Those skilled in the art will recognize the formulation of topical pharmaceutical compositions to alter the relative exposure of affected areas to the active pharmaceutical ingredient.

[0336] In other embodiments, the pharmaceutical compositions containing the modified NSAIDs may be formulated as patches that can be applied to the skin. The patches may be manufactured in a manner that ensures controlled release of the modified NSAIDs to the affected area.

[0337] Formulations suitable for topical administration and suitable pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO2019 / 067919, which is incorporated herein by reference in its entirety.

[0338] In some embodiments, formulations of modified NSAIDs suitable for topical administration may include PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, the modified NSAID may be present in a concentration of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, the modified NSAID can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, the modified NSAID can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, the modified NSAID can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0339] A single application to both hands (i.e., gloves) may require less than about 5 ml of the pharmaceutical composition, for example, about 3 ml of the pharmaceutical composition (i.e., about 1.5 ml of the pharmaceutical composition per hand).A single application to both legs (i.e., socks) may require less than about 6 ml of the pharmaceutical composition, for example, about 4 ml of the pharmaceutical composition (i.e., about 2 ml of the pharmaceutical composition per foot).

[0340] The pharmaceutical composition containing the modified NSAID may alternatively be formulated for any other administration form suitable for treating and / or preventing neuropathic pain associated with CIPN or DPN. For example, the composition may be formulated for transdermal administration or injection, e.g., subcutaneous injection.

[0341] For example, a pharmaceutical composition for topical administration can include two or more of the modified NSAIDs disclosed herein. In certain embodiments, for example, a pharmaceutical composition for topical administration can include one or more of the modified NSAIDs disclosed herein other than PS in combination with PS.

[0342] The areas for local administration of PS equally apply to the local administration of modified NSAIDs. For example, for treating pain associated with central sensitization, particularly useful pharmaceutical compositions containing modified NSAIDs can be applied directly to the peripheral location where pain is experienced. For treating and preventing pain associated with PTPN, particularly useful pharmaceutical compositions containing modified NSAIDs can be applied directly to the peripheral location where neuropathic pain is experienced. Furthermore, pharmaceutical compositions containing modified NSAIDs can be applied to the location where one or more sensory symptoms of PTPN are experienced. For treating and / or preventing pain associated with PHN, particularly useful pharmaceutical compositions containing modified NSAIDs can be applied directly to the peripheral location where neuropathic pain is experienced, for example, the thoracic dermatomes on the torso of a subject. Furthermore, pharmaceutical compositions containing modified NSAIDs can be applied to the location where one or more sensory symptoms of PHN are experienced. Furthermore, for treating and / or preventing pain due to migraine (or pain from other headache disorders), particularly useful pharmaceutical compositions containing modified NSAIDs can be applied directly to the peripheral location where pain is experienced, for example, the head and / or neck of a subject.

[0343] In certain embodiments, the modified NSAIDs may be administered orally. Suitable oral formulations disclosed herein for PS may equally be utilized for oral formulations of other modified NSAIDs.

[0344] In certain embodiments, the orally administered modified NSAID is a phosphoroamide NSAID, such as phosphosulindacamide, such as that represented by Formula X; or phospho-ibuprofenamide, such as that represented by Formula XI. In some embodiments, the orally administered modified NSAID is phospho-ibuprofen, such as that represented by Formula III; phospho-glycerol-ibuprofen, such as that represented by Formula LXXI; NO-sulindac, such as that represented by Formula XLIV; HS-sulindac, such as that represented by Formula XXXIV; or phosphonaproxen (Formula VIII). In certain embodiments, the orally administered modified NSAID is a modified sulindac, such as PS (e.g., Formula I or II), NO-sulindac (e.g., Formula XLIV), HS-sulindac (e.g., Formula XXXIV), or preferably phosphosulindacamide (e.g., Formula X). In certain embodiments, the orally administered modified NSAID is a modified ibuprofen, for example, phospho-ibuprofen, such as that of Formula III; phospho-glycerol-ibuprofen, such as that of Formula LXXI; or phospho-ibuprofen-amide, such as that of Formula XI, particularly phospho-ibuprofen-amide, such as that of Formula XI.

[0345] As demonstrated herein, even when administered orally, modified NSAIDs (e.g., phosphonaproxen and phosphosulindacamide) can traverse the vagus nerve and reach regions of the CNS, even within the brain, in therapeutically significant amounts. Thus, in some embodiments, oral administration of a modified NSAID reduces pain signaling occurring in the brain. Upon oral administration, the modified NSAID can accumulate (via the vagus nerve) at therapeutically significant levels in the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter (PAG). In certain embodiments, upon oral administration, the modified NSAID accumulates at therapeutically significant levels in the medulla oblongata and / or cerebellum. For example, upon oral administration, the modified NSAID can reduce pain signaling in the somatosensory cortex, e.g., the primary somatosensory cortex. Orally administered modified NSAIDs may reduce pain signaling in one or more of the following regions of the brain: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray. In certain embodiments, orally administered modified NSAIDs may reduce pain signaling in the medulla oblongata and / or cerebellum.

[0346] In some embodiments, the modified NSAID may be administered both orally and topically.

[0347] PS administration regimen An appropriate dosing regimen for PS for treating an indication described herein (e.g., pain associated with central sensitization, neuropathic pain associated with PTPN, neuropathic pain associated with PHN, migraine pain (and pain of other headache disorders), or corneal neuropathic pain) will depend on variables such as the type and progression of pain (e.g., as determined by the World Health Organization "pain ladder" guidelines), the severity of the pain (e.g., acute, subacute, or chronic), the age, weight, and general condition of the particular patient, the formulation of excipients, the route of administration, and the judgment of the attending clinician.

[0348] For local administration, PS can be administered to cover one or more affected areas (i.e., peripheral areas experiencing pain) of the subject. In some embodiments, about 0.01 to about 5 g of PS can be administered to the affected area. In terms of the size of the affected area, PS can be administered in a volume of about 0.005 to 0.25 g / 10 cm. 2 Therefore, PS can be administered at a dose of about 0.005 g / 10 cm 2 , 0.01g / 10cm 2 , 0.05g / 10cm 2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 It can be administered locally.

[0349] In the case of local administration to treat and / or prevent neuropathic pain associated with PHN, PS can be administered to cover one or more affected areas of a subject, for example, one or more thoracic dermatomes. PS can be administered, for example, topically, to the site of the rash or to the area experiencing sensory symptoms preceding the onset of the rash. Thus, PS can be administered locally (e.g., to one or more thoracic dermatomes) during the prodromal phase or rash phase. Thus, PS can be administered prophylactically to prevent the development of neuropathic pain associated with PHN after the rash has resolved. In certain embodiments, PS is administered, for example, topically, to the original rash site after the rash and / or skin lesions have resolved. Thus, PS can be administered locally (e.g., to one or more thoracic dermatomes) after the rash and / or skin lesions have resolved. In these cases, PS can prevent PHN-associated neuropathic pain from occurring or treat PHN-associated neuropathic pain already established at the original rash site.

[0350] For local administration to treat and / or prevent migraine pain (or pain associated with other headache disorders), PS can be administered to cover one or more affected areas, for example, the subject's temples or behind each ear.

[0351] For topical administration to the ocular surface, PS can be administered to cover the affected area (i.e., the ocular surface). For topical administration to the outer surface of the eyelid, PS can be administered to ensure that a therapeutically appropriate amount of PS reaches the ocular surface upon topical administration to the outer surface of the eyelid. As described above, for topical administration to the outer surface of the eyelid, PS is applied substantially entirely to the outer surface of the eyelid.

[0352] In embodiments of topical administration to the ocular surface, about 0.001 to about 1 mg of PS may be administered to the ocular surface. In terms of ocular surface size, PS may be administered in the range of about 0.005 to 0.25 mg / cm. 2 It can be administered on the ocular surface. Thus, PS can be administered at a concentration of about 0.005 mg / cm 2 , 0.01 mg / cm 2 , 0.05 mg / cm 2 , 0.1 mg / cm 2 , 0.15 mg / cm 2 , 0.2 mg / cm 2 or 0.25 mg / cm 2 The PS may be administered to the ocular surface at about 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, or 0.25 mg per drop.

[0353] In embodiments of topical administration to the outer surface of the eyelid, about 0.1 to about 250 mg of PS may be administered to the outer surface of the eyelid. With respect to the size of the outer surface of the eyelid, PS may be administered in a range of about 0.5 to 100 mg / cm. 2 It can be administered on the outer surface of the eyelid. Thus, PS can be administered at a dose of about 0.5 mg / cm 2 , 5 mg / cm 2 , 10 mg / cm 2 , 25 mg / cm 2 , 50 mg / cm 2 , 75 mg / cm 2 or 100 mg / cm 2 It may be administered on the outer surface of the eyelid.

[0354] In some cases, PS for use in topical administration for the methods of the present invention may be applied to the affected area and then removed from the affected area (e.g., by washing off) before reapplication. In some cases, the PS is washed off after a certain period of time. Alternatively, because the analgesic effect may decrease over time, making reapplication necessary, in some cases the PS is not washed off; instead, the PS is simply reapplied to the affected area after an appropriate administration period has elapsed. For example, the PS may be applied to the affected area and left on the affected area for about 0.5 to about 5 hours (before removal or reapplication). Thus, the PS may be applied topically to the affected area and left on for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours (before removal or reapplication).

[0355] Because the analgesic effect may decrease over time, PS for topical administration to the ocular surface and / or outer eyelid surface may, in some cases, be reapplied to the ocular surface and / or outer eyelid surface after an appropriate administration period has elapsed. For embodiments involving topical administration to the outer eyelid surface, PS may be removed from the outer eyelid surface (e.g., by rinsing) before reapplication. In some cases, PS is washed off after a period of time. In some cases, PS is not washed off; instead, PS is simply reapplied. For example, PS may be applied to the ocular surface and / or outer eyelid surface and left on the ocular surface and / or outer eyelid surface for about 0.5 to about 5 hours (before removal or reapplication). Thus, PS may be topically applied to the ocular surface and / or outer eyelid surface and left on the ocular surface and / or outer eyelid surface for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours (before removal or reapplication).

[0356] Pain associated with the indications described herein (e.g., pain associated with central sensitization, neuropathic pain associated with PTPN, and neuropathic pain associated with PHN) is chronic, necessitating repeated topical administration of PS. Similarly, pain from migraine (and other headache disorders) can be prolonged, e.g., up to 72 hours, and even longer in the case of chronic migraine, necessitating repeated topical administration of PS. Therefore, PS can be applied topically one to four times daily. Thus, PS can be applied once daily, twice daily, three times daily, or four times daily. In certain formulations of PS, such as hydrogels or ointments with a PS concentration of approximately 5% (w / w) of the pharmaceutical composition, the formulation can be applied topically three times daily. In more severe cases, additional applications of PS can be applied approximately 0.5 hours after each application.

[0357] Because corneal neuropathic pain is chronic, repeated topical administration of PS is necessary. Therefore, PS can be applied topically to the ocular surface and / or outer surface of the eyelid one to four times daily. Therefore, PS can be applied once daily, twice daily, three times daily, or four times daily. In certain formulations of PS, such as hydrogels or ointments with a PS concentration of approximately 5% (w / w) of the pharmaceutical composition, the formulation can be applied topically to the ocular surface and / or outer surface of the eyelid three times daily. In more severe cases, additional applications of PS can be applied approximately 0.5 hours after each application. Because PS can have a long-lasting analgesic effect, it can be administered less frequently. For example, PS can be administered topically less than once daily, e.g., once every two days. Indeed, for patients who experience long-term pain relief with a single administration, PS can be administered topically less than once a week, e.g., once every two weeks.

[0358] In some embodiments of topical administration to the ocular surface and / or outer surface of the eyelid, PS can have a long-lasting analgesic effect, so it can be administered less frequently.For example, PS can be topically administered to the ocular surface and / or outer surface of the eyelid less than once a day, for example, once every two days.In fact, for patients who experience long-term analgesia with a single administration, PS can be topically administered to the ocular surface and / or outer surface of the eyelid less than once a week, for example, once every two weeks.

[0359] In the case of topical administration of some pharmaceutical compositions, after applying the pharmaceutical composition, it is useful to cover the affected area with, for example, a bandage (for example, a plastic wrap or film) to ensure that an appropriate amount of the composition can be applied for an appropriate period of time.Therefore, after topical application of PS, the affected area may be bandaged.

[0360] In some embodiments, PS can be administered topically in the form of a patch, such as a medicated patch. The use of a patch can reduce the administration interval and / or frequency, for example, because the patch ensures controlled release of PS. Thus, the patch can be applied to the affected area once a day.

[0361] In some embodiments of topical administration to the outer surface of the eyelid, PS can be topically administered to the outer surface of the eyelid in the form of a patch, for example, a medicated patch.The use of a patch can reduce the administration interval and / or administration frequency, for example, because the patch ensures controlled release of PS.Therefore, the patch can be applied to the outer surface of the eyelid once a day.

[0362] PS may be orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight. In certain embodiments, PS may be administered at a dosage level of about 1 mg / kg to about 5 mg / kg, e.g., about 3 mg / kg of the subject's body weight.

[0363] PS may be orally administered at a dosage of about 1 mg to about 2000 mg. In some embodiments, PS may be orally administered at a dosage of about 100 mg to 1500 mg, e.g., about 200 mg to about 1000 mg. In some embodiments, PS may be orally administered at a dosage of about 50 mg to about 400 mg, e.g., about 100 mg to about 350 mg, e.g., about 150 mg to about 300 mg, e.g., about 150 mg to about 250 mg. In certain embodiments, PS is orally administered at a dosage of about 250 mg to about 300 mg, preferably about 250 mg. In some embodiments of multiple doses, equal amounts of PS may be administered with each dose. In other embodiments, a higher initial dose, followed by a lower maintenance dose, may be administered.

[0364] In some embodiments, PS can be orally administered once a day or more frequently.For example, PS can be orally administered twice a day, three times a day, four times a day, or more frequently as needed.In certain embodiments, PS can be orally administered twice or three times a day.

[0365] In certain embodiments, PS is orally administered twice daily at a dosage of about 150 mg to about 200 mg. Thus, a subject may be orally administered a daily dosage of about 300 mg to about 400 mg of PS.

[0366] In certain embodiments, PS is orally administered at a dosage of about 250 mg to about 300 mg (e.g., about 250 mg) two or three times daily. Thus, a subject may be orally administered PS at a daily dosage of about 500 mg to a maximum of about 900 mg.

[0367] Administration of PS may be continued as long as necessary. For example, PS may be administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, more than 28 days, more than 56 days, or more than 84 days. As described above, PS may be administered continuously, for example, chronically for at least 3 months, for chronically effective treatment. Thus, in some cases, continuous administration is achieved and maintained as long as necessary. PS may be administered intermittently in response to recurrence of pain and / or associated sensory symptoms associated with the indications described herein.

[0368] The PS can be used in mammals for the treatment (and prevention) of pain associated with the indications described herein. For example, the subject can be a human.

[0369] As mentioned above, PS can be formulated into a pharmaceutical composition suitable for administration to a subject with any one of the indications described herein (e.g., pain associated with central sensitization, PTPN, PHN, migraine (other headache disorders), or corneal neuropathic pain). Thus, PS can be administered in a suitable pharmaceutical composition according to the above-mentioned dosage regimen. In certain embodiments, PS, or a suitable pharmaceutical composition of PS, is administered as a monotherapy.

[0370] The dosing regimens disclosed herein are suitable for treating corneal pain, such as corneal pain caused by central sensitization and / or corneal pain that occurs at a central site of action. Indeed, the dosing regimens disclosed herein are applicable for use in any of the methods of treatment disclosed herein.

[0371] Those skilled in the art will understand that in certain embodiments, the dosage of such compounds may be adjusted depending on the mammal being treated. For example, the treatment of mice is described herein, and such dosage may or may not be modified when administering PS to humans. However, those skilled in the art may, if necessary, convert the dosages provided herein as set forth in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, USDapartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. The human equivalent dose (HED) may be determined from the animal dose and may be multiplied by the following conversion factors to obtain units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, micropig = 0.73, and minipig = 0.95.

[0372] Modified NSAID Dosing Regimen Appropriate dosing regimens for modified NSAIDs for treating and / or preventing the indications herein (e.g., subjects with CIPN or DPN, or pain associated with central sensitization, subjects with PTPN, subjects with PHN, subjects with migraine pain (and pain from other headache disorders), or subjects with corneal neuropathic pain) will depend on variables such as the type and progression of pain (e.g., as determined by the World Health Organization "pain ladder" guidelines), the severity of the pain (e.g., acute, subacute, or chronic), the age, weight, and general condition of the particular patient, the formulation of the excipients, the route of administration, and the judgment of the attending clinician.

[0373] For topical administration, the modified NSAID can be administered to cover one or more affected areas, such as the upper and lower extremities of a subject. In some embodiments, about 0.01 to about 5 g of the modified NSAID can be administered to the affected area. With respect to the size of the affected area, the modified NSAID can be administered in a volume of about 0.005 to 0.25 g / 10 cm. 2 The modified NSAID can be administered at the affected area. Thus, the modified NSAID can be administered at a dose of about 0.005 g / 10 cm. 2 , 0.01g / 10cm 2 , 0.05g / 10cm 2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 It can be administered locally.

[0374] In some cases, modified NSAIDs for topical administration may be applied to the affected area and then removed from the affected area (e.g., by washing off) before reapplication. In some cases, the modified NSAID is washed off after a certain period of time. Alternatively, because the analgesic effect may decrease over time, making reapplication necessary, in some cases the modified NSAID is not washed off; instead, the modified NSAID is simply reapplied to the affected area after an appropriate administration period has elapsed. For example, the modified NSAID may be applied to the affected area and left on the affected area for about 0.5 to about 5 hours (before removal or reapplication). Thus, the modified NSAID may be applied topically to the affected area and left on for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours (before removal or reapplication).

[0375] Because pain associated with the indications described herein (e.g., pain associated with CIPN or DPN, pain associated with central sensitization, neuropathic pain associated with PTPN, and neuropathic pain associated with PHN) is chronic, repeated topical administration of the modified NSAID is necessary. Therefore, the modified NSAID may be applied topically one to four times daily. Thus, the modified NSAID may be applied once daily, twice daily, three times daily, or four times daily. In certain formulations of the modified NSAID, such as a hydrogel or ointment having a modified NSAID concentration of about 5% (w / w) of the pharmaceutical composition, the formulation may be applied topically three times daily. In more severe cases, additional applications of the modified NSAID may be applied approximately 0.5 hours after each application.

[0376] Modified NSAID can have long-lasting analgesic effect, so it can be administered less frequently.For example, modified NSAID can be topically administered less than once a day, for example, once every two days.In fact, for patients who experience long-term analgesia with a single administration, modified NSAID can be topically administered less than once a week, for example, once every two weeks.

[0377] For topical administration of some pharmaceutical compositions, it may be useful to cover the affected area with, for example, a bandage (e.g., plastic wrap or film) after applying the pharmaceutical composition, for example, to ensure that an appropriate amount of the composition is applied for an appropriate period of time. Thus, after topical application of the modified NSAID, a bandage may be applied to the affected area.

[0378] In some embodiments, the modified NSAID can be administered topically in the form of a patch, for example, a medicated patch. The use of a patch can reduce the administration interval and / or administration frequency, for example, because the patch ensures controlled release of the modified NSAID. Thus, the patch can be applied to the affected area once a day.

[0379] The administration of modified NSAID can be continued as long as necessary.For example, modified NSAID can be administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, more than 28 days, more than 56 days, or more than 84 days.As mentioned above, modified NSAID can be administered continuously for chronic effective treatment, for example, chronically for at least 3 months.Therefore, in some cases, continuous administration can be achieved and maintained as long as necessary.Modified NSAID can be administered intermittently depending on the recurrence of neuropathic pain and / or related sensory symptoms.

[0380] If appropriate, two or more of the modified NSAIDs disclosed herein can be administered, for example, locally.Two or more modified NSAIDs can be administered sequentially or simultaneously.In certain cases, one or more of the modified NSAIDs disclosed herein other than PS can be administered in combination with locally administered PS, for example, sequentially or simultaneously, for example, locally.

[0381] The modified NSAIDs can be used to treat and / or prevent CIPN in a mammal. For example, the subject can be a human.

[0382] As described above, the modified NSAID can be formulated into a pharmaceutical composition suitable for administration to a subject with an indication described herein, such as CIPN or DPN. Thus, the modified NSAID can be administered in a suitable pharmaceutical composition according to the administration regimen described above.

[0383] The suitable oral dosage levels and regimens disclosed herein for PS may equally be utilized for oral dosage levels and regimens for other modified NSAIDs.

[0384] Those skilled in the art will understand that in certain embodiments, the dosage of such compounds may be adjusted depending on the mammal being treated. For example, the treatment of mice is described herein, and such dosage may or may not be modified when administering PS to humans. However, those skilled in the art may, if necessary, convert the dosages provided herein as set forth in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, USDapartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. The human equivalent dose (HED) may be determined from the animal dose and may be multiplied by the following conversion factors to obtain units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, micropig = 0.73, and minipig = 0.95.

[0385] Pharmaceutically acceptable forms of PS or modified NSAIDs Pharmaceutical compositions comprising PS can contain pharmaceutically acceptable forms of PS, which can be solvates, derivatives, and / or prodrugs.

[0386] Similarly, a pharmaceutical composition comprising a modified NSAID can contain a pharmaceutically acceptable form of the modified NSAID, which can be a solvate, derivative, and / or prodrug.

[0387] solvate As used herein, the term "solvate" refers to a compound that further contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable forms of PS can include solvates of PS, such as solvates of PS-I and / or PS-II. Pharmaceutically acceptable forms of modified NSAIDs can include solvates of modified NSAIDs. In some embodiments, the solvate contains at least one molecule of solvent. In some embodiments, the solvate contains less than one molecule of solvent. In some embodiments, the solvate is a hydrate.

[0388] Isotopes Pharmaceutically acceptable forms of PS can include isotopically labeled derivatives of PS-I. Pharmaceutically acceptable forms of PS can include isotopically labeled derivatives of PS-II. Isotopically labeled derivatives are compounds that are identical to PS except that one or more atoms have been replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, isotopically labeled derivatives of PS contain one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, isotopically labeled derivatives of PS contain one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine, respectively. 2 H, 3 H, 13 C. 14 C. 18 O. 17 O. 31 P, 32 P, 35 S, and 18 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of F. 2 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of H (e.g., deuterium). 3 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of H (e.g., tritium). 14 Contains one or more isotopes of C.

[0389] Pharmaceutically acceptable forms of modified NSAIDs can include isotopically labeled derivatives of the modified NSAIDs. Isotopically labeled derivatives are compounds that are identical to the modified NSAIDs except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, the isotopically labeled derivatives of the modified NSAIDs contain one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, the isotopically labeled derivatives of the modified NSAIDs contain one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine, respectively. 2 H, 3 H, 13 C. 14 C. 18 O. 17 O. 31 P, 32 P, 35 S, and 18 In some embodiments, the isotopically labeled derivative of the modified NSAID comprises one or more isotopes of F. 2 In some embodiments, the isotope-labeled derivative of the modified NSAID comprises one or more isotopes of H (e.g., deuterium). 3 In some embodiments, the isotope-labeled derivative of the modified NSAID comprises one or more isotopes of H (e.g., tritium). 14 Contains one or more isotopes of C.

[0390] Derivatives and Prodrugs Pharmaceutically acceptable forms of PS can include derivatives of PS-I. Pharmaceutically acceptable forms of PS can include derivatives of PS-II. In some embodiments, a derivative of PS (e.g., PS-I or PS-II) is a metabolite. In other embodiments, a pharmaceutically acceptable form of PS is a prodrug of PS (e.g., a prodrug of PS-I or a prodrug of PS-II).

[0391] The sulfone group can be structurally represented as RS(=O)2-R'. In some embodiments, the derivative of PS is the sulfone form of PS.

[0392] PS contains an organophosphate functional group, which can be structurally represented as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR''). For example, O=P(OR)2(OR') can represent PS when R=CH2CH3 and R'= the remainder of the molecule conforms to PS in Formula I or II (e.g., PS-I, PS-II, or a derivative thereof).

[0393] In some embodiments, the derivative of PS is PS in which one of the ethoxy (e.g., -OCH2CH3) groups is an OH group, or a pharmaceutically acceptable salt thereof. In some embodiments, the derivative of PS is PS in which both of the ethoxy (e.g., -OCH2CH3) groups are OH groups, or a pharmaceutically acceptable salt thereof.

[0394] The activities of PS demonstrated herein may also be shared by pharmaceutically acceptable forms thereof. Accordingly, the present invention provides pharmaceutically acceptable forms of PS for use in the methods of the present invention.

[0395] Pharmaceutically acceptable forms of the modified NSAID can include derivatives of the modified NSAID. In some embodiments, the derivatives of the modified NSAID are metabolites. In other embodiments, the pharmaceutically acceptable forms of the modified NSAID are prodrugs of the modified NSAID.

[0396] The activity of the modified NSAIDs will also be shared by their pharmaceutically acceptable forms. Accordingly, the present invention provides pharmaceutically acceptable forms of modified NSAIDs for use in the methods of the present invention.

[0397] While preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the present invention.

[0398] Numbered Embodiments The present invention further provides the following numbered embodiments:

[0399] 1. A method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the pain associated with central sensitization is treated.

[0400] 2. The method of embodiment 1, wherein said treating pain comprises reducing said pain.

[0401] 3. The method of any one of the preceding embodiments, wherein said treating pain comprises reducing one or more symptoms associated with central sensitization.

[0402] 4. The method of embodiment 3, wherein the one or more symptoms are selected from mood swings, fatigue, cognitive impairment, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia, and / or phonophobia.

[0403] 5. The method of any one of the preceding embodiments, wherein said PS reduces neuronal signaling involved in pain sensation.

[0404] 6. The method of any one of the preceding embodiments, wherein said PS reduces centrally generated pain signaling.

[0405] 7. The method of any one of the preceding embodiments, wherein said PS reduces pain signaling originating in the dorsal horn of the spinal cord.

[0406] 8. The method of any one of the preceding embodiments, wherein said PS reduces pain signaling occurring in the CNS.

[0407] 9. The method of any one of the preceding embodiments, wherein said pain is allodynia.

[0408] 10. The method of embodiment 9, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0409] 11. The method of any one of the preceding embodiments, wherein said pain is hyperalgesia.

[0410] 12. A method for treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the neuropathic pain associated with PTPN is treated and / or prevented.

[0411] 13. The method of embodiment 12, wherein said treating neuropathic pain comprises reducing said neuropathic pain.

[0412] 14. The method of embodiment 12 or 13, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

[0413] 15. The method of any one of embodiments 12-14, wherein treating said neuropathic pain comprises reducing one or more of the sensory symptoms associated with PTPN.

[0414] 16. The method of any one of embodiments 12-15, wherein preventing said neuropathic pain comprises reducing the incidence of one or more of the sensory symptoms associated with said PTPN.

[0415] 17. The method of embodiment 15 or 16, wherein the one or more sensory symptoms are selected from paresthesia, burning sensation, and tingling sensation.

[0416] 18. The method of embodiment 17, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or crawling.

[0417] 19. The method of any one of embodiments 12-18, wherein said PS reduces neuronal signaling involved in pain sensation.

[0418] 20. The method of any one of embodiments 12-19, wherein the PS reduces pain that occurs via peripheral sensitization.

[0419] 21. The method of any one of embodiments 12 to 20, wherein the PS reduces pain that occurs via central sensitization.

[0420] 22. The method of any one of embodiments 12-21, wherein said PS reduces centrally generated pain signaling.

[0421] 23. The method of any one of embodiments 12-22, wherein said PS reduces pain signaling originating in peripheral nerves.

[0422] 24. The method of any one of embodiments 12-23, wherein said PS reduces pain signaling originating in the dorsal root ganglion.

[0423] 25. The method of any one of embodiments 12-24, wherein said PS reduces pain signaling originating in the dorsal horn of the spinal cord.

[0424] 26. The method of any one of embodiments 12-25, wherein said neuropathic pain is allodynia.

[0425] 27. The method of embodiment 26, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0426] 28. The method of any one of embodiments 12-27, wherein the neuropathic pain is hyperalgesia.

[0427] 29. The method of any one of embodiments 12 to 28, wherein the neuropathic pain associated with PTPN is caused by transient nerve conduction disorders, such as nerve compression injury.

[0428] 30. The method of any one of embodiments 12-29, wherein the PTPN-associated neuropathic pain is caused by axonal transection, such as a nerve crush injury.

[0429] 31. The method of any one of embodiments 12-30, wherein the neuropathic pain associated with PTPN is caused by one or more of the following: carpal tunnel syndrome, pronator teres syndrome, radial tunnel syndrome, suprascapular nerve entrapment, thoracic outlet syndrome, ulnar nerve entrapment (cubital tunnel syndrome or Guyon canal syndrome), dysesthesias of femoral neuralgia, peroneal nerve compression, pudendal nerve entrapment syndrome, sciatica, tarsal tunnel syndrome, cervical disc herniation, thoracic disc herniation, and / or lumbar disc herniation.

[0430] 32. A method for treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the migraine pain is treated and / or prevented.

[0431] 33. The method of embodiment 32, wherein treating said pain comprises reducing said pain, e.g., throbbing headache.

[0432] 34. The method of embodiment 32 or 33, wherein preventing said pain comprises reducing the incidence of said pain, e.g., throbbing headache.

[0433] 35. The method of any one of embodiments 32-34, wherein treating pain comprises reducing one or more symptoms associated with migraine.

[0434] 36. The method of any one of embodiments 32-35, wherein preventing said pain comprises reducing the incidence of one or more symptoms associated with said migraine.

[0435] 37. The method of embodiment 35 or 36, wherein the one or more symptoms are selected from aura, nausea, vomiting, photophobia, phonophobia, and / or cranial autonomic symptoms.

[0436] 38. The method of embodiment 37, wherein the aura comprises one or more sensory disturbances, such as visual symptoms, tingling, and / or numbness.

[0437] 39. The head autonomic symptoms, bloodshot eyes or tearing, according to embodiment 37 or 38.

[0438] 40. The method of any one of embodiments 32-39, wherein the subject experiences cutaneous allodynia.

[0439] 41. The method of any one of embodiments 32-40, wherein said PS reduces neuronal signaling involved in pain sensation.

[0440] 42. The method of any one of embodiments 32-41, wherein the PS reduces pain that occurs via peripheral sensitization.

[0441] 43. The method of any one of embodiments 32-42, wherein the PS reduces pain that occurs via central sensitization.

[0442] 44. The method of any one of embodiments 32-43, wherein the PS reduces centrally generated pain signaling.

[0443] 45. The method of any one of embodiments 32-44, wherein the PS reduces pain signaling originating in the trigeminal nerve.

[0444] 46. ​​The method of any one of embodiments 32-45, wherein the PS reduces pain signaling originating in the trigeminal ganglion.

[0445] 47. The method of any one of embodiments 32-46, wherein the PS reduces pain signaling originating in the trigeminal nucleus caudalis.

[0446] 48. The method of any one of embodiments 32-47, wherein said PS reduces pain signaling occurring in higher neurons and / or pain-sensing areas of the brain, such as trigeminothalamic neurons.

[0447] 49. The method of any one of embodiments 32-48, wherein the pain is allodynia, such as cutaneous allodynia.

[0448] 50. The method of embodiment 49, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0449] 51. The method of any one of embodiments 32-50, wherein the pain is hyperalgesia.

[0450] 52. The method of any one of embodiments 32-51, wherein the migraine is episodic migraine or chronic migraine.

[0451] 53. The method of any one of embodiments 32-52, wherein the migraine is migraine with aura or migraine without aura.

[0452] 54. A method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the neuropathic pain associated with said PHN is treated and / or prevented.

[0453] 55. The method of embodiment 54, wherein treating said neuropathic pain comprises reducing said neuropathic pain.

[0454] 56. The method of embodiment 54 or 55, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

[0455] 57. The method of any one of embodiments 54-56, wherein treating said neuropathic pain comprises reducing one or more of the sensory symptoms associated with PHN.

[0456] 58. The method of any one of embodiments 54-57, wherein preventing said neuropathic pain comprises reducing the incidence of one or more of the sensory symptoms associated with said PHN.

[0457] 59. The method of any one of embodiments 54-58, wherein the neuropathic pain is a sharp, burning, throbbing, or stabbing sensation.

[0458] 60. The method of any one of embodiments 57-59, wherein the one or more sensory symptoms are selected from itching or numbness.

[0459] 61. The method of any one of embodiments 54-60, wherein the PS reduces neuronal signaling involved in pain sensation.

[0460] 62. The method of any one of embodiments 54-61, wherein the PS reduces pain that occurs via peripheral sensitization.

[0461] 63. The method of any one of embodiments 54-62, wherein the PS reduces pain that occurs via central sensitization.

[0462] 64. The method of any one of embodiments 54-63, wherein the PS reduces centrally generated pain signaling.

[0463] 65. The method of any one of embodiments 54-64, wherein the PS reduces pain signaling occurring in peripheral nerves, such as nerves that innervate one or more dermatomes.

[0464] 66. The method of any one of embodiments 54-65, wherein the PS reduces pain signaling occurring in one or more spinal nerves, such as one or more cervical nerves, one or more thoracic nerves, one or more lumbar nerves, and / or one or more sacral nerves.

[0465] 67. The method of any one of embodiments 54-66, wherein the PS reduces pain signaling originating in the dorsal root ganglion.

[0466] 68. The method of any one of embodiments 54-67, wherein said PS reduces pain signaling originating in the dorsal horn of the spinal cord.

[0467] 69. The method of any one of embodiments 54-68, wherein the neuropathic pain is allodynia.

[0468] 70. The method of embodiment 69, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0469] 71. The method of any one of embodiments 54-70, wherein the neuropathic pain is hyperalgesia.

[0470] 72. The method of any one of the preceding embodiments, wherein the subject is a human.

[0471] 73. The PS has formula I (PS-I): [ka] 10. The method of any one of the preceding embodiments, comprising:

[0472] 74. The PS has formula II (PS-II): [ka] 10. The method of any one of the preceding embodiments, comprising:

[0473] 75. The method of any one of the preceding embodiments, wherein the therapeutically effective amount of PS is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0474] 76. The method of embodiment 75, wherein the pharmaceutical composition comprising the PS is formulated for topical administration.

[0475] 77. The method of embodiment 76, wherein the pharmaceutical composition comprising the PS is formulated as a semi-solid.

[0476] 78. The method of embodiment 76, wherein the pharmaceutical composition comprising the PS is formulated as a liquid.

[0477] 79. The method of any one of embodiments 76 to 78, wherein the pharmaceutical composition comprising PS is a cream.

[0478] 80. The method of any one of embodiments 76 to 78, wherein the pharmaceutical composition comprising the PS is a gel, for example, the gel is a hydrogel.

[0479] 81. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a lotion.

[0480] 82. The method according to any one of embodiments 76 to 78, wherein the pharmaceutical composition comprising the PS is an ointment.

[0481] 83. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a spray.

[0482] 84. The method according to embodiment 76, wherein the pharmaceutical composition comprising the PS is formulated as a patch.

[0483] 85. The method of any one of embodiments 75-84, wherein the pharmaceutical composition comprises the PS at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

[0484] 86. The method of embodiment 85, wherein the pharmaceutical composition comprises the PS at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0485] 87. The method of embodiment 86, wherein the pharmaceutical composition comprises the PS at a concentration of 8% (w / w) or less of the pharmaceutical composition, such as about 5% or about 3% (w / w) of the pharmaceutical composition.

[0486] 88. The method of embodiment 86, wherein the pharmaceutical composition comprises the PS at a concentration of about 3% (w / w) or less of the pharmaceutical composition, such as about 2% or about 1% (w / w) of the pharmaceutical composition.

[0487] 89. The PS has a viscosity of about 0.005 g / 10 cm 2 ~About 0.25g / 10cm 2 The method of any of embodiments 75-88, wherein the administration is at the affected site.

[0488] 90. The PS has a viscosity of about 0.005 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0489] 91. The PS has a viscosity of about 0.01 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0490] 92. The PS has a viscosity of about 0.05 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0491] 93. The PS has a viscosity of about 0.1 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0492] 94. The PS is about 0.15 g / 10 cm 290. The method of embodiment 89, wherein the administration is at the affected site.

[0493] 95. The PS is about 0.2 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0494] 96. The PS is about 0.25 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0495] 97. The method of any one of embodiments 75-96, wherein the PS is applied to the affected area and left on the affected area for about 1 hour to about 5 hours.

[0496] 98. The method of embodiment 97, wherein the PS is applied to the affected area and left on the affected area for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0497] 99. The method of embodiment 97 or 98, wherein the PS is removed from the affected area after the administration period, for example by washing it off.

[0498] 100. The method of embodiment 97 or 98, wherein after the administration period, a second or subsequent application of the PS is applied to the affected area.

[0499] 101. The method of any one of embodiments 75-100, wherein the PS is applied once a day.

[0500] 102. The method of any one of embodiments 75-100, wherein the PS is applied twice a day.

[0501] 103. The method of any one of embodiments 75 to 100, wherein the PS is applied three times a day.

[0502] 104. The method of any one of embodiments 75 to 100, wherein the PS is applied four times a day.

[0503] 105. The method of any one of embodiments 75 to 104, wherein the PS is administered in a pharmaceutical composition.

[0504] 106. A method for treating corneal neuropathic pain, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the corneal neuropathic pain is treated.

[0505] 107. The method of embodiment 106, wherein treating the corneal neuropathic pain comprises reducing the corneal neuropathic pain.

[0506] 108. The method of embodiment 106 or 107, wherein treating the corneal neuropathic pain comprises reducing one or more symptoms associated with the corneal neuropathic pain.

[0507] 109. The method of embodiment 108, wherein the one or more symptoms are selected from paresthesia, photosensitivity, photoallodynia, anxiety, depression, or apathy.

[0508] 110. The method of embodiment 109, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or crawling.

[0509] 111. The method of any one of embodiments 106-110, wherein the PS reduces pain that occurs via central sensitization.

[0510] 112. The method of any one of embodiments 106-111, wherein said PS reduces centrally generated pain signaling.

[0511] 113. The method of any one of embodiments 106-112, wherein the PS reduces pain signaling originating in the trigeminal ganglion.

[0512] 114. The method of any one of embodiments 106-113, wherein the PS reduces pain signaling originating in the trigeminal nucleus caudalis.

[0513] 115. The method of any one of embodiments 106-114, wherein said PS reduces pain signaling occurring in higher neurons and / or pain-sensing areas of the brain, such as trigeminothalamic neurons.

[0514] 116. The method of any one of embodiments 106-115, wherein the corneal neuropathic pain is allodynia.

[0515] 117. The method of embodiment 116, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0516] 118. The method of any one of embodiments 106-117, wherein the corneal neuropathic pain is hyperalgesia.

[0517] 119. The method of any one of embodiments 106-118, wherein the subject is a human.

[0518] 120. The method of any one of embodiments 106-119, wherein the PS has formula I (PS-I).

[0519] 121. The method of any one of embodiments 106-120, wherein the PS has formula II (PS-II).

[0520] 122. The method of any one of embodiments 106 to 121, wherein the PS is administered to the ocular surface.

[0521] 123. The method of any one of embodiments 106 to 122, wherein the PS is administered to the outer surface of one or more eyelids, for example, the one or more eyelids are one or both upper eyelids and / or one or both lower eyelids.

[0522] 124. The method of any one of embodiments 106-123, wherein the therapeutically effective amount of PS is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0523] 125. The method of embodiment 124, wherein the pharmaceutical composition comprising the PS is formulated for topical administration.

[0524] 126. The method of embodiment 125, wherein the topical administration is to the ocular surface.

[0525] 127. The method of embodiment 125, wherein the topical administration is to the outer surface of one or more eyelids, for example, the one or more eyelids are one or both upper eyelids and / or one or both lower eyelids.

[0526] 128. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising the PS is formulated as a semi-solid.

[0527] 129. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising the PS is formulated as a liquid.

[0528] 130. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising PS is a cream.

[0529] 131. The method of any one of embodiments 125 to 127, wherein the pharmaceutical composition comprising PS is a gel, for example, the gel is a hydrogel.

[0530] 132. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising PS is a lotion.

[0531] 133. The method according to embodiments 125 to 127, wherein the pharmaceutical composition comprising PS is an ointment.

[0532] 134. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising the PS is formulated as eye drops.

[0533] 135. The method of embodiment 134, wherein the eye drop composition is an eye drop solution or eye drop emulsion for dropwise administration to the eye.

[0534] 136. The method of embodiment 134 or 135, wherein the drop volume is about 10 to about 100 μL.

[0535] 137. The method of any one of embodiments 124-136, wherein the pharmaceutical composition comprises the PS at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

[0536] 138. The method of embodiment 137, wherein the pharmaceutical composition comprises the PS at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0537] 139. The method of embodiment 138, wherein the pharmaceutical composition comprises the PS at a concentration of 8% (w / w) or less of the pharmaceutical composition, such as about 5% or about 3% (w / w) of the pharmaceutical composition.

[0538] 140. The method of embodiment 139, wherein the pharmaceutical composition comprises the PS at a concentration of about 3% (w / w) or less of the pharmaceutical composition, such as about 2% or about 1% (w / w) of the pharmaceutical composition.

[0539] 141. The PS is about 0.005 mg / cm 2 ~about 0.25mg / cm 2 The method of any of embodiments 124-140, wherein the administration is on the ocular surface.

[0540] 142. The PS is about 0.005 mg / cm 2 , 0.01 mg / cm 2 , 0.05 mg / cm 2 , 0.1 mg / cm 2 , 0.15 mg / cm 2 , 0.2 mg / cm 2 , or 0.25 mg / cm 2The method of embodiment 141, wherein the administration is ocular surface.

[0541] 143. The PS is about 0.5 mg / cm 2 ~about 100mg / cm 2 The method of any of embodiments 124-140, wherein the administration is on the outer surface of the eyelid.

[0542] 144. The PS is about 0.5 mg / cm 2 , 5 mg / cm 2 , 10 mg / cm 2 , 25 mg / cm 2 , 50 mg / cm 2 , 75 mg / cm 2 or 100 mg / cm 2 The method of embodiment 143, wherein the administration is on the outer surface of the eyelid.

[0543] 145. The method of any one of embodiments 124-144, wherein the PS is applied to the ocular surface and / or the outer surface of the eyelid and left on the ocular surface and / or the outer surface of the eyelid for about 1 hour to about 5 hours.

[0544] 146. The method of embodiment 145, wherein the PS is applied to the ocular surface and / or the outer surface of the eyelid and left on the ocular surface and / or the outer surface of the eyelid for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0545] 147. The method of embodiment 145 or 146, wherein the PS is removed from the outer surface of the eyelid after the administration period, for example by washing it off.

[0546] 148. The method of any one of embodiments 145-147, wherein after an administration period, a second or subsequent application of the PS is applied to the ocular surface and / or the outer surface of the eyelid.

[0547] 149. The method of any one of embodiments 124-148, wherein the PS is applied once a day.

[0548] 150. The method of any one of embodiments 124-148, wherein the PS is applied twice a day.

[0549] 151. The method of any one of embodiments 124-148, wherein the PS is applied three times a day.

[0550] 152. The method of any one of embodiments 124-148, wherein the PS is applied four times a day.

[0551] 153. The method according to any one of embodiments 141-152, wherein the PS is administered to the ocular surface and / or the outer surface of the eyelid in a pharmaceutical composition.

[0552] 154. A method for treating and / or preventing an ocular disease or ocular condition, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the ocular disease or ocular condition is treated and / or prevented, wherein the PS is administered topically to the outer surface of one or more eyelids.

[0553] 155. The method of embodiment 154, wherein the one or more eyelids are one or both upper eyelids.

[0554] 156. The method of embodiment 154, wherein the one or more eyelids are one or both lower eyelids.

[0555] 157. The method of any one of embodiments 154-156, wherein the eye disease or eye condition is an inflammatory eye disease or eye condition.

[0556] 158. The method of any one of embodiments 154-157, wherein the eye disease or eye condition is dry eye disease (DED).

[0557] 159. The method of any one of embodiments 154-158, wherein the eye disease or eye condition is corneal pain, such as corneal neuropathic pain.

[0558] 160. A method for treating and / or preventing pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that said pain is treated and / or prevented.

[0559] 161. PS for use in the treatment of pain associated with central sensitization.

[0560] 162. PS for use in the treatment and / or prevention of pain due to migraine in a subject.

[0561] 163. PS for use in the treatment and / or prevention of neuropathic pain associated with PTPN.

[0562] 164. PS for use in the treatment and / or prevention of neuropathic pain associated with PHN.

[0563] 165. PS for use in the treatment of corneal neuropathic pain.

[0564] 166. A PS for use in the treatment and / or prevention of an ocular disease or condition, wherein the PS is administered topically to the outer surface of one or more eyelids.

[0565] 167. PS for use in the treatment and / or prevention of pain.

[0566] 168. Use of PS for the manufacture of a medicament for treating pain associated with central sensitization.

[0567] 169. Use of PS for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PTPN.

[0568] 170. Use of PS for the manufacture of a medicament for treating and / or preventing migraine pain in a subject.

[0569] 171. Use of PS for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PHN.

[0570] 172. Use of PS for the manufacture of a medicament for treating corneal neuropathic pain.

[0571] 173. Use of PS for the manufacture of a medicament for treating and / or preventing an ocular disease or condition, wherein the PS is administered topically to the outer surface of one or more eyelids.

[0572] 174. Use of PS for the manufacture of a medicament for treating and / or preventing pain.

[0573] 175. The method of any one of embodiments 1-75, 106-121, and 154-160, wherein the PS is administered orally.

[0574] 176. PS for use according to any one of embodiments 161 to 167, wherein the PS is administered orally.

[0575] 177. The use according to any one of embodiments 168 to 174, wherein the PS is administered orally.

[0576] 178. A method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the neuropathic pain associated with CIPN is treated and / or prevented, wherein the PS is administered orally.

[0577] 179. A method for treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the neuropathic pain associated with DPN is treated and / or prevented, wherein the PS is administered orally.

[0578] 180. The method, the PS for use, or the use according to any one of embodiments 175-179, wherein the PS is formulated as a liquid dosage form or a solid dosage form.

[0579] 181. The method, PS for use, or use according to embodiment 180, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup or elixir.

[0580] 182. The method, PS for use, or use according to embodiment 180, wherein the solid dosage form is a capsule, tablet, pill, powder, or granule.

[0581] 183. The method, the PS for use, or the use according to any one of embodiments 175 to 182, wherein the PS is orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight, for example, about 1 mg / kg to about 5 mg / kg, for example, about 3 mg / kg of the subject's body weight.

[0582] 184. The method, the PS for use, or the use according to any one of embodiments 175 to 183, wherein the PS is orally administered at a dosage of about 1 mg to about 2000 mg, about 100 mg to 1500 mg, about 200 mg to about 100 mg, about 50 mg to about 400 mg, for example, about 100 mg to about 350 mg, for example, about 150 mg to about 300 mg, for example, about 150 mg to about 250 mg.

[0583] 185. The method, the PS for use, or the use according to any one of embodiments 175 to 184, wherein the PS is orally administered in a dosage of about 250 mg to about 300 mg, preferably about 250 mg.

[0584] 186. The method, the PS for use, or the use according to any one of embodiments 175-185, wherein the PS is administered orally once a day.

[0585] 187. The method, the PS for use, or the use according to any one of embodiments 175-186, wherein the PS is administered orally at least twice a day, at least three times a day, or at least four times a day.

[0586] 188. The method, the PS for use, or the use according to any one of embodiments 175-187, wherein the PS is administered orally two or three times a day.

[0587] 189. The method, the PS for use, or the use according to any one of embodiments 175-188, wherein the PS is administered orally twice a day at a dosage of about 150 mg to about 200 mg.

[0588] 190. The method, the PS for use, or the use according to any one of embodiments 175-189, wherein the PS is administered orally in a daily dosage of about 300 mg to about 400 mg.

[0589] 191. The method, the PS for use, or the use according to any one of embodiments 175 to 190, wherein the PS is administered orally two or three times a day at a daily dosage of about 250 mg to about 300 mg (e.g., about 250 mg).

[0590] 192. The method, the PS for use, or the use according to any one of embodiments 175-191, wherein the PS is administered orally in a daily dosage of about 500 mg to a maximum of about 900 mg per day.

[0591] 193. The method of any one of claims 175-192, wherein the PS is administered orally in a pharmaceutical composition.

[0592] 194. A method for treating and / or preventing neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN), comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with CIPN is treated and / or prevented, wherein the modified NSAID is not PS.

[0593] 195. A method for treating and / or preventing neuropathic pain associated with diabetic peripheral neuropathy (DPN), comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented, wherein the modified NSAID is not PS.

[0594] 196. The method of embodiment 194 or 195, wherein treating said neuropathic pain comprises reducing said neuropathic pain.

[0595] 197. The method of any one of embodiments 194-196, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

[0596] 198. The method of any one of embodiments 194-197, wherein treating the neuropathic pain comprises reducing one or more of the sensory symptoms associated with CIPN or DPN.

[0597] 199. The method of any one of embodiments 194-198, wherein preventing said neuropathic pain comprises reducing the incidence of one or more of the sensory symptoms associated with said CIPN or DPN.

[0598] 200. The method of embodiment 198 or 199, wherein the one or more sensory symptoms are selected from paresthesia, a burning sensation, and an electric shock sensation.

[0599] 201. The method of embodiment 200, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or crawling.

[0600] 202. The method of any one of embodiments 194-201, wherein the modified NSAID reduces nerve cell signaling involved in pain sensation.

[0601] 203. The method of any one of embodiments 194-202, wherein the modified NSAID reduces pain that occurs via peripheral sensitization.

[0602] 204. The method of any one of embodiments 194-203, wherein the modified NSAID reduces pain that occurs via central sensitization.

[0603] 205. The method of any one of embodiments 194-204, wherein the modified NSAID reduces centrally generated pain signaling.

[0604] 206. The method of any one of embodiments 194-205, wherein the modified NSAID reduces pain signaling occurring in the sciatic nerve.

[0605] 207. The method of any one of embodiments 194-206, wherein the modified NSAID reduces pain signaling originating in the dorsal root ganglion.

[0606] 208. The method of any one of embodiments 194-207, wherein the neuropathic pain is allodynia.

[0607] 209. The method of embodiment 208, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0608] 210. The method of any one of embodiments 194-209, wherein the neuropathic pain is hyperalgesia.

[0609] 211. The method of any one of embodiments 194 or 196-210, wherein the subject has cancer and is receiving or has previously been treated with one or more chemotherapeutic compounds.

[0610] 212. The method of embodiment 211, wherein said one or more chemotherapeutic compounds are selected from one or more of platinum-based drugs, taxanes, immunomodulators, epothilones, vinca alkaloids, and proteasome inhibitors.

[0611] 213. The method of embodiment 212, wherein said one or more chemotherapeutic compounds are selected from one or more of oxaliplatin, cisplatin, carboplatin, taxanes, paclitaxel, docetaxel, cabazitaxel, thalidomide and its analogs, vincristine, vinblastine, vinorelbine, vindesine, and bortezomib.

[0612] 214. The method of any one of embodiments 211-213, wherein the chemotherapeutic compound is a taxane, such as paclitaxel.

[0613] 215. The method of any one of embodiments 211-213, wherein the chemotherapeutic compound is a vinca alkaloid, such as vincristine.

[0614] 216. The method of any one of embodiments 211-213, wherein the chemotherapeutic compound is a platinum-based antitumor drug, such as oxaliplatin.

[0615] 217. The method of any one of embodiments 211-216, wherein the subject has a solid tumor cancer.

[0616] 218. The method of any one of embodiments 211-217, wherein the subject has ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, and / or pancreatic cancer.

[0617] 219. The method of any one of embodiments 194-218, wherein the subject is a human.

[0618] 220. A method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the pain associated with central sensitization is treated.

[0619] 221. A method for treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with PTPN is treated and / or prevented.

[0620] 222. A method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with said PHN is treated and / or prevented.

[0621] 223. A method for treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the migraine pain is treated and / or prevented.

[0622] 224. A method for treating and / or preventing corneal neuropathic pain, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the corneal neuropathic pain is treated and / or prevented.

[0623] 225. The method of any one of embodiments 194-224, wherein the modified NSAID is selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs, phosphoroamide-modified NSAIDs, selenium-modified NSAIDs, metal complex-NSAIDs, H2S-releasing NSAIDs, NO-releasing NSAIDs, and NOSH-releasing NSAIDs.

[0624] 226. The method of any one of embodiments 194-225, wherein the modified NSAID is a modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indomethacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib, or modified celecoxib.

[0625] 227. The modified NSAID may be, for example, a compound of formula X: [ka] 227. The method of embodiment 225 or 226, wherein the compound is a phosphosulindacamide having the formula:

[0626] 228. The modified NSAID may be, for example, a compound of formula XIII: [ka] The method of embodiment 225 or 226, wherein the compound is Se-sulindac,

[0627] 229. The modified NSAID may be, for example, a compound of formula XXXIV: [ka] The method of embodiment 225 or 226, wherein the HS-sulindac has the formula:

[0628] 230. The modified NSAID is, for example, a compound of formula XLIV or XLV: [ka] and NO-sulindac, having the formula: wherein R is of formula XLVI or XLVII: [ka] 227. The method of embodiment 225 or 226, wherein

[0629] 231. The modified NSAID may be, for example, a compound of formula LVII: [ka] The method of embodiment 225 or 226, wherein the NOSH-sulindac has the formula:

[0630] 232. The modified NSAID may be, for example, a compound of formula III: [ka] The method of embodiment 225 or 226, wherein the ibuprofen is phosphoibuprofen having the formula:

[0631] 233. The modified NSAID is, for example, a compound of formula V, VI, or VII: [ka] 227. The method of embodiment 225 or 226, wherein the compound is phosphoaspirin, having the formula:

[0632] 234. The modified NSAID may be, for example, a compound of formula IX: [ka] The method of embodiment 225 or 226, wherein the compound is phosphoflurbiprofen having the formula:

[0633] 235. The modified NSAID may be, for example, a compound of formula VIII: [ka] The method of embodiment 225 or 226, wherein the compound is phosphonaproxen having the formula:

[0634] 236. The modified NSAID may be, for example, a compound of formula XI: [ka] The method of embodiment 225 or 226, wherein the ibuprofenamide is phosphoibuprofenamide having the formula:

[0635] 237. The method of any one of embodiments 194-236, wherein the therapeutically effective amount of the modified NSAID is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0636] 238. The method of any one of embodiments 194-227, wherein the pharmaceutical composition comprising the modified NSAID is formulated for topical administration.

[0637] 239. The method of embodiment 238, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a semisolid.

[0638] 240. The method of embodiment 238, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a liquid.

[0639] 241. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a cream.

[0640] 242. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a gel, for example, the gel is a hydrogel.

[0641] 243. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a lotion.

[0642] 244. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is an ointment.

[0643] 245. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a spray.

[0644] 246. The method of embodiment 238, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a patch.

[0645] 247. The method of any one of embodiments 237-246, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

[0646] 248. The method of embodiment 247, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0647] 249. The method of embodiment 248, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of 8% (w / w) or less of the pharmaceutical composition, such as about 5% or about 3% (w / w) of the pharmaceutical composition.

[0648] 250. The method of embodiment 249, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of about 3% (w / w) or less of the pharmaceutical composition, such as about 2% or about 1% (w / w) of the pharmaceutical composition.

[0649] 251. The method of any one of embodiments 237-250, wherein the modified NSAID is administered at about 0.005 g / 10 cm2 to about 0.25 g / 10 cm2 of the affected area.

[0650] 252. The method of embodiment 251, wherein the modified NSAID is administered at about 0.005 g / 10 cm2 of the affected area.

[0651] 253. The method of embodiment 251, wherein the modified NSAID is administered at about 0.01 g / 10 cm2 of the affected area.

[0652] 254. The method of embodiment 251, wherein the modified NSAID is administered at about 0.05 g / 10 cm2 of the affected area.

[0653] 255. The method of embodiment 251, wherein the modified NSAID is administered at about 0.1 g / 10 cm2 of the affected area.

[0654] 256. The method of embodiment 251, wherein the modified NSAID is administered at about 0.15 g / 10 cm2 of the affected area.

[0655] 257. The method of embodiment 251, wherein the modified NSAID is administered at about 0.2 g / 10 cm2 of the affected area.

[0656] 258. The method of embodiment 251, wherein the modified NSAID is administered at about 0.25 g / 10 cm2 of the affected area.

[0657] 259. The method of any one of embodiments 237-258, wherein the modified NSAID is applied to the affected area and left on the affected area for about 1 hour to about 5 hours.

[0658] 260. The method of embodiment 259, wherein the modified NSAID is applied to the affected area and left on the affected area for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0659] 261. The method of embodiment 259 or 260, wherein the modified NSAID is removed from the affected area after the administration period, for example by washing it off.

[0660] 262. The method of embodiment 259 or 260, wherein after the administration period, a second or subsequent application of the modified NSAID is applied to the affected area.

[0661] 263. The method of any one of embodiments 237-262, wherein the modified NSAID is applied once a day.

[0662] 264. The method of any one of embodiments 237-262, wherein the modified NSAID is applied twice a day.

[0663] 265. The method of any one of embodiments 237-262, wherein the modified NSAID is applied three times a day.

[0664] 266. The method of any one of embodiments 237-262, wherein the modified NSAID is applied four times a day.

[0665] 267. The method of any one of embodiments 251-266, wherein the modified NSAID is administered in a pharmaceutical composition.

[0666] 268. The method of any one of claims 237-250 and 267, wherein the pharmaceutical composition comprises two or more of the modified NSAIDs.

[0667] 269. The method of any one of embodiments 194-268, wherein said method comprises administering, e.g., topically, said two or more modified NSAIDs to said subject.

[0668] 270. The method of embodiment 269, wherein the two or more modified NSAIDs are administered simultaneously or sequentially.

[0669] 271. A modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with CIPN, wherein said modified NSAID is not a PS.

[0670] 272. Use of a modified NSAID for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with CIPN, wherein the modified NSAID is not PS.

[0671] 273. A modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with DPN, wherein said modified NSAID is not PS.

[0672] 274. Use of a modified NSAID for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with DPN, wherein the modified NSAID is not PS.

[0673] 275. The method of any one of embodiments 194-274, wherein the modified NSAID is selected from phospho-naproxen, such as that of formula VIII; phospho-ibuprofen, such as that of formula III; phospho-glycerol ibuprofen, such as that of formula LXXI; glycerol-phospho-aspirin II, such as that of formula V; phosphosulindac amide, such as that of formula X; phospho-ibuprofen amide, such as that of formula XI; phospho-glycerol-ibuprofen-amide, such as that of formula XII; NO-sulindac, such as that of formula XLIV; platinum sulindac, such as that of formula LXVII; NO-aspirin, such as that of formula XLIX; HS-sulindac, such as that of formula XXXIV; or NOSH-aspirin, such as that of formula LIX.

[0674] 276. The method of any one of embodiments 194-275, wherein the modified NSAID is a modified sulindac, such as an NO-releasing sulindac (e.g., NO-sulindac, such as that of Formula XLIV), an HS-releasing sulindac (e.g., HS-sulindac, such as that of Formula XXXIV), a phosphoramido-modified sulindac (e.g., a phosphosulindac amide, such as that of Formula X), or a metal-chelated sulindac (e.g., a platinum sulindac, such as that of Formula LXVII).

[0675] 277. The method of embodiment 276, wherein the modified sulindac is an NO-releasing sulindac (e.g., NO-sulindac, such as of Formula XLIV), an H2S-releasing sulindac (e.g., HS-sulindac, such as of Formula XXXIV), or preferably a phosphoramido-modified sulindac (e.g., phosphosulindacamide, such as of Formula X).

[0676] 278. The method of any one of embodiments 194-275, wherein the modified NSAID is a phospho-NSAID, for example, phospho-naproxen, such as that of formula VIII; phospho-ibuprofen, such as that of formula III; phospho-glycerol ibuprofen, such as that of formula LXXI; or glycerol-phospho-aspirin II, such as that of formula V.

[0677] 279. The method of any one of embodiments 194-275, wherein the modified NSAID is a phosphoroamide NSAID, for example, phospho-glycerol ibuprofen amide, such as of formula XII; phospho-ibuprofen-amide, such as of formula XI; or phosphosulindacamide, such as of formula X.

[0678] 280. The method of any one of embodiments 194-275, wherein the modified NSAID is a modified ibuprofen, for example, phospho-ibuprofen, such as that of formula III; phospho-glycerol-ibuprofen, such as that of formula LXXI; or phospho-ibuprofen-amide, such as that of formula XI.

[0679] 281. The method of any one of embodiments 194-237, 268-270, and 275-280, wherein the modified NSAID is administered orally.

[0680] 282. The modified NSAID for use according to embodiment 271 or 273, wherein said modified NSAID is administered orally.

[0681] 283. The use according to any one of embodiments 272 or 274, wherein the modified NSAID is administered orally.

[0682] 284. The method, the modified NSAID for use, or the use according to any one of embodiments 281-283, wherein the modified NSAID is formulated as a liquid dosage form or a solid dosage form.

[0683] 285. The method, the modified NSAID for use, or the use according to embodiment 284, wherein said liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup or elixir.

[0684] 286. The method, the modified NSAID for use, or the use according to embodiment 284, wherein said solid dosage form is a capsule, a tablet, a pill, a powder, or a granule.

[0685] 287. The method, the modified NSAID for use, or the use according to any one of embodiments 281 to 286, wherein the modified NSAID is orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight, for example, about 1 mg / kg to about 5 mg / kg, for example, about 3 mg / kg of the subject's body weight.

[0686] 288. The method, the modified NSAID for use, or the use according to any one of embodiments 281 to 287, wherein the modified NSAID is orally administered at a dosage of about 1 mg to about 2000 mg, about 100 mg to 1500 mg, about 200 mg to about 100 mg, about 50 mg to about 400 mg, for example, about 100 mg to about 350 mg, for example, about 150 mg to about 300 mg, for example, about 150 mg to about 250 mg.

[0687] 289. The method, the modified NSAID for use, or the use according to any one of embodiments 281 to 288, wherein the modified NSAID is orally administered in a dosage of about 250 mg to about 300 mg, preferably about 250 mg.

[0688] 290. The method, the modified NSAID for use, or the use according to any one of embodiments 281-289, wherein the modified NSAID is administered orally once daily.

[0689] 291. The method, the modified NSAID for use, or the use according to any one of embodiments 281-289, wherein the modified NSAID is administered orally at least twice a day, at least three times a day, or at least four times a day.

[0690] 292. The method, the modified NSAID for use, or the use according to any one of embodiments 281-291, wherein the modified NSAID is administered orally two or three times daily.

[0691] 293. The method, the modified NSAID for use, or the use according to any one of embodiments 281-292, wherein the modified NSAID is administered orally twice daily at a dosage of about 150 mg to about 200 mg.

[0692] 294. The method, the modified NSAID for use, or the use according to any one of embodiments 281-293, wherein the modified NSAID is administered orally in a daily dosage of about 300 mg to about 400 mg.

[0693] 295. The method, the modified NSAID for use, or the use according to any one of embodiments 281-292, wherein the modified NSAID is administered orally two or three times daily at a daily dosage of about 250 mg to about 300 mg (e.g., about 250 mg).

[0694] 296. The method, the modified NSAID for use, or the use according to any one of embodiments 281-292 or 295, wherein the modified NSAID is administered orally in a daily dosage of from about 500 mg to a maximum of about 900 mg per day.

[0695] 297. The method, the modified NSAID for use, or the use according to any one of embodiments 281-296, wherein the modified NSAID is administered as a pharmaceutical composition.

[0696] 298. The method, the modified NSAID for use, or the use according to any one of embodiments 281 to 297, wherein the modified NSAID is a phospho-NSAID, for example, phosphosulindac, such as of formula I or II; phospho-naproxen, such as of formula VIII; phospho-ibuprofen, such as of formula III; phospho-glycerol ibuprofen, such as of formula LXXI; or glycerol-phospho-aspirin II, such as of formula V.

[0697] 299. The method, the modified NSAID for use, or the use according to any one of embodiments 281 to 297, wherein the orally administered modified NSAID is a phosphoroamide NSAID, for example, phosphosulindacamide, such as of formula X; or phospho-ibuprofenamide, such as of formula XI.

[0698] 300. The method, the modified NSAID for use, or the use of any one of embodiments 281-297, wherein the orally administered modified NSAID is phospho-ibuprofen, such as that of formula III; phospho-glycerol-ibuprofen, such as that of formula LXXI; NO-sulindac, such as that of formula XLIV; or HS-sulindac, such as that of formula XXXIV.

[0699] 301. The method, the modified NSAID for use, or the use according to any one of embodiments 281 to 297, wherein the orally administered modified NSAID is a modified ibuprofen, for example phospho-ibuprofen such as of formula III; phospho-glycerol-ibuprofen such as of formula LXXI; or phospho-ibuprofen-amide such as of formula XI, in particular phospho-ibuprofen-amide such as of formula XI.

[0700] 302. A method for treating and / or preventing pain, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that said pain is treated and / or prevented.

[0701] 303. Modified NSAIDs for use in the treatment and / or prevention of pain.

[0702] 304. Use of a modified NSAID for the manufacture of a medicament for treating and / or preventing pain. [Example]

[0703] Embodiments encompassed herein will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather to encompass any and all variations that become evident as a result of the teachings provided herein.

[0704] Example 1: Effect of PS in treating pain associated with central sensitization in a mouse model of CIPN method Central sensitization was established by intraperitoneally administering 10 mg / kg paclitaxel to C57 / BL mice. Paclitaxel was administered once daily for 3 days to all test groups. The results in Figure 2 demonstrate that paclitaxel causes a significant decrease in PWT compared to naive mice.

[0705] Mice were administered PS (as an 8% hydrogel) or vehicle control topically to both hind paws three times daily for 10 days, with the first dose administered 2 days after the last dose of paclitaxel.

[0706] The study groups were as follows: 1. Group 1: Paclitaxel only (n=9) 2. Group 2: Paclitaxel + vehicle (n=10) 3. Group 3: Paclitaxel + PS (n=10)

[0707] To determine treatment outcomes, pain threshold responses were measured using the well-established method of von Frey filaments. Specifically, a simplified up-down method for estimating paw withdrawal threshold (PWT) using von Frey filaments was used (as described by Bonin et al., Molecular Pain (2014); 10(26):1-10). Results of PWT tests are expressed as applied force (gm). PWT tests were performed at baseline (i.e., 4 days after the first dose of paclitaxel (day -1)) and then on the final day of treatment with PS or vehicle (i.e., day 10), approximately 30 minutes after the last application. Data are expressed as...

Claims

1. A method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof, such that the neuropathic pain associated with PHN is treated and / or prevented, wherein the modified NSAID is a modified sulindac.

2. the modified sulindac is (i) An NO-releasing sulindac, e.g., NO-sulindac, optionally wherein said NO-sulindac is represented by Formula XLIV: 【Chemistry 1】 The NO-releasing sulindac having the formula: (ii) Phosphosulindac (PS), optionally wherein said PS has formula I (PS-I): 【Chemistry 2】 or The PS has formula II (PS-II): 【Transformation 3】 the phosphosulindac (PS) having the formula: (iii) a phosphosulindacamide, optionally wherein the phosphosulindacamide has the formula X: 【Chemistry 4】 or the phosphosulindacamide having the formula (iv) An HS-releasing sulindac, e.g., HS-sulindac, optionally wherein the HS-sulindac is represented by Formula XXXIV: 【Transformation 5】 2. The method of claim 1, wherein the H2S-releasing sulindac has the formula:

3. 3. The method of claim 2, wherein the modified sulindac is NO-sulindac having the formula XLIV.

4. 10. The method of any one of the preceding claims, wherein treating the neuropathic pain comprises reducing the neuropathic pain.

5. 10. The method of any one of the preceding claims, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

6. 10. The method of any one of the preceding claims, wherein treating the neuropathic pain comprises reducing one or more of the sensory symptoms associated with PHN.

7. 10. The method of any one of the preceding claims, wherein preventing said neuropathic pain comprises reducing the incidence of one or more of said sensory symptoms associated with PHN.

8. 8. The method of claim 6 or 7, wherein the one or more sensory symptoms are selected from itching and numbness.

9. 10. The method of any one of the preceding claims, wherein the PS reduces neuronal signaling involved in pain sensation.

10. 10. The method of any one of the preceding claims, wherein the PS reduces pain that occurs via peripheral sensitization.

11. 10. The method of any one of the preceding claims, wherein the PS reduces pain that occurs via central sensitization.

12. 10. The method of any one of the preceding claims, wherein the PS reduces centrally generated pain signaling.

13. 10. The method of any one of the preceding claims, wherein the PS reduces pain signaling occurring in peripheral nerves, such as nerves innervating one or more dermatomes.

14. 14. The method of claim 13, wherein the nerves innervating the one or more dermatomes are one or more spinal nerves, such as one or more cervical nerves, one or more thoracic nerves, one or more lumbar nerves, and / or one or more sacral nerves.

15. 10. The method of any one of the preceding claims, wherein the PS reduces pain signaling originating in the dorsal root ganglion and / or dorsal horn of the spinal cord.

16. 10. The method of any one of the preceding claims, wherein the PS reduces pain signaling occurring in the CNS.

17. 10. The method of any one of the preceding claims, wherein the neuropathic pain is allodynia.

18. 18. The method of claim 17, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

19. 10. The method of any one of the preceding claims, wherein the neuropathic pain is hyperalgesia.

20. 10. The method of any one of the preceding claims, wherein the subject is a human.

21. 10. The method of any one of the preceding claims, wherein the therapeutically effective amount of the modified NSAID is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

22. 22. The method of claim 21, wherein the pharmaceutical composition comprising the modified NSAID is formulated for topical administration.

23. 23. The method of claim 22, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a semi-solid.

24. 23. The method of claim 22, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a liquid.

25. The method of any one of claims 22 to 24, wherein the pharmaceutical composition comprising the modified NSAID is a cream.

26. The method of any one of claims 22 to 24, wherein the pharmaceutical composition comprising the modified NSAID is a gel, for example, the gel is a hydrogel.

27. The method of any one of claims 22 to 24, wherein the pharmaceutical composition comprising the modified NSAID is a lotion.

28. The method of any one of claims 22 to 24, wherein the pharmaceutical composition comprising the modified NSAID is an ointment.

29. The method of any one of claims 22 to 24, wherein the pharmaceutical composition comprising the modified NSAID is a spray.

30. 30. The method of claim 29, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a patch.

31. 31. The method of any one of claims 21 to 30, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

32. 32. The method of claim 31, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

33. 33. The method of claim 32, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% or about 3% (w / w) of the pharmaceutical composition.

34. 34. The method of claim 33, wherein the pharmaceutical composition comprises the modified NSAID at a concentration of about 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.

35. The modified NSAID has a density of about 0.005 g / 10 cm ２ ~Approx. 0.25g / 10cm ２ The method according to any one of claims 21 to 34, wherein the method is administered at an affected site.

36. The modified NSAID has a density of about 0.005 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

37. The modified NSAID has a density of about 0.01 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

38. The modified NSAID has a density of about 0.05 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

39. The modified NSAID has a density of about 0.1 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

40. The modified NSAID has a density of about 0.15 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

41. The modified NSAID has a density of about 0.2 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

42. The modified NSAID has a density of about 0.25 g / 10 cm ２ 36. The method of claim 35, wherein the administration is at the affected site.

43. 43. The method of any one of claims 21 to 42, wherein the modified NSAID is applied to the affected area and left on the affected area for about 1 hour to about 5 hours.

44. 44. The method of claim 43, wherein the modified NSAID is applied to the affected area and left on the affected area for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

45. 45. The method of claim 43 or 44, wherein the modified NSAID is removed from the affected area after the administration period, for example by washing it off.

46. 45. The method of claim 43 or 44, wherein after the administration period, a second or subsequent application of the modified NSAID is applied to the affected area.

47. 47. The method of any one of claims 21 to 46, wherein the modified NSAID is applied once daily.

48. 47. The method of any one of claims 21 to 46, wherein the modified NSAID is applied twice daily.

49. 47. The method of any one of claims 21 to 46, wherein the modified NSAID is applied three times daily.

50. 47. The method of any one of claims 21 to 46, wherein the modified NSAID is applied four times daily.

51. 51. The method of any one of claims 35 to 50, wherein the modified NSAID is administered in a pharmaceutical composition.

52. 22. The method of any one of claims 1 to 21, wherein the modified NSAID is administered orally.

53. 53. The method of claim 52, wherein the modified NSAID is formulated as a liquid or solid dosage form.

54. 54. The method of claim 53, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir.

55. 54. The method of claim 53, wherein the solid dosage form is a capsule, tablet, pill, powder, or granule.

56. 56. The method of any one of claims 52-55, wherein the modified NSAID is orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight, e.g., about 1 mg / kg to about 5 mg / kg, e.g., about 3 mg / kg of the subject's body weight.

57. 57. The method of any one of claims 52 to 56, wherein the modified NSAID is orally administered at a dosage of about 1 mg to about 2000 mg, about 100 mg to 1500 mg, about 200 mg to about 100 mg, about 50 mg to about 400 mg, such as about 100 mg to about 350 mg, for example about 150 mg to about 300 mg, for example about 150 mg to about 250 mg.

58. 58. The method of any one of claims 52 to 57, wherein the modified NSAID is administered orally in a dosage of about 250 mg to about 300 mg, preferably about 250 mg.

59. 59. The method of any one of claims 52-58, wherein the modified NSAID is administered orally once daily.

60. 60. The method of any one of claims 52-59, wherein the modified NSAID is administered orally at least twice a day, at least three times a day, or at least four times a day.

61. 61. The method of claim 60, wherein the modified NSAID is administered orally two or three times daily.

62. 62. The method of any one of claims 52-61, wherein the modified NSAID is administered orally twice daily at a dosage of about 150 mg to about 200 mg.

63. 63. The method of any one of claims 52-62, wherein the modified NSAID is administered orally in a daily dosage of about 300 mg to about 400 mg.

64. 64. The method of any one of claims 52-63, wherein the modified NSAID is administered orally at a daily dosage of about 250 mg to about 300 mg (e.g., about 250 mg) two or three times daily.

65. 65. The method of any one of claims 52-64, wherein the modified NSAID is administered orally in a daily dosage of about 500 mg to a maximum of about 900 mg daily.

66. 66. The method of any one of claims 52 to 65, wherein the modified NSAID is administered orally in a pharmaceutical composition.

67. A modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with PHN.

68. 68. The modified NSAID for use according to claim 67, wherein the modified NSAID is administered by the method according to any one of claims 1 to 66.

69. Use of a modified NSAID for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PHN.

70. 70. The use of claim 69, wherein the modified NSAID is administered by the method of any one of claims 1 to 66.

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