Treatment of pain associated with central sensitization

Abstract

The present invention features methods of treating pain, e.g., pain associated with central sensitization, using modified NSAIDs, e.g., using sulindac phosphate.

Description

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 384,790, 63 / 384,792, 63 / 384,793, 63 / 384,794, 63 / 384,795, 63 / 384,796, filed November 23, 2022, and U.S. Provisional Application No. 63 / 483,353, filed February 6, 2023. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] The present invention relates to compounds and their use in treating pain associated with central sensitization. The present invention also relates to compounds and their use in treating 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 postherpetic neuralgia (PHN), migraine pain, and corneal neuropathic pain. Background Art

[0003] According to recent studies, pain associated with central sensitization is relatively common, affecting 1 in 5 patients with chronic pain from any cause. In fact, approximately 20% of adults report experiencing widespread body-wide pain associated with central sensitization.

[0004] When the subject's nervous system is continuously in a highly active state, resulting in a decrease in the threshold for triggering action potentials, pain associated with central sensitization occurs. Therefore, in this case, even if the input provided by the peripheral nervous system is limited, the central nervous system will react as if there is always peripheral input (i.e., the central nervous system is overexcited). This hypersensitivity state is called "wind-up", which manifests as pain sensation (abnormal pain) in response to harmless stimuli and an exaggerated reaction to painful stimuli (hyperalgesia). Since central sensitization is caused by changes in neuronal properties in the CNS (i.e., central neuronal plasticity), the perception of pain is no longer associated with the presence, intensity or duration of specific peripheral stimuli (noxious or other stimuli). Therefore, central sensitization is related to the generation and maintenance of pain, in which pain signal conduction is generated in the center (i.e., caused by the hypersensitivity of central pain signaling neurons), even in the absence of peripheral stimuli.

[0005] The dynamic changes (i.e., plasticity) of central neurons that occur during the development and maintenance of pain associated with central sensitization are considered to be the primary cause of many clinical pain syndromes. Pain associated with central sensitization, sometimes also referred to as central pain or central neuralgia, is influenced by both genetics and the environment, predisposing patients to it, and occurs in patients with, for example, fibromyalgia, chronic pain syndromes, and nervous system injuries such as stroke or spinal cord injury. Although pain may feel peripherally derived, the generation of pain occurs at the central site of action, leading to symptoms of allodynia and hyperalgesia.

[0006] Central sensitization may be a component of neuropathic pain associated with neuropathy, a disease or abnormality of the nervous system that afflicts more than 20 million Americans. In fact, according to recent studies, neuropathic pain has been observed to affect approximately 1 in 10 adults, and the economic burden of treating this pain is increasing.

[0007] Neuropathic pain is associated with the development of neuropathic pain. Neuropathic pain can be caused by damage to the peripheral nervous system or the central nervous system. Peripheral neuropathic pain is caused by damage to nerve structures such as peripheral nerve endings or nociceptors, which become extremely sensitive to stimuli and can generate impulses without stimulation. There are many causes of damage, such as traumatic injury (such as nerve compression, spinal cord injury and postoperative nerve damage), chemotherapy treatment, diseases such as diabetes, as well as advanced cancer and viruses (such as shingles or HIV).

[0008] Lesions in the peripheral nerves can lead to a pathological state characterized by the presence of persistent spontaneous pain, which is often associated with hyperalgesia (an increased response to noxious stimuli) and allodynia (pain caused by non-painful stimuli). Hyperalgesia and allodynia are associated with central sensitization, in which nociceptive neurons in the CNS exhibit increased excitability due to a lowered threshold for stimulation caused by persistent input or peripheral injury. As described herein, central sensitization has been implicated in the generation and maintenance of neuropathic pain associated with peripheral neuropathy.

[0009] From a symptomatic perspective, pain associated with central sensitization may cause sharp pain, dull pain, burning or cold pain, paresthesia, loss of proprioception, numbness, or even loss of pain sensation. Similarly, peripheral neuropathy may cause sharp pain, dull pain, burning or cold pain, paresthesia, loss of proprioception, numbness, or even loss of pain sensation.

[0010] There is a global need for additional pain treatments, and pain associated with central sensitization has become a major health problem for a wide range of populations. From a therapeutic perspective, pain associated with central sensitization typically responds to neuromodulators, antiepileptic drugs, 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 has also become a major health problem for the general population. Treatment of neuropathic pain is often attempted with so-called unconventional analgesics, such as antidepressants like duloxetine and amitriptyline, or antiepileptic drugs like gabapentin or pregabalin. Local anesthetics, including lidocaine, have also been 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 for treating neuropathic pain associated with central sensitization. In fact, a review of recent clinical trials showed no evidence that NSAIDs significantly reduce pain in patients with neuropathic pain (Moore et al., Cochrane Database of Systematic Reviews (2015); 10:1–25), nor did any clinical results show a statistically significant difference between NSAIDs and placebo. The Cochrane Library concluded that the use of NSAIDs for the treatment of neuropathic pain is not recommended. Therefore, the anti-inflammatory activity of typical NSAIDs is unable to produce analgesic effects, especially when the pain is caused by central sensitization or is associated with peripheral neuropathy.

[0013] Therefore, there is an urgent need for compounds that treat pain-related central sensitization. In addition, there is also an urgent need for compounds that can treat and / or prevent pain associated with peripheral neuropathies (such as PTPN and PHN) and migraine pain. Summary of the Invention

[0014] The inventors of this case unexpectedly discovered that phosphosulindac (PS) can effectively treat pain associated with central sensitization. In fact, data obtained from a variety of different animal models that produce central sensitization confirm that PS can treat allodynia, which is a manifestation of central sensitization, and central sensitization is caused by amplifying signals in neurons located in the center in response to usually harmless stimuli. The observations of treating allodynia in a variety of different models, as well as the observation that PS can reach key sites of action by being delivered to the CNS along peripheral neurons, support the role of PS in directly acting on neuronal signaling related to central sensitization. Therefore, the combination of the observations herein shows that PS, as a centrally acting analgesic, has wide applicability in treating pain associated with central sensitization (i.e., pain generated in the central site of action and manifested as, for example, allodynia).

[0015] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike the parent compound NSAID sulindac, PS does not inhibit COX-1 and COX-2 or prostaglandin synthesis and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties by inhibiting NF-κB activation and changes in the MAPK signaling branch, and has activity in treating rheumatoid arthritis by inhibiting key proinflammatory 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 showed that PS has anti-inflammatory activity in an acute dry eye (DED) model and showed that PS reduced corneal sensitivity in an acute model. The observation that acute stimulation sensitivity is reduced without persistent pain does not confirm its efficacy in treating pain associated with central sensitization (i.e., pain arising at the central site of action). Furthermore, in this acute model, the effects of PS are immediately observed, suggesting that the local effects of this atypical NSAID are similar to the activity of typical NSAIDs (e.g., ketorolac) observed in the same model. Furthermore, this peripheral activity does not confirm the efficacy of PS in treating pain arising at the central site of action. Indeed, clinical guidance in this field recommends avoiding the use of NSAIDs for all types of neuropathic pain typically associated with central sensitization, and ketorolac has been shown to have limited analgesic activity in this pain model. Furthermore, the finding that PS can restore suppressed ocular sensitivity in the DED model suggests that the effect of PS is to increase rather than decrease nociception. Therefore, these observations fail to demonstrate a role for PS in treating pain associated with central sensitization, and the observations herein demonstrate that PS has unprecedented activity in reducing pain arising at the central site of action.

[0016] The inventors of this case considered the activity of PS in specific animal models in which central sensitization manifesting as allodynia has been established and demonstrated surprising therapeutic efficacy, equivalent to direct-acting nerve blocking anesthetics that can reduce pain associated with central sensitization. Specific animal models are very important in the development of therapies for treating pain associated with central sensitization. In fact, considering the pathogenesis of this pain, which involves changes in the sensitivity of neurons located in the central nervous system, the observations on the efficacy of specific compounds in, for example, acute pain models cannot indicate the effectiveness of the compound in treating pain associated with central sensitization. Therefore, the efficacy of the compound in treating pain associated with central sensitization is demonstrated by the following observations, which show that the compound can reverse the manifestation of central sensitization (e.g., allodynia) in a model system where chronic pain has been established. Therefore, the animal model used in early testing is crucial before further clinical development is carried out. Based on a specific animal model in which pain (e.g., allodynia) is produced by central neuronal sensitization, the observations herein demonstrate that PS has unprecedented efficacy in treating pain associated with central sensitization.

[0017] Thus, 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, thereby treating pain associated with central sensitization. In some embodiments, the pain associated with central sensitization is not pain associated with central sensitization caused by chemotherapy-induced peripheral neuropathy (CIPN) or diabetic peripheral neuropathy (DPN).

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

[0019]

[0020] In other embodiments, the PS is a sulfide form of PS. Thus, the PS may have Formula II (PS-II):

[0021]

[0022] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfoxide form of this compound is preferred. Compounds of Formula I and II are described in U.S. Patent No. 8,236,820, which is incorporated herein by reference in its entirety.

[0023] As described above, the pain associated with central sensitization is caused by the overactivity of neurons located in the center, which exhibit a reduced stimulation threshold and depolarize even in the absence of peripheral stimulation. In fact, the perception of pain is no longer associated with the presence, intensity or duration of a specific peripheral stimulus (noxious or other stimulus). Therefore, subjects experiencing pain associated with central sensitization may experience pain caused by non-painful stimuli (allodynia) or experience increased pain in response to noxious stimuli (hyperalgesia). According to the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Therefore, PS can reduce pain signaling occurring in the center. PS can reduce pain signaling occurring in the dorsal root ganglia. PS can reduce pain signaling occurring in the dorsal horn of the spinal cord. Given that PS has been shown to ascend to the spinal cord along peripheral neurons, PS can reduce pain signaling occurring in the CNS. In some embodiments, the pain associated with central sensitization is allodynia. Allodynia may be a response to mechanical and / or thermal stimulation. In addition, in some embodiments, the pain associated with central sensitization is hyperalgesia.

[0024] 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 post-herpetic neuralgia. In some embodiments, the pain associated with central sensitization is migraine pain (or pain of other headache disorders). In some embodiments, the pain associated with central sensitization is corneal neuropathic pain.

[0025] Furthermore, in vivo evidence suggests that PS has efficacy in treating neuropathic pain associated with PTPN, migraine pain, neuropathic pain associated with PHN, and corneal neuropathic pain. Further experiments in specific animal models have confirmed these initial observations.

[0026] Therefore, 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, thereby treating and / or preventing neuropathic pain associated with PTPN.

[0027] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), comprising administering a therapeutically effective amount of PS to a subject in need thereof, thereby treating and / or preventing neuropathic pain associated with PHN.

[0028] In another aspect, the present invention provides a method for treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, thereby treating and / or preventing migraine pain.

[0029] In yet another aspect, the present invention provides a method for treating and / or preventing pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, thereby treating and / or preventing pain.

[0030] 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. For topical administration, PS is particularly preferably in the form of a formulation. PS can, for example, be administered topically to the area where pain is felt. 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, thereby treating pain associated with central sensitization, wherein the PS is administered orally. In some embodiments, PS is administered both orally and topically.

[0031] The observations of treating allodynia in various models herein, as well as the observations that PS can reach key sites of action by being delivered to the CNS via peripheral neurons, support the role of PS in directly acting on neuronal signaling involved in central sensitization. Since sulindac (the parent compound of PS) does not share these activities, the observations herein show that modifying sulindac not only makes PS that acts directly on neural signaling have surprising analgesic activity, but also makes PS more capable of being delivered to key central sites of action, enabling it to more effectively impart its analgesic activity to neural signaling. Therefore, without wishing to be bound by theory, the observations herein show that NSAIDs can be modified so that they can act directly on neuronal signaling and more easily approach key sites of action by being delivered along peripheral neurons projected by the central nervous system, thereby overcoming the obvious defects of NSAIDs in treating pain associated with central sensitization. Therefore, as an alternative to PS, the method of the present invention can be performed using one or more modified NSAIDs disclosed herein. In this article, "modified NSAID" refers to a compound produced by modifying an NSAID molecule (i.e., parent compound).

[0032] Thus, in another aspect, the present invention provides a method of treating pain associated with central sensitization, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating pain associated with central sensitization.

[0033] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with CIPN. In a specific embodiment, the modified NSAID is not PS.

[0034] In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with DPN. In a specific embodiment, the modified NSAID is not PS.

[0035] 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 to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with PTPN.

[0036] 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 to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with PHN.

[0037] In another aspect, the present invention provides a method of treating and / or preventing migraine pain, comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing migraine pain.

[0038] In yet another aspect, the present invention provides 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, thereby treating and / or preventing corneal neuropathic pain.

[0039] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-amidated 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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate.

[0040] In certain embodiments, the modified NSAID does not have Formula LXIX and / or Formula LXX.

[0041] In certain embodiments, the modified NSAID can be selected from: naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; glyceribuprofen phosphate, such as Formula LXXI; glycerophosphate aspirin II, such as Formula V; sulindac amide phosphate, such as Formula X; ibuprofen amide phosphate, such as Formula XI; glyceribuprofen amide phosphate, such as Formula XII; NO-sulindac, such as Formula XLIV; sulindac platinum, such as Formula LXVII; NO-aspirin, such as Formula XLIX; HS-sulindac, such as Formula XXXIV; or NOSH-aspirin, such as Formula LIX.

[0042] In certain embodiments, the modified NSAID is a modified sulindac, such as NO-releasing sulindac (e.g., NO-sulindac, such as Formula XLIV), HS-releasing sulindac (e.g., HS-sulindac, such as Formula XXXIV), phosphamide-modified sulindac (e.g., sulindac amide phosphate, such as Formula X), or metal-chelated sulindac (e.g., sulindac platinum, such as Formula LXVII). In specific embodiments, the modified NSAID is a modified sulindac, 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 phosphamide-modified sulindac (e.g., sulindac amide phosphate, such as Formula X). In specific embodiments, the modified NSAID is a phosphorylated NSAID, such as naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; ibuprofen glycerophosphate, such as Formula LXXI; or aspirin glycerophosphate II, such as Formula V. In specific embodiments, the modified NSAID is a phosphoamidated NSAID, e.g., ibuprofen phosphate amide, such as Formula XII; ibuprofen phosphate amide, such as Formula XI; or sulindac phosphate amide, such as Formula X. In specific embodiments, the modified NSAID is a modified ibuprofen, e.g., ibuprofen phosphate, such as Formula III; ibuprofen phosphate glycerol, such as Formula LXXI; or ibuprofen phosphate amide, such as Formula XI.

[0043] In some embodiments, the modified NSAID is formulated for oral administration. Thus, the modified NSAID can be administered orally. In specific embodiments, the orally administered modified NSAID is a phosphamidate NSAID, such as sulindac amide phosphate, such as Formula X; or ibuprofen amide phosphate, such as Formula XI. In some embodiments, the orally administered modified NSAID is ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; NO-sulindac, such as Formula XLIV; or HS-sulindac, such as Formula XXXIV. In specific embodiments, the orally administered modified NSAID is a modified sulindac, such as PS, such as Formula I or II; NO-sulindac, such as Formula XLIV; or HS-sulindac, such as Formula XXXIV; or sulindac amide phosphate, such as Formula X. In specific embodiments, the orally administered modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI, particularly ibuprofen amide phosphate, such as Formula XI. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 – Schematic overview of research on the treatment of pain associated with central sensitization.

[0046] Figure 2–The role of PS in the treatment of pain associated with central sensitization.

[0047] Figure 3 - Effect of PS on the treatment of central sensitization-related pain caused by paclitaxel. Compared with the vehicle control, the effect of PS was very significant starting from the 5th day and gradually increased thereafter ( p<0.002, p = 4.9 × 10 -5 , & , p = 1.7 × 10 -7 ,*,p=2.2×10 -7 ).

[0048] Figure 4 - Effect of PS on the treatment of pain associated with central sensitization induced by vincristine. Compared with the vehicle control, the effect of PS was highly significant on day 16 (*p = 8.6 × 10 -6 ).

[0049] Figure 5 - Effect of PS on the treatment of pain associated with central sensitization induced by oxaliplatin. Compared with the vehicle control, the effect of PS was highly significant on day 22 (*p=0.004).

[0050] Figure 6 - Comparison of the effects of PS with sulindac, lidocaine, and pregabalin for the treatment of pain associated with central sensitization. Figure 6A Mechanical allodynia was involved (*, statistically significant difference; NS, not statistically significant). Figure 6B Involvement in cold allodynia (values: mean ± SEM; *, p < 0.0001).

[0051] Figure 7 – Schematic overview of research on the treatment of pain associated with central sensitization. STZ is streptozotocin. PWT is paw withdrawal threshold test.

[0052] Figure 8 - Comparison of the effects of PS and vehicle on pain associated with central sensitization induced by STZ.

[0053] Figure 9 – Effects of sulindac, lidocaine, and pregabalin on pain associated with central sensitization.

[0054] Figure 10 - A) Confirmation of the efficacy of the model system; B) Comparison of the effects of PS with sulindac and pregabalin on PTPN-related pain. Compared with the vehicle control, the effect of PS was highly significant on day 14 (p < 0.005).

[0055] Figure 11 - Schematic overview of the metabolism of PS.

[0056] Figure 12 - Biodistribution of PS in different tissues after topical application. SN = sciatic nerve. DRG = dorsal root ganglion.

[0057] Figure 13 - Biodistribution of PS metabolites in different tissues after topical administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion.

[0058] FIG14 - A) Biodistribution of PS in ocular tissues after topical application of PS to the outer surface of the eyelid; B) Levels of sulindac detected in ocular tissues due to hydrolysis of PS after application of PS to the outer surface of the eyelid.

[0059] Figure 15 – Schematic overview of studies on prevention of neuropathic pain associated with CIPN. PWT is the paw withdrawal threshold test.

[0060] Figure 16 - Comparison of the effects of PS and vehicle on the prevention of CIPN-associated neuropathic pain.

[0061] Figure 17 - Effect of PS on the prevention of neuropathic pain associated with paclitaxel-induced CIPN. Compared with the vehicle control, the effect of PS was highly significant (*, p = 3.0 × 10 -8 ,**,p=2.3×10 -6 ).

[0062] Figure 18 – Schematic overview of studies on prevention of DPN-related neuropathic pain. STZ is streptozotocin. PWT is paw withdrawal threshold test.

[0063] Figure 19 - Effect of PS on the prevention of DPN-related neuropathic pain. *, p<0.0001 (STZ vs. no treatment); **, p<0.004 (PS vs. vehicle), ***, p<0.001 (lidocaine vs. vehicle).

[0064] Figure 20 - Effects of aspirin II glycerophosphate, naproxen phosphate, and ibuprofen phosphate on the treatment of CIPN-related neuropathic pain. Compared with vehicle control: *, p < 0.0001, p<0.001, & , p<0.02. DETAILED DESCRIPTION

[0065] definition

[0066] The following definitions of pain types are in accordance with 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 the increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent inputs. "Peripheral sensitization" refers to the increased responsiveness of peripheral nociceptive neurons to stimuli of their receptive fields and a lowered threshold. The exact causes of central and peripheral sensitization of neuropathic pain are different from those of other forms of pain (e.g., inflammatory pain). "Abnormal pain" is pain caused by stimuli that do not normally cause pain. "Hyperalgesia" is exacerbated pain caused by stimuli that normally cause pain. Pain associated with central sensitization can be systemic or occur in multiple parts of the body. Given the involvement of the relevant nervous system, pain associated with central sensitization exhibits symptoms corresponding to the symptoms observed in neuropathic pain. Thus, patients with pain associated with central sensitization may experience one or more sensations described as heat, burning, throbbing, shooting, stabbing, sharp pain, cramping, aching, tingling, numbness, or pins and needles. Pain associated with central sensitization is also associated with mood changes, fatigue, cognitive impairment, sleep changes, and pain catastrophizing. In addition, patients with pain associated with central sensitization may also experience multifocal pain, memory impairment, and comorbidities including major depressive disorder or generalized anxiety disorder.

[0067] "Neuropathic pain" is caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain is a clinical description (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 heat, burning, throbbing, shooting, tingling, sharp pain, cramping, aching, tingling, numbness, or pins and needles. The term "somatosensory nervous system injury" is generally used when diagnostic investigations (e.g., imaging, neurophysiology, biopsy, laboratory tests) reveal abnormalities or when there is obvious trauma. The term "somatosensory nervous system disease" is generally used when the underlying cause of the lesion is known (e.g., stroke, vasculitis, diabetes, genetic abnormalities). "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.

[0068] The following definitions of headache types are based on the International Classification of Headache Disorders (ICHD), 3rd edition (ICHD-3). There are two main types of migraine: "migraine without aura," which is a clinical syndrome characterized by a headache with specific features and associated symptoms; and "migraine with aura," which is characterized by transient focal neurological symptoms that usually precede or sometimes accompany the headache. "Migraine without aura" (i.e., common migraine; simple migraine) is a recurrent headache disorder characterized by attacks lasting 4-72 hours. This headache is usually unilateral, throbbing, moderate to severe in intensity, aggravated by daily physical activity, and accompanied by nausea and / or photophobia and phonophobia. "Migraine with aura" (i.e., classic or classical migraine) involves recurrent attacks lasting several minutes with unilateral, fully reversible visual, sensory, or other CNS symptoms, usually with a gradual development, and is usually accompanied by headache and associated migraine symptoms. "Episodic migraine" typically involves migraines / headaches occurring about 1-2 times per month. "Chronic migraine" refers to headaches occurring 15 or more days per month for more than three months, with migraine-type headache features on at least 8 days per month.

[0069] Generally, the term "disease" refers to a state or health condition in a patient or subject that can be treated using the methods provided herein.

[0070] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to achieve the intended use. Thus, when the intended use is the treatment of a disease, a "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to treat the disease. When the intended use is the treatment and / or prevention of a disease, a "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to treat and / or prevent the disease.

[0071] "Pharmaceutically acceptable excipients" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients included in pharmaceutical compositions. The use of such pharmaceutically acceptable excipients for formulating active pharmaceutical ingredients is well known in the art. Unless any conventional pharmaceutically acceptable excipient is incompatible with PS, it is contemplated for use in the therapeutic compositions of the present invention.

[0072] Use of the term "about" when referring to a number 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.

[0073] The term "comprising" encompasses "including" as well as "consisting of, eg, a composition "comprising" X may consist of X only, or may include other substances (eg, X+Y).

[0074] Modified NSAIDs

[0075] As used herein, a "modified NSAID" refers to a compound that is modified from an NSAID molecule (i.e., a parent compound). Exemplary modified NSAIDs are discussed in Ramos-Inza et al. (J. Med. Chem. (2021); 64: 16380-16421) and WO 2009 / 023631, which are hereby incorporated by reference in their entirety.

[0076] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phosphoamide-modified NSAIDs (phosphoamidated 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).

[0077] Phosphorylated NSAIDs

[0078] The phosphorylated NSAID may be PS, for example having formula I or II.

[0079] The phosphorylated NSAID may be ibuprofen phosphate, for example having the formula III:

[0080]

[0081] The phosphorylated NSAID may be ibuprofen phosphate-PEG, for example having formula IV:

[0082]

[0083] The molecular weight (g / mol) of PEG can be in the range of about 200 to about 15,000, for example, in the range of about 200 to 3,000 or about 200 to 1,000. The ibuprofen phosphate-PEG can be in its anionic form, as shown in Formula IV, and / or can be in its protonated form.

[0084] The phosphorylated NSAID may be aspirin phosphate, for example having formula V, VI or VII:

[0085]

[0086]

[0087] Thus, the aspirin phosphate may be glycerophosphate aspirin I (e.g., having formula VI), or in particular glycerophosphate aspirin II (e.g., having formula V). The aspirin phosphate may be: 2-acetoxybenzoic acid 4-(diethoxy-phosphoryloxymethyl)-phenyl ester or 2-acetoxybenzoic acid 3-(diethoxy-phosphoryloxymethyl)-phenyl ester.

[0088] The phosphorylated NSAID may be naproxen phosphate, for example having formula VIII:

[0089]

[0090] The phosphorylated NSAID may be flurbiprofen phosphate, for example having the formula IX:

[0091]

[0092] Phosphamide-NSAID

[0093] The phosphamide-NSAID may be sulindac amide phosphate, for example having the formula X:

[0094]

[0095] The phosphamide-NSAID may be ibuprofenamide phosphate, for example having the formula XI:

[0096]

[0097] The phosphoamido-NSAID may be glycerophosphoglyceramide, for example having the formula XII:

[0098]

[0099] Selenium-modified NSAIDs

[0100] For Se-NSAIDs, Se can be incorporated in the form of selenocyanate, sulfur selenide, selenazolidine, or selenoester.

[0101] The Se-NSAID may be Se-sulindac, for example having the formula XIII:

[0102]

[0103] The Se-NSAID may be Se-ibuprofen, for example of formula XIV or XV:

[0104]

[0105] wherein R is SeCN or SeCF3.

[0106] The Se-NSAID may be Se-aspirin, for example having formula XVI, XVII or XVIII:

[0107]

[0108]

[0109] wherein R is SeCN or SeCF3.

[0110] The Se-NSAID may be Se-celecoxib, for example having the formula XIXI or XX:

[0111]

[0112] The Se-NSAID may be Se-naproxen, for example having the formula XXI:

[0113]

[0114] The Se-NSAID may be Se-flurbiprofen, for example having formula XXII:

[0115]

[0116] The Se-NSAID may be Se-ketoprofen, for example having the formula XXIII:

[0117]

[0118] Metal-NSAIDs

[0119] The metal-NSAID can be coordinated with copper (Cu), cobalt (Co), platinum (Pt), zinc (Zn), iridium (Ir), ruthenium (Ru), nickel (Ni), silver (Ag), manganese (Mn), or an organotin. The Cu complex can be tetra- or hexa-coordinated. The Co complex can be hexa-coordinated. The organotin can be tetrabutyltin, tributyltin oxide, triphenyltin acetate, triphenyltin chloride, methyltin chloride, triphenyltin hydroxide, azocyclotin, cyhexatin, hexamethylditin, or tetraethyltin.

[0120] The metal-NSAID may be Cu(II)-naproxen, for example having formula XXIV:

[0121]

[0122] The metal-NSAID may be Cu(II)-flufenamic acid, for example having the formula XXV:

[0123]

[0124] The metal-NSAID may be Cu(II)-indomethacin, for example having formula XXVI, XXVII, XXVIII or XXIX:

[0125]

[0126]

[0127] The metal-NSAID may be Co(II)-diflunisal, for example having the formula XXX:

[0128]

[0129] The metal-NSAID may be Cu(II)-naproxen, for example having the formula XXXI:

[0130]

[0131] The metal-NSAID may be Cu(II)-ibuprofen, for example having formula XXXII:

[0132]

[0133] The metal-NSAID may be Cu(II)-aspirin, for example having the formula XXXIII:

[0134]

[0135] H2S-releasing NSAIDs

[0136] The HS-releasing NSAID may be HS-sulindac, for example having formula XXXIV:

[0137]

[0138] The HS-releasing NSAID may be HS-ibuprofen, for example having the formula XXXV:

[0139]

[0140] The HS-releasing NSAID may be HS-aspirin, for example having the formula XXXVI:

[0141]

[0142] The HS-releasing NSAID may be HS-naproxen, for example having formula XXXVII, XXXVIII, XXXIX or XL:

[0143]

[0144]

[0145] The HS-releasing NSAID may be HS-ketoprofen, for example having the formula XLI:

[0146]

[0147] The HS-releasing NSAID may be HS-diclofenac, for example of formula XLII or XLIII:

[0148]

[0149] NO-releasing NSAIDs

[0150] The NO-releasing NSAID may be NO-sulindac, for example of formula XLIV or XLV:

[0151]

[0152] wherein R has the formula XLVI or XLVII:

[0153]

[0154] The NO-releasing NSAID may be NO-aspirin, for example having the formula XLVIII or XLIX:

[0155]

[0156]

[0157] The NO-releasing NSAID may be NO-naproxen, for example having the formula L:

[0158]

[0159] The NO-releasing NSAID may be HS-flurbiprofen, for example having the formula LI:

[0160]

[0161] The NO-releasing NSAID may be NO-indomethacin, for example having the formula LII:

[0162]

[0163] The NO-releasing NSAID may be NONO-aspirin, for example having formula LIII, LIV or LV:

[0164]

[0165]

[0166] The NO-releasing NSAID may be NONO-naproxen, for example having the formula LVI:

[0167]

[0168] NSAIDs that release NOSH

[0169] The NOSH-releasing NSAID may be NOSH-sulindac, for example having the formula LVII:

[0170]

[0171] The NOSH-releasing NSAID may be NOSH-naproxen, for example having the formula LVIII:

[0172]

[0173] The NOSH-releasing NSAID may be NOSH-aspirin, for example having the formula LIX, LX, LXI or LXII:

[0174]

[0175] As is apparent from the molecular formula of the NOSH-releasing NSAID herein, a NOSH-releasing NSAID releases both NO and H2S. Thus, a NOSH-NSAID is an NSAID that releases both NO and H2S. This terminology is well established in the art.

[0176] Other modified NSAIDs

[0177] A modified NSAID may be one that does not fall within one of the classes disclosed above.

[0178] For example, the modified NSAID may be nitroxide-aspirin, for example having the formula LXIII:

[0179]

[0180] The modified NSAID may be a triazole-thioether-naproxen, for example having the formula LXIV:

[0181]

[0182] The modified NSAID may be an anthraquinone-aspirin, for example having the formula LXV:

[0183]

[0184] The modified NSAID may be a diclofenac-N-derivative, for example having the formula LXVI:

[0185]

[0186] The modified NSAID may be an NSAID drug hybrid, such as 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.

[0187] The modified NSAID may be platinum-sulindac, for example having the formula LXVII:

[0188]

[0189] The modified NSAID may be Q922, for example having the formula LXVIII:

[0190]

[0191] In another aspect, the present invention provides a modified NSAID, or a pharmaceutical composition comprising a modified NSAID, wherein the modified NSAID has the formula LXVIII.

[0192] The modified NSAID may have the formula LXIX:

[0193]

[0194] The modified NSAID may have the formula LXX:

[0195]

[0196] In some embodiments, the modified NSAID is a phosphorylated NSAID, such as glycerophosphate ibuprofen, e.g., having the formula LXXI:

[0197]

[0198] Production of modified NSAIDs

[0199] Those skilled in the art can use conventional methods to produce the modified NSAIDs disclosed herein, for example, by modification of the carboxylic acid group.

[0200] Pain associated with chemotherapy-induced peripheral neuropathy (CIPN) or diabetic peripheral neuropathy (DPN)

[0201] CIPN and its associated neuropathic pain are frequent, dose-dependent side effects of commonly used chemotherapy. Peripheral nerve damage dominates the neurological damage associated with chemotherapy toxicity and is the most common chemotherapy-limiting factor after hematological toxicity. It is believed that the pain is caused by direct toxic effects on sensory axons, demyelination, or impaired calcium metabolism. Neuropathic pain associated with CIPN is particularly difficult to treat. Currently, antidepressants (such as duloxetine) and / or antiepileptic drugs (such as gabapentin and pregabalin) are used to manage this pain. Unfortunately, pain control is not very satisfactory, and these systemic treatments can induce serious side effects, resulting in very poor treatment compliance. In fact, to date, there is no satisfactory method for preventing or even treating CIPN-related pain: the only approved drug (duloxetine) is generally considered ineffective.

[0202] DPN is peripheral nerve damage caused by diabetes and is one of the most serious complications of diabetes. About half of people with diabetes experience some form of nerve damage, with high blood sugar being the main cause of peripheral neuropathy in DPN. DPN can affect both small and large nerves, which protect the body by sending signals to the brain about pain and temperature changes, detecting touch, pressure, and helping maintain balance. Clinical guidelines recommend relief of diabetic neuropathy through the use of antidepressants (such as duloxetine) and / or anti-epileptic drugs (such as gabapentin and pregabalin), as well as topical medications such as opioids and capsaicin. Current treatments for DPN-related pain have limited efficacy and can cause serious side effects.

[0203] Therefore, there is an urgent need for compounds that treat and / or prevent pain associated with peripheral neuropathies, in particular CIPN or DPN.

[0204] The inventors of this case unexpectedly discovered that sulindac phosphate (PS) can effectively treat and prevent pain associated with CIPN or DPN, as well as other neuropathic pain disorders and pain associated with central sensitization.

[0205] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike the parent compound NSAID sulindac, PS does not inhibit COX-1 and COX-2 and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties by inhibiting NF-κB activation and changes in the MAPK signaling branch, and has activity in treating rheumatoid arthritis by inhibiting key proinflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32; and Matt Heolabakis et al. (2013) Pharm Res 30(6):1471–82). WO 2019 / 067919 proposed that PS has anti-inflammatory activity in an acute dry eye (DED) model. Furthermore, in this model, PS was found to restore the suppressed ocular sensitivity in DED, suggesting that the effect of PS is to increase rather than decrease nociception. Although PS is not a typical NSAID, as described above, it exhibits NSAID-like activity 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 guidelines in this field recommend avoiding the use of NSAIDs for all types of neuropathic pain; therefore, anti-inflammatory activity alone is considered insufficient for treatment.

[0206] Nevertheless, the inventors of this case considered the activity of PS in specific animal models of neuropathic pain and demonstrated surprising therapeutic efficacy, which is equivalent to direct-acting nerve blocking anesthetics such as lidocaine and pregabalin. Specific animal models are very important in the development of therapies for treating neuropathic pain. In fact, considering the pathogenesis of pain associated with peripheral neuropathy, the efficacy of specific compounds observed in alternative pain models (such as inflammatory pain models) does not indicate the effectiveness of the compound in treating neuropathic pain. Therefore, animal models for early testing are crucial before further clinical development. Based on specific animal models of neuropathic pain associated with CIPN or DPN, the observations herein demonstrate that PS has unprecedented efficacy in treating and / or preventing neuropathic pain associated with CIPN or DPN, respectively.

[0207] The inventors of this case unexpectedly demonstrated analgesic activity of PS in treating neuropathic pain associated with CIPN or DPN that is similar to the analgesic activity of centrally acting analgesics. These observations are consistent with the findings herein that topically administered PS can reach key sites of action (e.g., dorsal root ganglia (DRG)) known to be involved in the generation of neuropathic pain associated with CIPN or DPN. In addition, PS has also been shown to be particularly stable in peripheral neurons and sites of action closer to the central nervous system. Without wishing to be bound by theory, these observations support the theory that PS exerts its analgesic activity directly on neurons and may exert its analgesic activity within sites of action closer to the central nervous system, consistent with its activity equivalent to that of centrally acting analgesics. In contrast, the non-phosphorylated "parent" of PS (i.e., sulindac, a typical NSAID) is unable to treat and / or prevent neuropathic pain associated with CIPN or DPN. Further observations by the inventors of this case unexpectedly demonstrated that PS has analgesic effects on other forms of neuropathic pain, while its parent compound, sulindac, does not have this effect. This confirms the theory that PS has a direct effect on neural signal transmission from neurons located in the central nervous system, indicating that PS is generally applicable to the treatment of pain associated with central sensitization.

[0208] Therefore, based on the inventors' observations, modification of sulindac would provide a compound that not only exhibits analgesic activity directly on neural signaling, but also achieves analgesic activity by delivery to key central sites of action, allowing the modified NSAID to exert its analgesic activity even more effectively on central neural signaling.

[0209] These observations suggest for the first time that compounds within the broader class of modified NSAIDs have direct analgesic effects on pain perception mechanisms and may treat or prevent neuropathic pain associated with CIPN or DPN. Therefore, based on these observations, similar to PS, these modified NSAIDs are expected to deliver to key central sites of action and exhibit analgesic activity directly on neural signaling, relative to the parent NSAID compound.

[0210] Thus, in one specific aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with CIPN, wherein the modified NSAID is not PS. In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with DPN, wherein the modified NSAID is not PS.

[0211] The modified NSAID for treating and / or preventing CIPN or DPN by topical administration is not PS. In some embodiments, the modified NSAID is not a PS disclosed in WO2022 / 251805 or WO2022 / 251806. In some embodiments, the modified NSAID is not PS, nor is it 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. Thus, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with CIPN, with the proviso that WO2022 / 251805 and WO2022 / 251806 are disclaimed. In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with DPN, with the proviso that WO2022 / 251805 and WO2022 / 251806 are disclaimed. In some embodiments, references to "PS" or "sulindac phosphate" encompass 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 Formula I and II are described in US Patent No. 8,236,820, which is incorporated herein by reference in its entirety. For the purposes of this application, the term PS does not encompass sulindac amide phosphate, for example, having Formula IX.

[0212] Therefore, the modified NSAID for use in the treatment and / or prevention of CIPN or DPN is not a sulfoxide form of PS and has Formula I (PS-I):

[0213]

[0214] or a solvate thereof,

[0215] Nor is it the sulfide form of PS, having the chemical formula II (PS-II):

[0216]

[0217] or a solvate thereof.

[0218] The modified NSAID can be any modified NSAID disclosed herein except PS. For example, the modified NSAID can be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. In specific embodiments, the modified NSAID may be a phosphorylated NSAID. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate. In specific embodiments, the modified NSAID may be naproxen phosphate, ibuprofen phosphate, and / or aspirin glycerophosphate II.

[0219] In specific embodiments, the modified NSAID for treating and / or preventing pain associated with CIPN or DPN can be selected from one or more of the following: naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; glycerobuprofen phosphate, such as Formula LXXI; glycerophosphoaspirin 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; sulindac amide phosphate, such as Formula X; ibuprofen amide phosphate, such as Formula XI; glycerophosphoaspirin amide, such as Formula XII; or a compound having Formula LXVIII or LXIX.

[0220] In specific embodiments, the modified NSAID may be a phosphorylated NSAID, such as naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; glycerophosphoprofen, such as Formula LXXI; or glycerophosphoaspirin II, such as Formula V. In specific embodiments, the modified NSAID may be an NO-releasing NSAID, such as NO-sulindac, such as Formula XLIV; or NO-aspirin, such as Formula XLIX. In specific embodiments, the modified NSAID may be an HS-releasing NSAID, such as HS-sulindac, such as Formula XXXIV. In specific embodiments, the modified NSAID may be an NOSH-releasing NSAID, such as NOSH-aspirin, such as Formula LIX. In particularly preferred embodiments, the modified NSAID may be a phosphoamidated NSAID, such as sulindac amide phosphate, such as Formula X; ibuprofen amide phosphate, such as Formula XI; or glycerophosphoprofen amide phosphate, such as Formula XII.

[0221] In specific embodiments, the modified NSAID 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 phosphamide-modified sulindac (e.g., phosphosulinamide, such as Formula X).

[0222] In specific embodiments, the modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI, in particular ibuprofen amide phosphate, such as Formula XI.

[0223] As described above, nerve damage associated with CIPN or DPN may overactivate pain signaling pathways, leading to sensitization of peripheral and / or central neurons, thereby demonstrating a reduced stimulation threshold. Therefore, subjects with CIPN or DPN may experience pain due to this sensitization, such as experiencing pain caused by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). According to the observations herein, modified NSAIDs may have a direct analgesic effect, such as by reducing neuronal signaling involved in pain sensation. In addition, modified NSAIDs can reduce pain caused by peripheral sensitization or central sensitization caused by neuropathy. Therefore, modified NSAIDs can reduce pain signaling occurring in the center. Modified NSAIDs can reduce pain signaling occurring in the sciatic nerve. Modified NSAIDs can reduce pain signaling occurring in the dorsal root ganglion. In view of the observation that modified NSAIDs, i.e., PS, are confirmed to ascend along peripheral neurons to the spinal cord, modified NSAIDs can reduce pain signaling occurring in the spinal cord. In some embodiments, the neuropathic pain is allodynia. Allodynia may be a response to mechanical and / or thermal stimulation. Additionally, in some embodiments, the neuropathic pain is hyperalgesia.

[0224] 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 cover the distribution range of a stocking or glove).

[0225] In some embodiments, the modified NSAID is formulated for oral administration. Thus, the modified NSAID can be administered orally. Thus, in some embodiments, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with CIPN, wherein the modified NSAID is administered orally. Thus, in some embodiments, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with DPN, wherein the modified NSAID is administered orally. In these embodiments, the modified NSAID can be PS.

[0226] Thus, in some aspects, the present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing neuropathic pain associated with CIPN, wherein the PS is administered orally.

[0227] Thus, in other aspects, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing neuropathic pain associated with DPN, wherein the PS is administered orally.

[0228] In specific embodiments for the treatment and / or prevention of CIPN or DPN based on oral administration, the modified NSAID can be one or more of the following: PS, such as Formula I or II; naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; ibuprofen amide phosphate, such as Formula XI; NO-sulindac, for example, Formula XLIV; sulindac amide phosphate, 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.

[0229] In specific embodiments for the treatment and / or prevention of CIPN or DPN based on oral administration, the modified NSAID can be a phosphorylated NSAID, such as PS, such as Formula I or II; naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; or glycerophosphate ibuprofen, such as Formula LXXI.

[0230] In specific embodiments for the treatment and / or prevention of CIPN or DPN based on oral administration, the modified NSAID can be a phosphamidate NSAID, such as ibuprofen amide phosphate, such as Formula XI; or sulindac amide phosphate, such as Formula X.

[0231] In specific embodiments for the treatment and / or prevention of CIPN or DPN based on oral administration, the modified NSAID can be an NO-releasing NSAID, such as NO-sulindac, such as Formula XLIV; an HS-releasing NSAID, such as HS-sulindac, such as Formula XXXIV; or a NOSH-releasing NSAID, such as NOSH-aspirin, such as Formula LIX.

[0232] In specific embodiments for the treatment and / or prevention of CIPN or DPN based on oral administration, the modified NSAID can be a modified sulindac, such as PS, such as Formula I or II; NO-sulindac, such as Formula XLIV; HS-sulindac, such as Formula XXXIV; Pt-sulindac, such as Formula LXVII; or sulindac amide phosphate, such as Formula X.

[0233] In specific embodiments for the treatment and / or prevention of CIPN or DPN based on oral administration, the modified NSAID can be a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI, in particular ibuprofen amide phosphate, such as Formula XI.

[0234] Other Embodiments of Pain Associated with CIPN

[0235] As outlined above, chemotherapy can damage neurons, leading to peripheral neuropathy and associated neuropathic pain. Pain can occur during or after a patient undergoes chemotherapy and 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 preventing neuropathic pain associated with CIPN, comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby preventing neuropathic pain associated with CIPN. In other embodiments, the present invention provides a method for treating neuropathic pain associated with CIPN, comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating neuropathic pain associated with CIPN. A subject may experience neuropathic pain caused by one or more previous doses of chemotherapy before receiving one or more subsequent doses, and therefore, the subject would benefit from an analgesic that can both treat existing neuropathic pain and prevent the development of further neuropathic pain. Thus, in some embodiments, modified NSAIDs can be used to treat and prevent neuropathic pain associated with CIPN. In accordance with the above, the present invention provides a modified NSAID for use in treating and / or preventing neuropathic pain associated with CIPN. In addition, the present invention also provides the use of a modified NSAID for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with CIPN.

[0236] Because CIPN develops as a result of chemotherapy, the subject can be a human patient with cancer who will be receiving, is currently receiving, or has previously received treatment with one or more chemotherapeutic compounds. Generally, a chemotherapeutic compound refers to an agent that has anti-neoplastic properties or is capable of inhibiting cell growth or proliferation. The prevalence of CIPN varies depending on the agent, with reported rates ranging from 19% to over 85% in patients treated with different agents, and is highest with platinum-based drugs, taxanes, immunomodulatory drugs, and epothilones, although CIPN has also been observed in patients treated with other common cancer chemotherapies, including vinca alkaloids and proteasome inhibitors. Thus, the one or more chemotherapeutic compounds may be platinum-based antineoplastic drugs (e.g., oxaliplatin, cisplatin, or carboplatin), taxanes (e.g., paclitaxel, docetaxel, or cabazitaxel), vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, or vindesine), or proteasome inhibitors (e.g., bortezomib). The one or more chemotherapeutic compounds may be one or more immunomodulatory drugs, including thalidomide and / or its analogs. The one or more chemotherapeutic compounds may be platinum-based antineoplastic drugs, such as oxaliplatin, taxanes (e.g., paclitaxel), and vinca alkaloids, such as vincristine. The subject may have any cancer associated with the development of CIPN and associated neuropathic pain that is treated with a chemotherapeutic compound. In some embodiments, the subject suffering from 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.

[0237] Based on the observations herein, modified NSAIDs may have a direct analgesic effect on neuropathic pain associated with CIPN. Neuropathic pain associated with CIPN may be burning pain. Subjects who are undergoing chemotherapy or have received chemotherapy may experience persistent and symmetrical neuropathic pain in the lower and upper limbs. When treating neuropathic pain associated with CIPN, modified NSAIDs can reduce neuropathic pain. In some cases, the reduction is complete, thereby eliminating neuropathic pain. When treating neuropathic pain associated with CIPN, modified NSAIDs can also reduce one or more sensory symptoms associated with CIPN. When preventing neuropathic pain associated with CIPN, modified NSAIDs can reduce the incidence of neuropathic pain. When preventing neuropathic pain associated with CIPN, modified NSAIDs can also reduce the incidence of one or more sensory symptoms associated with CIPN.

[0238] Patients with CIPN describe a range of sensory, bilateral symptoms, such as symptoms in the hands and feet (also described as a "stocking and glove" distribution). The sensory symptoms include paresthesias (e.g., numbness, tingling, pricking, and / or forking), burning, or shooting (i.e., electric shock-like) sensations. Even if the sensory symptoms experienced by a subject undergoing or after chemotherapy are not considered painful (or do not reach the threshold to be considered pain per se), the modified NSAID can reduce any one or more sensory symptoms experienced by a subject undergoing or after chemotherapy, including those listed above. The modified NSAID can be used to reduce the stocking and glove distribution in a subject undergoing or after chemotherapy. In some cases, the reduction is complete, thereby eliminating one or more sensory symptoms.

[0239] As described above, neuropathic pain associated with CIPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. Modified NSAIDs can reduce neuronal signaling involved in pain sensation in subjects undergoing or after chemotherapy. Modified NSAIDs can reduce pain caused by peripheral sensitization or by central sensitization. In some cases, the reduction can be complete, thereby eliminating the generation of pain. Therefore, modified NSAIDs can reduce pain signaling occurring in the central nervous system. Modified NSAIDs can reduce pain signaling occurring in the sciatic nerve. Modified NSAIDs can reduce pain signaling occurring in the dorsal root ganglia. Given that PS has been shown to ascend along peripheral neurons to the spinal cord, without wishing to be bound by theory, modified NSAIDs can reduce pain signaling occurring in the spinal cord. In some cases, the reduction can be complete, thereby eliminating pain signaling. Neuropathic pain in subjects undergoing or after chemotherapy for CIPN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, neuropathic pain in a CIPN subject undergoing or following chemotherapy may be hyperalgesia.

[0240] Neuropathic pain in patients undergoing or after chemotherapy can be measured using a visual analog pain scale or any other appropriate method in the art.

[0241] Other Embodiments of Pain Associated with DPN

[0242] Conditions that develop in diabetic patients, particularly hyperglycemia, can cause neuronal damage, leading to peripheral neuropathy and associated neuropathic pain. Neuropathic pain in these patients develops over time and is often more severe in patients with long-term illness, and may include tingling, burning, and / or piercing 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, thereby preventing neuropathic pain associated with DPN. 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, thereby treating neuropathic pain associated with DPN. When diabetic patients develop DPN over time, they may experience increasingly worsening neuropathic pain over time, and therefore, they would benefit from an analgesic that can both treat ongoing neuropathic pain and prevent the development of further neuropathic pain. Therefore, in some embodiments, modified NSAIDs can be used to treat and prevent neuropathic pain associated with DPN. In accordance with the above, the present invention provides a modified NSAID for use in treating and / or preventing neuropathic pain associated with DPN. In addition, the present invention also provides the use of a modified NSAID for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with DPN.

[0243] According to the observations herein, modified NSAIDs may have a direct analgesic effect on the neuropathic pain associated with DPN. The neuropathic pain associated with DPN may be tingling, burning and / or drilling pain. Subjects with DPN may experience persistent and symmetrical neuropathic pain in the lower and upper limbs. When treating the neuropathic pain associated with DPN, modified NSAIDs can reduce the neuropathic pain. In some cases, the reduction is complete, thereby eliminating the neuropathic pain. When treating the neuropathic pain associated with DPN, modified NSAIDs can also reduce one or more sensory symptoms associated with DPN. When preventing the neuropathic pain associated with DPN, modified NSAIDs can reduce the incidence of neuropathic pain. When preventing the neuropathic pain associated with DPN, modified NSAIDs can also reduce the incidence of one or more sensory symptoms associated with DPN.

[0244] The sensory symptoms of DPN include paresthesias (e.g., numbness, tingling, stinging, or forking), burning, or shooting pains (i.e., electric shock-like) sensations. DPN typically affects the extremities, such as the feet, hands, legs, and arms, where the nerve fibers are the longest and most numerous, and patients typically present with a "stocking-and-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 per se), a modified NSAID can be used to alleviate any one or more sensory symptoms experienced by a subject with DPN, including those listed above. Modified NSAIDs can be used to reduce the stocking-and-glove distribution in a subject with DPN. In some cases, the reduction is complete, thereby eliminating one or more sensory symptoms.

[0245] As described above, the neuropathic pain associated with DPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. Modified NSAIDs can reduce the neuronal signaling involved in the pain sensation of subjects with DPN. Modified NSAIDs can reduce pain caused by peripheral sensitization or by central sensitization. In some cases, the reduction can be complete, thereby eliminating the generation of pain. Therefore, modified NSAIDs can reduce pain signaling occurring in the center. Modified NSAIDs can reduce pain signaling occurring in the sciatic nerve. Modified NSAIDs can reduce pain signaling occurring in the dorsal root ganglia. Given that PS has been shown to ascend along peripheral neurons to the spinal cord, without wishing to be bound by theory, modified NSAIDs can reduce pain signaling occurring in the spinal cord. In some cases, the reduction can be complete, thereby eliminating pain signaling. The neuropathic pain in subjects with DPN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in subjects with DPN may be hyperalgesia.

[0246] Neuropathic pain in patients with DPN can be measured using a visual analog pain scale or using any other appropriate method in the art.

[0247] Pain associated with central sensitization

[0248] As outlined above, pain associated with central sensitization occurs when the sensitivity of neurons located in the central nervous system to triggering action potentials decreases (i.e., the neurons become sensitized). This occurs due to peripheral sensitization caused by continuous noxious signaling from the periphery, which ultimately leads to overexcitation of central neurons, manifesting as pain even in the absence of continuous peripheral input. In fact, central sensitization is associated with spontaneous pain, but usually manifests as abnormal pain (pain caused by non-painful stimuli) or hyperalgesia (enhanced pain sensation in response to harmful stimuli). Central sensitization is associated with chronic pain states, in which pain is generated or amplified by overexcitation of higher-order neurons. Pain can manifest as widespread or diffuse pain, sometimes localized near the site of the initial triggering of nociception. In some embodiments, 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, thereby treating pain associated with central sensitization. Subjects experiencing pain associated with central sensitization would benefit from an analgesic that can both reduce the pain resulting from central sensitization and prevent the development of further pain associated with central sensitization. Thus, in some embodiments, PS can be used to treat and prevent pain associated with central sensitization. Consistent with the foregoing, the present invention provides PS for use in treating pain associated with central sensitization. Furthermore, the present invention also provides the use of PS for the manufacture of a medicament for treating pain associated with central sensitization.

[0249] The pain associated with central sensitization is not acute nociceptive pain (i.e., pain that is relieved when the noxious stimulus is removed). Therefore, in some embodiments, the pain associated with central sensitization is chronic pain (i.e., pain that persists or recurs for more than three months). In specific embodiments, pain is felt in the absence of peripheral nociceptive input, for example, in response to noxious or innocuous stimuli. The pathogenesis of central sensitization may vary depending on the initial pathology that triggers peripheral input and leads to central sensitization. For example, central sensitization may be the result of an inflammatory pain mechanism, that is, the initial trigger is an inflammatory response, but the resulting central sensitization can cause pain even in the absence of ongoing inflammation. In specific cases, central sensitization is the result of a neuropathic pain mechanism. Central sensitization is a characteristic of many chronic pain symptoms. The 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; spondyloarthropathy; lupus; temporomandibular joint disorder; and / or idiopathic low back pain. Central sensitization-related pain caused by inflammatory pain is not caused by an ongoing peripheral inflammatory response. In specific embodiments, the pain associated with central sensitization may be pain associated with one or more of the following: neuropathic pain; fibromyalgia; chronic pain; chronic regional pain syndrome; osteoarthritis; temporomandibular joint disorder; and / or idiopathic low back pain. In some embodiments, the pain associated with central sensitization occurs after a stroke or spinal cord injury, or in subjects with multiple sclerosis. In some embodiments, the pain associated with central sensitization may be pain associated with post-traumatic peripheral neuropathy. In some embodiments, the pain associated with central sensitization may be pain associated with postherpetic neuralgia. In some embodiments, the pain associated with central sensitization may be migraine pain. In some embodiments, the pain associated with central sensitization is pain from other headache disorders. In some embodiments, the pain associated with central sensitization is pain associated with corneal neuropathic pain.

[0250] Based on the observations herein, PS has a direct analgesic effect on pain associated with central sensitization. When treating pain associated with central sensitization, PS can reduce pain. In some cases, the reduction is complete, thereby eliminating the pain. When treating pain associated with central sensitization, PS can also reduce one or more symptoms associated with central sensitization. When treating and preventing pain associated with central sensitization, PS can reduce the incidence of pain. When treating and preventing pain associated with central sensitization, PS can also reduce the incidence of one or more symptoms associated with central sensitization.

[0251] The pain associated with central sensitization can be diffuse pain. The pain can be widely distributed. In some embodiments, the pain can spread around the area of ​​the initial injury. In some embodiments, the pain associated with central sensitization can have the characteristics of neuropathic pain and therefore can cause one or more sensations described as fever, burning, throbbing, shooting, tingling, sharp pain, cramping, aching, tingling, numbness or pins and needles. Patients with pain associated with central sensitization may experience a range of symptoms. These symptoms include mood changes, 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 pain (or do not reach the threshold required to be considered pain itself), PS can reduce any one or more symptoms experienced by the subject. In some cases, the reduction is complete, thereby eliminating one or more symptoms experienced by the subject. In fact, resolving the potential pain associated with central sensitization will alleviate many of the symptoms associated with it.

[0252] As described above, the pain associated with central sensitization can be allodynia and / or hyperalgesia. In specific embodiments, the pain associated with central sensitization is allodynia (e.g., mechanical or thermal allodynia). PS can reduce the neuronal signaling involved in the pain sensation caused by central sensitization. In some cases, the reduction can be complete, thereby eliminating the generation of pain. Therefore, PS can reduce pain signaling occurring in the center. PS can reduce pain signaling occurring in the dorsal root ganglia. PS can reduce pain signaling occurring in the dorsal horn of the spinal cord. Given that PS has been shown to ascend to the spinal cord along peripheral neurons, PS can reduce pain signaling occurring in the CNS. In some cases, the reduction can be complete, thereby eliminating pain signaling. The pain associated with central sensitization in a subject can be neuropathic pain. In specific 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 cannot prevent the development of central sensitization.

[0253] A patient's pain associated with central sensitization can be measured by a visual analog pain scale or using any other appropriate method in the art.

[0254] The observations herein of treating allodynia in a variety of different models, and the observation that PS can reach key sites of action by being delivered to the CNS via peripheral neurons, support the role of PS in directly acting on neuronal signaling involved in central sensitization. Since sulindac (the parent compound of PS) does not share these activities, the observations herein suggest that modifying sulindac not only results in surprising analgesic activity of PS acting directly on neural signaling, but also makes PS more capable of being delivered to key central sites of action, enabling it to more effectively impart its analgesic activity to neural signaling. Therefore, without wishing to be bound by theory, the observations herein suggest that NSAIDs can be modified so that they can act directly on neuronal signaling and more easily access key sites of action by being delivered along peripheral neurons projecting from the central nervous system, thereby overcoming the obvious shortcomings of NSAIDs in treating pain associated with central sensitization. Therefore, as an alternative to PS, the methods of the present invention can be performed using one or more modified NSAIDs disclosed herein. Therefore, the present invention provides a method for treating pain associated with central sensitization, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating pain associated with central sensitization. As used herein, "modified NSAID" refers to a compound produced by modifying an NSAID molecule (i.e., a parent compound).

[0255] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-amidated 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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate.

[0256] In certain embodiments, the modified NSAID for treating pain associated with central sensitization is selected from one or more of the following: naproxen phosphate, e.g., Formula VIII; ibuprofen phosphate, e.g., Formula III; glycerobuprofen phosphate, e.g., Formula LXXI; glycerophosphoaspirin II, e.g., Formula V; sulindac amide phosphate, e.g., Formula X; ibuprofen amide phosphate, e.g., Formula XI; glycerophosphoaspirin amide, e.g., Formula XII; NO-sulindac, e.g., Formula XLIV; sulindac platinum, e.g., Formula LXVII; NO-aspirin, e.g., Formula XLIX; HS-sulindac, e.g., Formula XXXIV; or NOSH-aspirin, e.g., Formula LIX.

[0257] In certain embodiments, the modified NSAID used to treat 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), phosphamide-modified sulindac (e.g., sulindac amide phosphate, such as Formula X), or metal-chelated sulindac (e.g., sulindac platinum, such as Formula LXVII). In specific embodiments, the modified NSAID used to treat 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 phosphamide-modified sulindac (e.g., sulindac amide phosphate, such as Formula X).

[0258] In specific embodiments, the modified NSAID used to treat pain associated with central sensitization is a phosphorylated NSAID other than PS, such as naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; glycerophosphoprofen, such as Formula LXXI; or glycerophosphoaspirin II, such as Formula V.

[0259] In specific embodiments, the modified NSAID used to treat pain associated with central sensitization is a phosphamidate NSAID, such as ibuprofenamide phosphate, such as Formula XII; ibuprofenamide phosphate, such as Formula XI; or sulindacamide phosphate, such as Formula X.

[0260] In specific embodiments, the modified NSAID used to treat pain associated with central sensitization is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI.

[0261] In specific embodiments for treating pain associated with central sensitization, the modified NSAID is a modified form of sulindac, 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 phosphamide-modified sulindac (e.g., sulindac amide phosphate, such as Formula X).

[0262] In some embodiments for treating pain associated with central sensitization, the modified NSAID is administered orally.

[0263] In specific embodiments, the orally administered modified NSAID can be one or more of the following: PS, e.g., Formula I or II; sulindac amide phosphate, e.g., Formula X; ibuprofen amide phosphate, e.g., Formula XI; ibuprofen phosphate, e.g., Formula III; glyceribuprofen phosphate, e.g., Formula LXXI; NO-sulindac, e.g., Formula XLIV; or HS-sulindac, e.g., Formula XXXIV; Pt-sulindac, e.g., Formula LXVIII; or naproxen phosphate, e.g., Formula VIII.

[0264] In some embodiments, the orally administered modified NSAID is a phosphorylated NSAID, such as PS, for example, Formula I or II; naproxen phosphate, for example, Formula VIII; ibuprofen phosphate, for example, Formula III; or ibuprofen glycerol phosphate, for example, Formula LXXI. In specific embodiments, the orally administered modified NSAID is a phosphamidate NSAID, such as sulindac amide phosphate, for example, Formula X; or ibuprofen amide phosphate, for example, Formula XI.

[0265] In some embodiments, the orally administered modified NSAID is a modified sulindac, e.g., PS, such as Formula I or II; NO-sulindac, such as Formula XLIV; HS-sulindac, such as Formula XXXIV; or sulindac amide phosphate, such as Formula X.

[0266] In specific embodiments, the orally administered modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI, particularly ibuprofen amide phosphate, such as Formula XI.

[0267] In a specific embodiment for treating pain associated with central sensitization, the orally administered modified NSAID is sulindac amide phosphate, such as Formula X.

[0268] Pain associated with post-traumatic peripheral neuropathy

[0269] Post-traumatic peripheral neuropathy (PTPN) may be caused by a series of traumatic peripheral nerve injuries, and is accompanied by neuropathic pain, which can lead to mild discomfort or even lifelong disorders. Traumatic nerve injuries can be divided into several categories (Seddon and Sunderland's I-VI grades) according to the presence of demyelination and the degree of damage to nerve axons and connective tissue (see Menorca et al., Hand Clin. (2013); 29 (3): 317-330). Sorted by severity, they are mainly classified into neuropraxia (grade I), axon truncation (including grades II-IV) and neurotruncation (grade V). Grade VI (a subsequent supplement to the Seddon and Sunderland classification) involves different levels of damage along the nerve (grades III-V).

[0270] Certainly, such peripheral nerve trauma may be associated with chronic neuropathic pain. Trauma may result in the development of tangles of nerve fibers and connective tissue (traumatic neuromas) following nerve damage, with this area being associated with paresthesias. The damaged nerve and any peripheral nerves may show changes in gene expression that make them hypersensitive and spontaneously discharge. Thus, trauma can cause either a hypersensitivity to pain (allodynia) to non-noxious stimuli or an exaggerated pain response (hyperalgesia) to noxious stimuli, reflecting central sensitization. Traumatic neuropathic pain can cause patients to experience burning, tingling, aching, gnawing, or nausea, as well as numbness, tingling, and prickling sensations.

[0271] The neuropathic pain associated with PTPN is particularly difficult to treat. Currently, this pain is 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. In addition, procedures designed to interfere with, interrupt, or modulate pain pathways, including nerve blocks, ablations, and neurostimulation, are available. Unfortunately, pain control is suboptimal, and many systemic therapies induce significant side effects, leading to poor treatment adherence.

[0272] Therefore, there is an urgent need for compounds that treat and / or prevent pain associated with peripheral neuropathies, particularly PTPN.

[0273] The inventors of the present invention unexpectedly discovered that PS is effective for treating and preventing pain associated with PTPN.

[0274] As described herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike the parent compound, the NSAID sulindac, PS does not inhibit COX-1 and COX-2 or prostaglandin synthesis and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties by inhibiting NF-κB activation and changes in the MAPK signaling branch, and has been shown to be active in treating rheumatoid arthritis in inflammatory mouse models by inhibiting key proinflammatory signaling pathways (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32; and Mattheolabakis et al. (2013) Pharm Res 30(6):1471–82). WO 2019 / 067919 proposes that PS has anti-inflammatory activity in an acute dry eye (DED) model. Furthermore, in this model, PS was found to restore the suppressed ocular sensitivity in DED, suggesting that the effect of PS is to increase rather than decrease nociception. Although PS is not a typical NSAID, as described above, it exhibits NSAID-like activity 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 PTPN. Furthermore, clinical guidelines in this field recommend avoiding the use of NSAIDs for all types of neuropathic pain; therefore, anti-inflammatory activity alone is considered insufficient for treatment.

[0275] Nonetheless, preliminary in vivo evidence suggests that PS has efficacy in treating neuropathic pain associated with PTPN. Further experiments in specific animal models of neuropathic pain associated with PTPN confirmed these preliminary observations.

[0276] Therefore, 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, thereby treating and / or preventing neuropathic pain associated with PTPN.

[0277] In some embodiments, the PS is a sulfoxide form of PS. Thus, PS may have Formula I (PS-I):

[0278]

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

[0280]

[0281] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfoxide form of this compound is preferred. Compounds of Formula I and II are described in U.S. Patent No. 8,236,820, which is incorporated herein by reference in its entirety.

[0282] Neuropathic pain associated with PTPN may be caused by traumatic nerve injury in one or more categories of the Seddon and Sunderland classification (i.e., grades I-VI). For example, the traumatic nerve injury may be neuropraxia (grade I, defined as focal demyelination (resulting in asynchronous conduction, or even conduction block), but no damage to the axons or connective tissue). Neuropraxia may be caused by mild compression or traction on the nerve. Compression injuries may occur at locations that cause the nerve to pass through narrow anatomical passages, such as those in the upper limb, including the carpal and cubital tunnels. Nerves may also be compressed by displacement of fracture fragments, joint dislocations, or expanding hematomas.

[0283] Traumatic nerve injury may be axontosis (grades II-IV, with increasing severity involving the axon with intact endoneurium (grade II); involving the axon and endoneurium with intact perineurium (grade III); and involving the axon, endoneurium, and perineurium with intact epineurium (grade IV). Axontosis may result from a crush injury that does not completely transcribe the nerve. This crush injury, with its attendant varying degrees of nerve injury, may result from acute traumatic compression of the nerve with a blunt instrument, such as a bat, forceps, or other compressive object.

[0284] In some cases, traumatic nerve injury may be a neurotmesis (grade V, defined as complete transection of the axon and connective tissue layers, where complete discontinuity of the nerve is observed). Injuries involving a complete blockade of a nerve may result from a knife wound, gunshot wound, cut by glass shards, or from a car accident or surgical complication.

[0285] Finally, traumatic nerve injury may be a combination of any of these categories (Grade VI).

[0286] In some embodiments, the traumatic nerve injury is a compression injury. In specific 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 injury may be caused by the following causes: accidents and trauma; joint sprains (such as ankle, knee or wrist sprains); arthritis; fractures; bone spurs; joint dislocations (such as elbow or shoulder dislocations); herniated discs; hypothyroidism; surgical complications; tumors and / or cysts.

[0287] The traumatic nerve injury may affect one or more of the following nerves: the median nerve, radial nerve, suprascapular nerve, ulnar nerve, lateral femoral cutaneous nerve, peroneal nerve, pudendal nerve, sciatic nerve, tibial nerve, and / or spinal nerve. The spinal nerve may be one or more of the following: cervical nerve; thoracic nerve; lumbar nerve; sacral nerve and / or coccygeal nerve. Thus, the neuropathic pain associated with PTPN may 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); meralgia paresthesia; 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 may be pain caused by a herniated disc.

[0288] Neuropathic pain associated with PTPN may be caused by a herniated disc in the spine. A herniated disc (disc herniation or slipped disc) occurs when the outer fibers of the intervertebral disc rupture or tear, causing the disc to bulge outward from the spine. This herniated disc may cause compression of the nerves located between adjacent vertebrae, or even the spinal cord itself. This may cause pain, numbness, tingling, or weakness in the arms or legs. Long-term compression of the intervertebral disc can lead to symptoms associated with neuropathic pain (such as allodynia and hyperalgesia). A bulging disc is not as serious as a herniated disc, but it is also a cause of neuropathic pain associated with PTPN. The herniated disc (or bulge) may be a cervical herniated disc (or bulge), for example, causing pain in the neck, shoulder, or arm. The herniated disc (or bulge) may be a thoracic herniated disc (or bulge), for example, causing pain in the mid-back around the level of the herniated disc (or bulge). The herniated (or bulging) disc may be a lumbar disc herniation (or bulging), for example, causing intermittent or persistent back pain and / or sciatica.

[0289] Neuropathic pain associated with post-traumatic peripheral neuropathy, such as that caused by traumatic injury to peripheral neurons, may occur immediately after injury and may manifest as, for example, burning, tingling, raw, gnawing, sickening pain, poorly localized and sometimes diffuse, and accompanied by other sensory symptoms. Therefore, 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, thereby preventing neuropathic pain associated with PTPN. Pain may also occur with a delayed onset after injury. Therefore, 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, thereby preventing neuropathic pain associated with PTPN. Given that pain can occur immediately or with a delayed onset, a subject may experience pain immediately upon injury that develops into a different pain sensation that occurs with a delayed onset. Therefore, in some embodiments, PS can be used to treat and prevent neuropathic pain associated with PTPN. In accordance with the above, the present invention provides a PS for treating and / or preventing neuropathic pain associated with PTPN. In addition, the present invention also provides the use of PS for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PTPN.

[0290] Based on the observations herein, PS may have a direct analgesic effect on neuropathic pain associated with PTPN. Neuropathic pain associated with PTPN may be a tingling or burning pain. When treating neuropathic pain associated with PTPN, PS may reduce neuropathic pain. In some cases, the reduction may be complete, thereby eliminating the neuropathic pain associated with PTPN. When treating neuropathic pain associated with PTPN, PS may also reduce one or more sensory symptoms associated with PTPN. When preventing neuropathic pain associated with PTPN, PS may reduce the incidence of neuropathic pain. When preventing neuropathic pain associated with PTPN, PS may also reduce the incidence of one or more sensory symptoms associated with PTPN.

[0291] Patients with PTPN describe a range of sensory symptoms. These include paresthesias (e.g., numbness, tingling, stinging, and / or forking), burning, or tingling 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 per se), PS can reduce any one or more sensory symptoms experienced by the subject, including those listed above. In some cases, the reduction is complete, thereby eliminating one or more sensory symptoms associated with PTPN.

[0292] As described above, nerve damage associated with PTPN may overactivate pain signaling pathways, leading to sensitization of peripheral and / or central neurons, thereby demonstrating a lowered stimulation threshold. Therefore, subjects with PTPN may experience pain due to this sensitization, such as experiencing pain caused 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 the neuronal signaling involved in pain sensation. As described above, neuropathic pain associated with PTPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. PS may reduce the neuronal signaling involved in pain sensation in subjects with traumatic peripheral nerve injury. PS can reduce pain caused by peripheral sensitization or by central sensitization. In particular, because PS can reach key sites of pain generation, it can reduce pain caused by central sensitization. In some cases, the reduction can be complete, thereby eliminating the generation of pain. Therefore, PS can reduce pain signaling occurring in the center. PS can reduce pain signaling occurring in peripheral nerves. PS can reduce pain signaling that occurs in the dorsal root ganglia. PS can reduce pain signaling that occurs in the dorsal horn of the spinal cord. Given that PS has been shown to ascend along peripheral neurons to the spinal cord, PS can reduce pain signaling that occurs in the CNS. In some cases, the reduction can be complete, thereby eliminating pain signaling. Neuropathic pain in subjects with PTPN can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, neuropathic pain in subjects with PTPN can be hyperalgesia.

[0293] A patient's neuropathic pain can be measured using a visual analog pain scale or using any other appropriate method in the art.

[0294] 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, particularly topical administration to a subject's body near or to the site of a wound.

[0295] In specific embodiments for treating and / or preventing pain associated with PTPN, the PS may be administered orally.

[0296] The observation herein that PS has a significant analgesic effect on neuropathic pain associated with PTPN is further supported by the observation that PS can reach key sites of action by being delivered to the CNS via peripheral neurons, confirming a role for PS in directly acting on neuronal signaling resulting from trauma to peripheral nerves, for example by reducing the generation of pain caused by central sensitization. Since sulindac (the parent compound of PS) does not share these activities, the observations herein suggest that modifying sulindac not only imparts surprising analgesic activity to PS acting directly on neural signaling, but also makes PS more capable of being delivered to central sites of action, enabling it to more effectively impart its analgesic activity to neural signaling. Thus, without wishing to be bound by theory, the observations herein suggest that NSAIDs can be modified to enable them to act directly on neuronal signaling and more readily access key sites of action by being delivered along centrally projecting peripheral neurons, thereby overcoming the significant drawback of NSAIDs in their inability to exert a meaningful analgesic effect on neuropathic pain associated with PTPN. Thus, as an alternative to PS, the methods of the present invention can be performed using one or more modified NSAIDs disclosed herein. Therefore, the present invention also provides a method for treating and / or preventing neuropathic pain associated with PTPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with PTPN. As used herein, a "modified NSAID" refers to a compound produced by modifying an NSAID molecule (i.e., a parent compound).

[0297] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-amidated 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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate.

[0298] In certain embodiments, the modified NSAID does not have Formula LXIX and / or Formula LXX.

[0299] In specific embodiments, the modified NSAID used to treat and / or prevent neuropathic pain associated with PTPN is one or more of: PS, e.g., Formula I or II; naproxen phosphate, e.g., Formula VIII; ibuprofen phosphate, e.g., Formula III; sulindac amide phosphate, e.g., Formula X; ibuprofen amide phosphate, e.g., Formula XI; NO-sulindac, e.g., Formula XLIV; HS-sulindac, e.g., Formula XXXIV; Q922, e.g., Formula LXVIII; NOSH-1, e.g., Formula LIX; or a compound having formula LXIX or LXX.

[0300] In specific embodiments, the modified NSAID used to treat and / or prevent neuropathic pain associated with PTPN is a phosphorylated NSAID, such as PS, such as Formula I or II; naproxen phosphate, such as Formula VIII; or ibuprofen phosphate, such as Formula III. In other embodiments, the modified NSAID used to treat and / or prevent neuropathic pain associated with PTPN is an NO-releasing NSAID, such as NO-sulindac, such as Formula XLIV; or an HS-releasing NSAID, such as HS-sulindac, such as Formula XXXIV.

[0301] In specific embodiments, the modified NSAID used to treat and / or prevent neuropathic pain associated with PTPN is a phosphamidate NSAID, such as sulindac amide phosphate, such as Formula X; or phosphoprofen amide, such as Formula XI.

[0302] In specific embodiments, the modified NSAID used to treat and / or prevent neuropathic pain associated with PTPN is a modified sulindac, e.g., PS, such as Formula I or II; NO-sulindac, such as Formula XLIV; HS-sulindac, such as Formula XXXIV; or sulindacamide phosphate, such as Formula X. In other embodiments, the modified NSAID used to treat and / or prevent neuropathic pain associated with PTPN is a modified ibuprofen, e.g., ibuprofen phosphate, such as Formula III; or ibuprofenamide phosphate, such as Formula XI.

[0303] In some embodiments for treating and / or preventing neuropathic pain associated with PTPN, the modified NSAID is administered orally. In specific embodiments for treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is selected from one or more of: PS, e.g., Formula I or II; ibuprofen phosphate, e.g., Formula III; sulindac amide phosphate, e.g., Formula X; or ibuprofen amide phosphate, e.g., Formula XI.

[0304] In specific embodiments, the orally administered modified NSAID is a phosphorylated NSAID, such as sulindac phosphate (PS), such as Formula I or II; or ibuprofen phosphate, such as Formula III. In certain embodiments for treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is a phosphamidate NSAID, such as sulindac amide phosphate, such as Formula X; or phosphoprofen amide, such as Formula XI.

[0305] In certain embodiments, the orally administered modified NSAID is a modified sulindac, such as sulindac phosphate (PS), such as Formula I or II, or sulindac amide phosphate, such as Formula X. In certain embodiments for treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III, or preferably ibuprofen amide phosphate, such as Formula XI.

[0306] Pain associated with postherpetic neuralgia

[0307] PHN is a common complication of herpes zoster (shingles) and is caused by reactivation of the varicella-zoster virus (VZV). VZV is a highly virulent neurotropic virus that causes primary infection with varicella (chickenpox) in susceptible individuals. The virus can be transported retrogradely from the skin along the axons of sensory neurons to establish a latent infection within the sensory ganglia of the peripheral nervous system. Even in previously infected subjects who are immunosuppressed, the virus can reactivate, presenting as acute herpes zoster (AHZ, “shingles”). Recovery from AHZ is often complicated by the development of postherpetic neuralgia, a neuropathic pain syndrome characterized by persistent pain in the area of ​​shingles infection. PHN is generally defined as pain that persists for 90 days or longer after the initial rash or for at least three months after the skin lesions have healed. In the United States alone, more than one million cases of AHZ are diagnosed annually. About 20% of AHZ patients experience PHN and will continue to suffer from intermittent neuropathic symptoms, including itching and pain. This pain manifests as sharp pain, tingling, throbbing or burning pain, usually confined to the site of the initial rash. Long-term pain is associated with allodynia (abnormal pain) to non-noxious stimuli or excessive pain response (hyperalgesia) to noxious stimuli, reflecting central sensitization. It is reported that if left untreated, the incidence of pain that continues for three months after the rash appears is about 8-15%, and this value increases rapidly in the elderly.

[0308] PHN-associated pain is associated with peripheral sensitization, 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 ganglion to the periphery. Viral spread can cause nerve damage (e.g., due to an immune response against neurons), resulting in more frequent depolarization of nociceptors. This lowering of the nociceptor signaling threshold leads to peripheral sensitization. Sustained peripheral signaling can lead to central sensitization, characterized by increased activation of centrally located neurons (e.g., dorsal root horn and higher-order neurons). Other pathological mechanisms that result in altered gene expression in centrally located neurons, loss of co-inhibitory signaling, or altered neuronal signaling networks (e.g., dedifferentiation) can contribute to the hypersensitivity seen in subjects with PHN-associated pain. Persistent pain is associated with central sensitization and manifests as hyperalgesia (an increased response to noxious stimuli) and / or allodynia (pain triggered by non-painful stimuli).

[0309] Neuropathic pain associated with PHN is particularly difficult to treat. Current treatments for PHN-related neuropathic pain include systemic tricyclic antidepressants, anticonvulsants, and opioids, as well as topical lidocaine and capsaicin. In addition, interventional therapies include subcutaneous botulinum toxin, nerve blocks, and neurostimulation. 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-related neuropathic pain causes significant suffering and economic burden, manifested in increased healthcare costs and loss of quality-adjusted life years, and the lack of efficacy of current treatments makes PHN-related pain an area of ​​urgent medical need.

[0310] Therefore, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathies, particularly PHN.

[0311] The present inventors unexpectedly discovered that PS is effective for treating and preventing pain associated with PHN.

[0312] As described herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike the parent compound, the NSAID sulindac, PS does not inhibit COX-1 and COX-2 or prostaglandin synthesis and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties by inhibiting NF-κB activation and changes in the MAPK signaling branch, and has been shown to be active in treating rheumatoid arthritis in inflammatory mouse models by inhibiting key proinflammatory signaling pathways (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32; and Mattheolabakis et al. (2013) Pharm Res 30(6):1471–82). WO 2019 / 067919 proposes that PS has anti-inflammatory activity in an acute dry eye (DED) model. Furthermore, in this model, PS was found to restore the suppressed ocular sensitivity in DED, suggesting that the effect of PS is to increase rather than decrease nociception. Although PS is not a typical NSAID, as described above, it exhibits NSAID-like activity 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 PHN. Furthermore, clinical guidelines in this field recommend avoiding the use of NSAIDs for all types of neuropathic pain; therefore, anti-inflammatory activity alone is considered insufficient for treatment. Indeed, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1–25) concluded that NSAIDs do not reduce pain in PHN.

[0313] Nonetheless, preliminary in vivo evidence suggests that PS has efficacy in treating neuropathic pain associated with PHN.

[0314] Therefore, 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, thereby treating and / or preventing neuropathic pain associated with PHN.

[0315] In some embodiments, the PS is a sulfoxide form of PS. Thus, PS may have Formula I (PS-I):

[0316]

[0317] In other embodiments, the PS is a sulfide form of PS. Thus, the PS may have Formula II (PS-II):

[0318]

[0319] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfoxide form of this compound is preferred. Compounds of Formula I and II are described in U.S. Patent No. 8,236,820, which is incorporated herein by reference in its entirety.

[0320] As outlined above, reactivation of the varicella-zoster virus can cause an acute herpes zoster rash, which is followed by the neuropathic pain associated with postherpetic neuralgia (PHN). As described above, the neuropathic pain associated with PHN can persist for 90 days or longer after the rash first appears, or for at least three months after the skin lesions resolve. The pain can manifest as, for example, sharp pain, burning, throbbing, or stinging. The neuropathic pain associated with PHN typically develops after the herpes zoster rash reactivates and the rash resolves, so patients need to take precautions to avoid developing neuropathic pain after the rash and skin lesions resolve. Therefore, 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, thereby preventing the neuropathic pain associated with PHN. In other embodiments, 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, thereby treating the neuropathic pain associated with PHN. Because pain associated with PHN develops during the onset of the rash and persists even after the rash resolves, subjects would benefit from an analgesic that can both treat existing neuropathic pain and prevent the development of further neuropathic pain associated with PHN. Therefore, in some embodiments, PS can be used to treat and prevent neuropathic pain associated with PHN. Consistent with the foregoing, the present invention provides PS for use in treating and / or preventing neuropathic pain associated with PHN. Furthermore, the present invention provides the use of PS in the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PHN.

[0321] As explained herein, the pain associated with PHN is usually confined to the rash site. Rash (e.g., maculopapular rash) may occur in one or more adjacent dermatomes (skin areas 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. Therefore, the neuropathic pain associated with PHN may be experienced in one or more adjacent dermatomes. The neuropathic pain associated with PHN may occur in one or more dermatomes, wherein each dermatome is innervated by a cervical nerve, a thoracic nerve, a lumbar nerve, or a sacral nerve. Typically, the neuropathic pain associated with PHN manifests along the chest dermatome on the trunk of the experimenter. In some cases, for example, in immunocompromised individuals, rash and the associated neuropathic pain caused thereby may be more extensive, affecting three or more dermatomes (i.e., caused by disseminated herpes zoster).

[0322] Based on the observations presented herein, PS may have a direct analgesic effect on neuropathic pain associated with PHN. Neuropathic pain associated with PHN may be sharp, throbbing, stabbing, or burning. When treating neuropathic pain associated with PHN, PS may reduce neuropathic pain. In some cases, the reduction is complete, thereby eliminating the neuropathic pain. When treating neuropathic pain associated with PHN, PS may also reduce one or more sensory symptoms associated with PHN. When preventing neuropathic pain associated with PHN, PS may reduce the incidence of neuropathic pain. When preventing neuropathic pain associated with PHN, PS may also reduce the incidence of one or more sensory symptoms associated with PHN.

[0323] Patients with PHN describe a range 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 per se), PS can reduce any one or more of the sensory symptoms experienced by the subject. In some cases, the reduction is complete, thereby eliminating one or more of the sensory symptoms experienced by the subject.

[0324] As described above, nerve damage associated with PHN may overactivate pain signaling pathways, leading to sensitization of peripheral and / or central neurons, thereby exhibiting a lowered stimulation threshold. Consequently, subjects with PHN may experience pain due to this sensitization, such as experiencing pain caused 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 perception. As described above, neuropathic pain associated with PHN may be the result of central sensitization leading to allodynia and / or hyperalgesia. PS can reduce neuronal signaling involved in pain perception in subjects with PHN. In some cases, this reduction can be complete, thereby eliminating pain. PS can reduce pain caused by peripheral sensitization or by central sensitization. In some cases, this reduction can be complete, thereby eliminating the occurrence of pain. In particular, because PS can be delivered to the central site of pain generation, it can reduce pain caused by central sensitization. Therefore, PS can reduce pain signaling occurring centrally. PS can reduce pain signaling that occurs in peripheral nerves, such as nerves that innervate one or more dermatomes. PS can reduce pain signaling that occurs 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. Specifically, PS can reduce pain signaling that occurs in one or more thoracic nerves. PS can reduce pain signaling that occurs in the dorsal root ganglia. PS can reduce pain signaling that occurs in the dorsal horn of the spinal cord. Given that PS has been shown to ascend along peripheral neurons to the spinal cord, PS can reduce pain signaling that occurs in the CNS. In some cases, the reduction can be complete, thereby eliminating pain signaling. The neuropathic pain in a subject suffering from PHN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject suffering from PHN may be hyperalgesia.

[0325] A patient's neuropathic pain can be measured using a visual analog pain scale or using any other appropriate method in the art.

[0326] On the other hand, PS can also be used to treat other herpes zoster-associated pain, such as prodromal pain (before the rash appears) or acute herpes zoster pain (occurring at the same time as the rash appears). Damage to peripheral neurons caused by viral translocation can lead to enhanced signal conduction from centrally located neurons. This may drive neurons to sensitize before the persistent pain characteristic of neuropathic pain associated with PHN occurs. Therefore, PS can be used to treat pain at these stages of infectious pathology. Therefore, the present invention also provides a method for treating pain caused by herpes zoster experienced by a subject, the method comprising administering a therapeutically effective amount of PS to a subject in need, thereby treating the pain. The present invention also provides a method for treating acute herpes zoster pain, the method comprising administering a therapeutically effective amount of PS to a subject in need, thereby treating acute herpes zoster pain. The present invention also provides a method for treating herpes zoster prodromal pain, the method comprising administering a therapeutically effective amount of PS to a subject in need, thereby treating herpes zoster prodromal pain.

[0327] 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, particularly topical administration to an area of ​​skin (e.g., a dermatome) affected by a rash, such as the trunk of a subject.

[0328] In specific embodiments for treating and / or preventing pain associated with PHN, the PS may be administered orally.

[0329] The observation herein is that PS has a significant analgesic effect on neuropathic pain associated with PHN. Furthermore, the observation that PS can reach key sites of action via delivery to the CNS via peripheral neurons confirms a role for PS in directly acting on neuronal signaling involved in the generation of neuropathic pain associated with PHN, for example by reducing the generation of pain caused by central sensitization. Since sulindac (the parent compound of PS) does not share these activities, the observations herein suggest that modifying sulindac not only imparts surprising analgesic activity to PS acting directly on neural signaling, but also makes PS more capable of delivery to key central sites of action, enabling it to more effectively impart its analgesic activity to neural signaling. Thus, without wishing to be bound by theory, the observations herein suggest that by modifying NSAIDs, enabling them to act directly on neuronal signaling and more readily access key sites of action via delivery along centrally projecting peripheral neurons, the significant drawback of NSAIDs in their inability to exert a meaningful analgesic effect on neuropathic pain associated with PHN can be overcome. Therefore, as an alternative to PS, the methods of the present invention can be performed using one or more modified NSAIDs disclosed herein. Therefore, the present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with PHN. As used herein, a "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., a parent compound).

[0330] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-amidated 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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate.

[0331] In specific embodiments, the modified NSAID for use in treating and / or preventing neuropathic pain associated with PHN is PS, eg, Formula I or II; or NO-sulindac, eg, Formula XLIV.

[0332] In some embodiments, the modified NSAID is a phosphorylated NSAID, such as PS, such as Formula I or II; or a NO-releasing NSAID, such as NO-sulindac, such as Formula XLIV.

[0333] In specific embodiments, the modified NSAID is a modified sulindac, e.g., PS, such as Formula I or II; NO-sulindac, such as Formula XLIV; HS-sulindac, such as Formula XXXIV; or sulindacamide phosphate, such as Formula X. Preferably, the modified sulindac is NO-sulindac, such as Formula XLIV.

[0334] In some embodiments for treating and / or preventing neuropathic pain associated with PHN, the modified NSAID is administered orally.

[0335] In specific embodiments, the oral modified NSAID is PS, eg, Formula I or II; or NO-sulindac, eg, Formula XLIV.

[0336] Migraine pain

[0337] Migraine is a disabling neurological disorder that affects over 1 billion people worldwide, with a prevalence of 15% per year. It is most prevalent among people aged 35-39 years and is the leading cause of disability in people under 50, resulting in a significant socioeconomic burden. Migraine is typically characterized by recurrent, unilateral, throbbing headaches of moderate to severe intensity, accompanied by nausea, vomiting, and hyperesthesia.

[0338] The pathophysiology of migraine has been controversial and is now classified as a neuronal disorder (Goadsby et al., Physiol Rev (2017); 97:553-622). Previous theories that pain is caused by dilated cranial arteries have lost their appeal, as effective treatments (e.g., sumatriptan) fail to reverse the mild dilation of cranial arteries observed during migraine attacks. Furthermore, the idea that migraine is caused by so-called neurogenic inflammation (local release of endogenous inflammatory mediators from the dura mater) has become implausible, especially given the clinical failure of compounds designed to inhibit this process. Indeed, evidence of an inflammatory pathology in migraine patients is lacking. Consequently, migraine is considered a purely neuronal disorder, caused by changes or dysfunction in brainstem and hypothalamic regions, leading to altered cellular and vascular function in many areas of the brain. These changes prevent neurons from properly regulating or gating sensory input. Dysfunction in these areas can lead to the perception of headache through normal vascular pulsations, while persistent dysfunction can lead to central sensitization of trigeminovascular neurons and increased pain in response to normal physical activity, as well as cutaneous allodynia. Indeed, peripheral and central sensitization of trigeminal neurons is thought to be a fundamental component of the pathophysiology, which has been observed clinically in patients with migraine. This neuronal mechanism would explain the duration of migraine attacks, the transition to chronic migraine, and specific associated symptoms (e.g., cutaneous allodynia).

[0339] Central sensitization occurs when neuronal circuit function in sensory pathways is enhanced or improperly regulated, leading to abnormal sensitivity, manifested as, for example, persistent spontaneous pain and allodynia (pain caused by non-painful stimuli), which is often associated with hyperalgesia (an increased response to noxious stimuli). Because central sensitization is caused by changes in neuronal properties in the CNS, the perception of pain is no longer associated with the presence, intensity, or duration of a specific peripheral stimulus (noxious or otherwise). Thus, central sensitization is associated with the generation and maintenance of pain, in which pain signaling is generated centrally (i.e., caused by hypersensitivity of central pain signaling neurons), even in the absence of peripheral stimuli.

[0340] As mentioned above, sensitization in migraine is the development of pain due to a failure in the integration and filtering of sensory signals, ultimately leading to the perception of activation of sensory systems that would normally be perceived, such as the cutaneous allodynia experienced by migraineurs. These symptoms occur in both episodic and chronic migraine, but pain amplification is thought to be more closely associated with chronic migraine.

[0341] There is a global need for additional pain therapies to treat migraine and other headache disorders.

[0342] A variety of pharmacological interventions have been proposed for the treatment of migraine, reflecting the diverse nature of this condition. Indeed, relatively nonselective drugs, such as ergot alkaloids, have been used for decades. Other treatment options include opioids (e.g., oxycodone), beta-blockers (e.g., propranolol), anticonvulsants (e.g., topiramate), or serotonin receptor agonists (e.g., sumatriptan). Patients with milder symptoms can use nonsteroidal anti-inflammatory drugs (NSAIDs) to control these symptoms, but as mentioned above, inflammation is considered to be of limited relevance when considering the pathophysiology of migraine. In fact, studies have shown that specific NSAIDs, such as naproxen, have no clinical utility in the treatment of migraine (e.g., see Law et al., Cochrane Database of Systematic Reviews (2013);10:1–45).

[0343] Therefore, there is a strong need for compounds that treat and / or prevent pain in migraine and other headache disorders, particularly pain associated with central sensitization.

[0344] The inventors of the present invention unexpectedly discovered that PS is effective in treating and preventing migraine pain.

[0345] As described herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike the parent compound, the NSAID sulindac, PS does not inhibit COX-1 and COX-2 or prostaglandin synthesis and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties by inhibiting NF-κB activation and changes in the MAPK signaling branch, and has been shown to be active in treating rheumatoid arthritis in inflammatory mouse models by inhibiting key pro-inflammatory signaling pathways (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32; and Mattheolabakis et al. (2013) Pharm Res 30(6):1471–82). WO 2019 / 067919 proposes that PS has anti-inflammatory activity in an acute dry eye disease (DED) model. Furthermore, in this model, PS was found to restore the suppressed ocular sensitivity in DED, suggesting that the effect of PS is to increase rather than decrease nociception. Although PS is not a typical NSAID, as mentioned above, it exhibits NSAID-like activity when administered to the normal eye in a DED model. However, these observations fail to suggest a role for PS in treating migraine pain, which is not the result of an inflammatory response but rather is caused by dysfunction in sensory neuron signaling. In fact, some typical NSAIDs (e.g., naproxen) have been shown to be clinically ineffective as analgesics for migraine, suggesting that anti-inflammatory activity alone is insufficient for treating migraine pain.

[0346] Nonetheless, preliminary in vivo evidence suggests the efficacy of PS in treating migraine pain. Further experiments in specific animal models of migraine pain confirmed these initial observations.

[0347] Therefore, the present invention provides a method for treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, thereby treating and / or preventing migraine pain.

[0348] In some embodiments, the PS is a sulfoxide form of PS. Thus, PS may have Formula I (PS-I):

[0349]

[0350] In other embodiments, the PS is a sulfide form of PS. Thus, the PS may have Formula II (PS-II):

[0351]

[0352] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfoxide form of this compound is preferred. Compounds of Formula I and II are described in U.S. Patent No. 8,236,820, which is incorporated herein by reference in its entirety.

[0353] As outlined above, migraine is characterized by unilateral onset of moderate to severe throbbing headaches, accompanied by photophobia, phonophobia, nausea, and / or vomiting. Therefore, 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, thereby treating the migraine pain. Typically, a migraine attack consists of three phases: the prodromal phase, the migraine headache itself, and the post-headache 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 an aura, which is a transient, focal neurological symptom of visual, sensory, or motor disturbances. Subjects within the prodromal phase, prior to the onset of the headache phase, can be administered a therapeutic agent to prevent the onset of the headache phase. Therefore, in some 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, thereby preventing the migraine pain. Subjects may experience recurrent migraine attacks, particularly when the intervals between attacks are short. Therefore, administration of a therapeutic agent can treat ongoing pain episodes and prevent subsequent episodes of pain. Thus, in some embodiments, PS can be used to treat and prevent migraine pain. Consistent with the above, the present invention provides PS for use in treating and / or preventing migraine pain. Furthermore, the present invention also provides the use of PS in the manufacture of a medicament for treating and / or preventing migraine pain.

[0354] In some embodiments, when treating and / or preventing migraine pain, PS can be administered during the prodromal phase, the headache phase, and / or the post-headache phase. Specifically, to prevent migraine pain, PS can be administered during the prodromal phase. To treat migraine pain, PS can be administered during the headache phase.

[0355] Migraines can be episodic. In some cases, they can be chronic. Migraines can occur without aura or with aura.

[0356] According to the observations herein, PS has a direct analgesic effect on migraine pain. Migraine pain can be a throbbing headache. Subjects with migraine, especially those with chronic migraine, may experience persistent migraine and / or aura-like periods, and neurological recovery and baseline recovery between each attack are limited. Subjects suffering from migraine may experience many related symptoms, including aura, nausea, vomiting, photophobia and / or phonophobia. Sensory disturbances associated with aura may include visual symptoms, tingling (tingling) and / or numbness. In addition, subjects may also experience cranial autonomic symptoms such as redness or tearing of the eyes. In addition, subjects may also experience abnormal skin pain.

[0357] Migraine with aura can be either classic or brainstem. Migraine can be hemiplegic (e.g., familial hemiplegic migraine or sporadic hemiplegic migraine); retinal; chronic; or probable (with and without aura).

[0358] When treating migraine pain, PS can reduce pain. In some cases, the reduction can be complete, thereby eliminating migraine pain. When treating migraine pain, PS can also reduce one or more symptoms associated with migraines. When preventing migraine pain, PS can reduce the incidence of pain. When preventing migraine pain, PS can also reduce the incidence of one or more symptoms associated with migraines. PS can reduce cutaneous allodynia. In certain embodiments, PS can reduce chronic migraine pain. As described above, the reduction can be complete, thereby eliminating pain.

[0359] Even if the symptoms experienced by a subject with migraine (e.g., aura or cranial autonomic symptoms) are not considered painful (or do not reach the threshold required to be considered pain per se), in treating and / or preventing migraine pain, PS can reduce any one or more symptoms experienced by a subject with migraine. In some cases, the reduction is complete, thereby eliminating one or more symptoms experienced by a subject with migraine.

[0360] Peripheral and central sensitization are characteristic features of migraine pain. Migraine pain may be the result of central sensitization leading to allodynia, such as cutaneous allodynia and / or hyperalgesia. Therefore, subjects with migraines may experience pain due to this sensitization, such as experiencing pain caused 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 perception. Therefore, PS may reduce neuronal signaling involved in pain perception in subjects with migraines. In some cases, the reduction may be complete, thereby eliminating pain. In addition, PS may reduce pain caused by peripheral sensitization or, in particular, by central sensitization. In particular, because PS can be delivered to the central site of pain generation, it can reduce pain caused by central sensitization. The reduction may be complete, thereby eliminating the generation of pain. Therefore, PS may reduce pain signaling occurring centrally. PS may reduce pain signaling occurring in the trigeminal nerve. PS may reduce pain signaling occurring in the trigeminal ganglion. PS can reduce pain signaling occurring in the caudate nucleus of the spinal trigeminal tract within the trigeminocervical complex (TCC). Given that PS has been shown herein to ascend to the CNS along peripheral neurons, preliminary observations of PS's analgesic activity in migraine suggest that PS can reduce pain signaling occurring in higher-order neurons of the brain and / or pain-sensing areas (e.g., trigeminal thalamic neurons). The reduction can be complete, thereby eliminating pain signaling. In some embodiments, the pain is allodynia, such as cutaneous allodynia. The allodynia may be a response to mechanical and / or thermal stimulation. Furthermore, in some embodiments, the pain is hyperalgesia. Migraine pain can be neuropathic pain.

[0361] Migraine patients can be diagnosed using the well-known ICHD-3 guidelines. Migraine pain can be measured using a visual analog pain scale or using any other appropriate method in the art.

[0362] 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. For topical administration, PS is preferably in the form of a formulation. 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 topically applied to the face and / or neck of a subject. PS can be topically applied to one or both temples of a subject. In certain instances, PS can be topically applied behind one or both ears of a subject.

[0363] In specific embodiments, PS may be administered orally for the treatment and / or prevention of migraine pain.

[0364] The observations herein that PS reduces allodynia, and that PS can reach key sites of action by being delivered to the CNS along peripheral neurons, confirm that PS can directly act on neuronal signaling generated by migraine pathophysiology, particularly signaling associated with central sensitization. In fact, the observations herein demonstrate the efficacy of PS in a migraine model utilizing NTG, which is known to establish central sensitization corresponding to the central sensitization that occurs in migraine patients. Since sulindac (the parent compound of PS) does not share these activities, the observations herein suggest that modifying sulindac not only imparts surprising analgesic activity to PS that acts directly on neural signaling, but also makes PS more capable of being delivered to key central sites of action, enabling it to more effectively impart its analgesic activity to neural signaling. Thus, without wishing to be bound by theory, the observations herein suggest that NSAIDs can be modified to enable them to act directly on neuronal signaling and more readily access key sites of action by being delivered along centrally projecting peripheral neurons, thereby overcoming the apparent deficiency of NSAIDs in being unable to exert a meaningful analgesic effect on neuronal signaling generated by migraine pathophysiology. Thus, as an alternative to PS, the methods of the present invention can be performed using one or more modified NSAIDs disclosed herein. Accordingly, the present invention provides a method for treating and / or preventing migraine pain, comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing migraine pain. As used herein, a "modified NSAID" refers to a compound resulting from modification of an NSAID molecule (i.e., a parent compound).

[0365] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-amidated 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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate.

[0366] In certain embodiments, the modified NSAID does not have Formula LXIX and / or Formula LXX.

[0367] In specific embodiments, the modified NSAID for use in treating and / or preventing migraine pain is selected from one or more of: PS, eg, Formula I or II; or naproxen phosphate, eg, Formula VIII.

[0368] Thus, the modified NSAID for treating and / or preventing migraine pain can be a modified sulindac, such as PS, such as Formula I or II; for example, NO-releasing sulindac, such as NO-sulindac (e.g., Formula XLIV); HS-releasing sulindac, such as HS-sulindac (e.g., Formula XXXIV); or a metal-chelated sulindac, such as sulindac platinum (e.g., Formula LXVII).

[0369] In some embodiments, the modified NSAID used to treat and / or prevent migraine pain is a phosphorylated NSAID, such as PS, such as Formula I or II; or naproxen phosphate, such as Formula VIII.

[0370] In some embodiments for treating and / or preventing migraine pain, the modified NSAID is administered orally. In specific embodiments, the orally administered modified NSAID for treating and / or preventing migraine pain is selected from one or more of: PS, e.g., Formula I or II; or naproxen phosphate, e.g., Formula VIII.

[0371] In some embodiments for treating and / or preventing migraine pain, the orally administered modified NSAID can be a phosphorylated NSAID, such as PS, for example, Formula I or II; or naproxen phosphate, for example, Formula VIII. In other embodiments for treating and / or preventing migraine pain, the orally administered modified NSAID is a phosphamidate NSAID, such as sulindac amide phosphate, for example, Formula X; or phosphoprofen amide, for example, Formula XI.

[0372] Pain caused by other headache disorders

[0373] Based on the observations herein regarding the efficacy of PS in treating migraine pain, PS may be useful in treating and / or preventing pain in other headache disorders, particularly those whose pathophysiology manifests as a dysfunction of the trigeminal system.

[0374] For example, PS can treat and / or prevent chronic headache pain, tension-type headache pain, and / or trigeminal autonomic headache pain. Trigeminal autonomic headache pain can be cluster headache, hemicrania continua, paroxysmal hemicrania, transient unilateral neuralgic headache with conjunctival injection and tearing, and transient unilateral neuralgic headache with cranial autonomic symptoms. In some embodiments, PS can treat and / or prevent trigeminal neuralgia pain, such as pain in the head and face.

[0375] 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. For topical administration, PS is preferably in the form of a formulation. 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 topically applied to the face and / or neck of a subject. PS can be topically applied to one or both temples of a subject. In certain instances, PS can be topically applied behind one or both ears of a subject.

[0376] In specific embodiments, PS may be administered orally for the treatment and / or prevention of pain from other headache disorders.

[0377] Consistent with the above, pain from other headache disorders may be treated and / or prevented by administering one or more modified NSAIDs disclosed herein. The one or more modified NSAIDs may be administered orally.

[0378] Corneal neuropathic pain

[0379] Corneal discomfort affects 5-30% of people over the age of 50. Corneal neuropathic pain is a condition in which corneal pain is experienced in response to normally painless stimuli (e.g. wind or air currents). This reflects centrally acting neuronal sensitization after prolonged and repeated nociceptive signaling by peripheral neurons in response to direct damage to the corneal nerves. Any mechanical or chemical damage to the corneal nerve endings may lead to ectopic sprouting and neuroma formation, thereby demonstrating spontaneous activity. Central sensitization manifests as pain hypersensitivity (allodynia) to non-noxious stimuli or excessive pain response (hyperalgesia) to noxious stimuli, or in fact spontaneous signaling, leading to persistent chronic corneal pain even in the absence of peripheral stimuli or clinical signs. Thus, the pain generation mechanism of corneal neuropathic pain is different from, for example, inflammatory eye diseases, which trigger acute peripheral pain signaling of the cornea due to persistent inflammation.

[0380] Patients with corneal neuropathic pain experience severe corneal pain, even without peripheral signs, along with irritation such as burning, photophobia, and grittiness. Therefore, this indication inevitably negatively impacts patients' quality of life. Chronic painful sensations accompanied by light sensitivity and irritation lead to functional impairment and an inability to perform daily activities.

[0381] Corneal neuropathic pain is particularly difficult to treat. For patients with corneal neuropathic pain, if the corneal pain occurs in the absence of any ongoing corneal disease, anti-inflammatory drugs are ineffective. In fact, centrally acting neuromodulators are often recommended. For example, anticonvulsants (such as gabapentin and pregabalin) can be considered first-line treatment; serotonin-norepinephrine reuptake inhibitors (such as duloxetine and venlafaxine) can be considered second-line treatment; and tricyclic antidepressants (such as nortriptyline, amitriptyline) can be considered third-line drugs. For generalized neuropathic pain, if it is resistant to treatment, combination therapy or weak opioids (tramadol) can also be used.

[0382] Unfortunately, pain control is not very satisfactory, and many systemic treatments induce severe side effects, resulting in very poor treatment compliance.

[0383] Therefore, there is an urgent need for compounds that treat and / or prevent corneal neuropathic pain.

[0384] The inventors of this case unexpectedly discovered that sulindac phosphate (PS) is effective in treating corneal neuropathic pain.

[0385] As described herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike the parent compound, the NSAID sulindac, PS does not inhibit COX-1 and COX-2 or prostaglandin synthesis and is therefore not a typical NSAID. PS has previously been shown to have anticancer and anti-inflammatory properties by inhibiting NF-κB activation and changes in the MAPK signaling branch, and has activity in treating rheumatoid arthritis by inhibiting key proinflammatory 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 showed that PS has anti-inflammatory activity in an acute dry eye (DED) model and that PS reduces corneal sensitivity in normal eyes in an acute pain production model. The observation that healthy eyes are less sensitive to acute stimuli, thus lacking persistent pain, does not support its efficacy in treating corneal neuropathic pain, which is associated with central sensitization and therefore likely arises at a central site of action. Furthermore, the effects of PS were observed immediately in this acute model, suggesting that the local effects of this atypical NSAID are similar to the activity observed with typical NSAIDs (e.g., ketorolac) in the same model. Furthermore, this peripheral activity does not support the efficacy of PS in treating pain arising at a central site of action. Indeed, clinical guidelines in this field recommend avoiding the use of NSAIDs for all types of neuropathic pain, and ketorolac has been shown to have limited analgesic activity in this pain model. Therefore, observations obtained in an acute pain model cannot be extrapolated to the treatment of corneal neuropathic pain. Furthermore, the finding that PS can restore suppressed corneal sensitivity in the DED model suggests that PS acts to increase, rather than decrease, nociception. Therefore, these observations fail to demonstrate a role for PS in treating corneal neuropathic pain, whereas the findings presented here demonstrate unprecedented activity of PS in reducing pain arising at a central site of action.

[0386] Indeed, preliminary in vivo evidence suggests the efficacy of PS in the treatment of corneal neuropathic pain.

[0387] Therefore, 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, thereby treating corneal neuropathic pain.

[0388] In some embodiments, the PS is a sulfoxide form of PS. Thus, PS may have Formula I (PS-I):

[0389]

[0390] In other embodiments, the PS is a sulfide form of PS. Thus, the PS may have Formula II (PS-II):

[0391]

[0392] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfoxide form of this compound is preferred. Compounds of Formula I and II are described in U.S. Patent No. 8,236,820, which is incorporated herein by reference in its entirety.

[0393] Corneal neuropathic pain is also called ocular neuropathic pain. Therefore, the terms "corneal neuropathic pain" and "ocular neuropathic pain" can be used interchangeably in this article. As explained above, corneal neuropathic pain is a persistent chronic pain that occurs due to changes in neuroplasticity of neurons located in the central nervous system caused by persistent nociceptive signaling from the periphery. This change leads to excessive excitation of nociceptors in the CNS, the so-called central sensitization, which manifests as, for example, allodynia. Even in the absence of persistent peripheral triggers, the pain will persist, which makes corneal neuropathic pain, like other neuropathic pain, particularly difficult to treat because resolving peripheral lesions will not affect the sensation of pain. In this way, corneal neuropathic pain may be chronic corneal pain.

[0394] Corneal neuropathic pain may be caused by a variety of peripheral nociceptive drivers. Typically, corneal neuropathic pain is caused by the cornea (one of the most densely innervated tissues) producing persistent pain signaling. As mentioned above, persistent peripheral signaling by corneal nerves ultimately leads to central sensitization, which is a key feature of corneal neuropathic pain, causing pain sensation even in the absence of peripheral triggering factors. Therefore, corneal neuropathic pain may be caused by any peripheral stimulation that can cause chronic stimulation of the corneal nerves. For example, corneal neuropathic pain may be caused by chronic corneal surface diseases or disorders, such as recurrent corneal erosions, corneal surface tumors and / or inflammatory eye diseases. Corneal neuropathic pain may be caused by surgical intervention, such as corneal refractive surgery (such as photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), small incision lens removal (SMILE) and corneal inlay surgery), cataract surgery (such as laser-assisted cataract surgery), corneal transplant surgery and / or laser retinopexy. Corneal neuropathic pain may be caused by laser surgery to treat retinal disorders (e.g., diabetic macular edema; proliferative diabetic retinopathy; macular edema caused by retinal vein occlusion; neovascularization secondary to retinal vein occlusion; peripheral retinal degeneration, perforations, and / or tears; Eales' disease and other retinal vasculitis; central severe retinopathy; retinopathy of prematurity; extrafoveal polyps in polypoidal choroidal vasculopathy (PCV). Corneal neuropathic pain may be caused by infections, such as herpes simplex keratitis and / or herpes zoster keratitis. Corneal neuropathic pain may be caused by toxic keratopathy, such as that caused by topical or systemic medications (e.g., preservatives containing benzalokium chloride or isotretinoin, respectively). Corneal neuropathic pain may be caused by radiation or ultraviolet light exposure. Corneal neuropathic pain may be the result of systemic neuropathy, such as small fiber neuropathy or multiple sclerosis. Additionally, corneal neuropathic pain may be caused by trauma, such as damage to the corneal nerves, such as chemical burns. The initial trigger of pain may be air pollution or dry weather, which triggers persistent corneal inflammation and ultimately corneal neuropathic pain. Thus, corneal neuropathic pain may be caused by allergens, such as those that cause allergic conjunctivitis. Corneal neuropathic pain may be caused by one or more chalazines, such as the continued irritation of the cornea caused by a chalazion when blinking. Continued peripheral nociceptor signaling in response to these peripheral triggers can increase the sensitivity of centrally located neurons, resulting in pain that can persist even after the initial clinical manifestations have subsided.In fact, even local anesthesia cannot relieve pain due to dysregulation of central neuronal signaling.

[0395] In addition, in some embodiments, corneal neuropathic pain is caused by direct damage to centrally located neurons, such as ischemia, hemorrhage, mechanical compression, infection, and / or degenerative processes. In addition, corneal neuropathic pain may be caused by damage to adjacent tissues or nerves, such as conjunctiva, eye muscles, eyeball, optic nerve, and / or autonomic or sympathetic nerves.

[0396] Corneal neuropathic pain is caused by neuronal sensitization due to persistent peripheral nociceptive signaling, manifesting as hypersensitivity to harmless peripheral triggers and associated long-term pain. Therefore, central sensitization is a characteristic of corneal neuropathic pain. The pain can manifest as, for example, shooting pain, burning pain, or stinging pain, accompanied by other sensory symptoms. Therefore, 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, thereby treating corneal neuropathic pain. Subjects suffering from corneal neuropathic pain would benefit from an analgesic that can both treat existing corneal neuropathic pain and prevent the development of further corneal neuropathic pain (i.e., prevent further central sensitization). Therefore, in some embodiments, PS can be used to treat and prevent corneal neuropathic pain. Consistent with the above, the present invention provides PS for the treatment of corneal neuropathic pain. In addition, the present invention also provides the use of PS for the manufacture of a medicament for the treatment of corneal neuropathic pain.

[0397] Based on the observations presented herein, PS may have a direct analgesic effect on corneal neuropathic pain. Corneal neuropathic pain can be a stinging or burning pain. When treating corneal neuropathic pain, PS may reduce corneal neuropathic pain. In some cases, the reduction may be complete, thereby eliminating corneal neuropathic pain. When treating corneal neuropathic pain, PS may also reduce one or more associated sensory symptoms.

[0398] Patients with corneal neuropathic pain describe a range of sensory symptoms. Sensory symptoms include paresthesias (e.g., numbness, tingling, stinging, and / or forking), photosensitivity, or photoallodynia. Even if the sensory symptoms experienced by a subject are not considered painful (or do not reach the threshold required to be considered pain per se), PS can reduce any one or more sensory symptoms experienced by the subject, including those listed above. In some cases, the reduction is complete, thereby eliminating one or more of the associated sensory symptoms. In addition, when treating corneal neuropathic pain, PS can improve other associated symptoms of the subject, such as anxiety, depression, and / or apathy.

[0399] As mentioned above, corneal neuropathic pain is caused by the excessive activity of neurons located in the center, which show a reduced stimulation threshold and depolarize even in the absence of peripheral stimulation. In fact, the perception of pain is no longer associated with the presence, intensity or duration of specific peripheral stimuli (noxious or other stimuli). Therefore, corneal neuropathic pain may be the result of central sensitization. Therefore, subjects with corneal neuropathic pain may experience pain caused by non-painful stimuli (allodynia) and / or may experience increased pain (hyperalgesia) in response to noxious stimuli. According to preliminary observations, PS may have a direct analgesic effect, for example, by reducing the neuronal signaling involved in pain sensation. Therefore, PS can reduce the neuronal signaling involved in pain sensation in subjects with corneal neuropathic pain. Since PS can be delivered to the central site where pain is generated, it can reduce the pain generated by central sensitization. Therefore, PS can reduce the pain signaling that occurs in the center. Corneal nociceptors constitute the first branch of the trigeminal nerve and travel to the trigeminal ganglion and the caudate nucleus of the spinal trigeminal tract. PS can reduce the pain signaling that occurs in the trigeminal ganglion. PS can reduce the pain signal conduction that occurs in the caudate nucleus of the trigeminal spinal tract within the trigeminal cervical complex (TCC). In view of the fact that PS can ascend to the CNS along peripheral neurons herein, PS can reduce the pain signal conduction that occurs in higher-order neurons and / or pain perception areas (e.g., trigeminal thalamic neurons) in the brain. In some cases, the reduction can be complete, thereby eliminating pain signal conduction. In some embodiments, corneal neuropathic pain is allodynia. Allodynia may be a response to mechanical and / or thermal stimulation. Additionally or alternatively, the corneal neuropathic pain of the subject may be hyperalgesia. In some embodiments, corneal neuropathic pain is chronic corneal neuropathic pain. In some embodiments, corneal neuropathic pain is not acute corneal pain.

[0400] A patient's corneal neuropathic pain can be measured using a visual analog pain scale or using any other appropriate method in the art.

[0401] According to the observations herein, PS exhibits direct activity on neurons associated with pain production caused by central sensitization. Therefore, PS can also be used to treat specific forms of corneal pain. Corneal pain is also called eye pain, so these terms can 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, the method comprising administering a therapeutically effective amount of PS to a subject in need, thereby treating corneal pain caused by central sensitization. In fact, PS can treat corneal pain that manifests as allodynia. PS can treat corneal pain that manifests as hyperalgesia. Since the pain is caused by central sensitization, pain can be felt even in the absence of persistent harmful peripheral triggers (such as corneal inflammation). Corneal pain can be chronic pain (i.e., pain that lasts for 3 months or longer). In certain embodiments, corneal pain is not acute pain, such as acute pain associated with DED (i.e., pain experienced due to persistent corneal inflammation).

[0402] PS can be used to treat corneal pain generated at a central site of action (i.e., the site responsible for central pain signal conduction in the absence of persistent peripheral triggers). Therefore, the present invention provides a method for treating corneal pain generated at a central site of action, the method comprising administering a therapeutically effective amount of PS to a subject in need, thereby treating the corneal pain generated at the central site of action. In fact, according to the observations herein, PS can treat corneal pain based on its ability to be delivered to the central site of action. For example, PS can reduce corneal pain by accumulating in the caudate nucleus of the trigeminal spinal tract or in higher-order neurons in the CNS. Therefore, PS can directly act on the pain generating center in the caudate nucleus of the trigeminal spinal tract or in higher-order neurons in the CNS. Therefore, the present invention provides a method for treating corneal pain, the method comprising administering a therapeutically effective amount of PS to a subject in need, thereby treating corneal pain, wherein PS reduces pain signal conduction occurring in the caudate nucleus of the trigeminal spinal tract or in higher-order neurons in the CNS. In some cases, the reduction can be complete, thereby eliminating pain signal conduction.

[0403] The observations presented herein demonstrate that PS, when topically applied to the outer surface of the eyelid, can penetrate eyelid tissue and reach the cornea in therapeutically relevant quantities. Application to the outer surface of the eyelid avoids the use of eye drops, which can sting and reduce patient compliance, thereby compromising treatment outcomes. Furthermore, application to the outer surface of the eyelid is advantageous for patients with decreased motor function or loss of fine motor skills, who may have difficulty administering eye drops. Of course, such application to the outer surface of the eyelid requires that the therapeutic agent effectively penetrate the eyelid to reach the ocular surface in therapeutically relevant quantities. Therefore, the observations presented herein demonstrate that application of PS to the outer surface of the eyelid is an appropriate topical administration route for treating various ocular diseases and conditions, particularly those requiring therapeutic delivery to the ocular surface in therapeutically relevant quantities for therapeutic efficacy. Without wishing to be bound by theory, the ability of PS to reach corneal nerves in therapeutically relevant quantities allows PS to be delivered along peripheral corneal neurons to a central site of action, thereby providing a pathway by which PS can reach the pain-generating centers associated with corneal pain, even when topically applied to the outer surface of the eyelid.

[0404] Thus, in another aspect, the present invention provides a PS for use in therapy, wherein the PS is topically applied to the outer surface of one or more eyelids. The present invention also provides a method for treating and / or preventing an ocular disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a PS, thereby treating and / or preventing the ocular disease or condition, wherein the PS is topically applied to the outer surface of one or more eyelids. The ocular disease or condition may be corneal pain, such as corneal pain described herein, such as corneal neuropathic pain. Thus, the present invention also provides a method for treating and / or preventing corneal pain, comprising administering to a subject in need thereof a therapeutically effective amount of a PS, thereby treating and / or preventing corneal pain, wherein the PS is topically applied to the outer surface of one or more eyelids. The one or more eyelids may be one or both upper eyelids and / or one or both lower eyelids.

[0405] Corneal pain may be caused by central sensitization. Corneal pain may be generated at the central site of action. As provided herein, corneal pain may be caused by one or more surgical interventions, such as corneal refractive surgery (including PRK, LASIK, SMILE and / or corneal inlay surgery); laser retinopexy; cataract surgery (such as laser-assisted cataract surgery); and / or corneal transplant surgery. In addition, as discussed herein, corneal pain may be caused by laser surgery for the treatment of retinal diseases (such as diabetic macular edema; proliferative diabetic retinopathy; macular edema caused by retinal vein occlusion; neovascularization secondary to retinal vein occlusion; peripheral retinal degeneration, perforation and / or tearing; Eales disease and other retinal vasculitis; central severe retinopathy; retinopathy of prematurity; extrafoveal polyps of polypoidal choroidal vasculopathy (PCV). Corneal pain may be caused by intravitreal injection (such as for the treatment of wet age-related macular degeneration (AMD)). Corneal pain may occur during or after surgical intervention or surgical operation. Thus, the PS may be administered before, during, or after a surgical intervention or procedure. In certain circumstances, corneal pain may occur during a surgical intervention or procedure. Thus, the PS may be administered before or during a surgical intervention or procedure. As explained herein, corneal pain may be caused by an inflammatory eye disease or condition. The inflammatory eye disease or condition may be dry eye (DED). The inflammatory eye disease or condition may be allergic conjunctivitis. Corneal pain may be caused by one or more chalazines, such as persistent irritation of the cornea caused by a chalazion when 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 tumors, and / or inflammatory eye conditions, such as dry eye (DED), or inflammatory eye conditions caused by allergens, such as allergic conjunctivitis); infection (e.g., herpes simplex keratitis and / or herpes zoster keratitis); toxic keratopathy (e.g., caused by topical or systemic medications); radiation or UV exposure; trauma (e.g., chemical burns).

[0406] The eye disease or disorder can be an inflammatory eye disease or disorder. The inflammatory eye disease or disorder can be dry eye (DED), conjunctivitis (e.g., allergic conjunctivitis), keratitis, scleritis, or uveitis. In specific embodiments, the eye disease or disorder is dry eye (DED).

[0407] Consistent with the above, the present invention provides PS for use in treating and / or preventing ocular diseases or conditions, wherein the PS is topically applied to the outer surface of one or more eyelids. Furthermore, the present invention provides the use of PS for the manufacture of a medicament for treating and / or preventing ocular diseases or conditions, wherein the PS is topically applied to the outer surface of one or more eyelids.

[0408] 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.

[0409] The formulations disclosed herein for topical administration of PS to the outer surface of the eyelid are suitable for use in the methods disclosed herein. The eyelid can be the upper eyelid or the lower eyelid. For topical administration to the outer surface of the eyelid, the PS is applied substantially entirely to the outer surface of the eyelid.

[0410] It is observed herein that PS has a significant analgesic effect on corneal neuropathic pain, and it is also observed that PS can reach the key action site by being delivered to the CNS along peripheral neurons, confirming the role of PS in the neuronal signaling involved in the generation of corneal neuropathic pain, such as the role in reducing the generation of pain caused by central sensitization. Since sulindac (the parent compound of PS) does not share these activities, the observations herein show that modifying sulindac not only makes PS that acts directly on neural signaling have surprising analgesic activity, but also makes PS more capable of being delivered to the key central action site, so that it can more effectively impart its analgesic activity to neural signaling. Therefore, without wishing to be bound by theory, the observations herein show that NSAIDs can be modified so that they can act directly on neuronal signaling and more easily approach the key action site by being delivered along peripheral neurons projected by the central nervous system, thereby overcoming the obvious defect that NSAIDs cannot exert a meaningful analgesic effect on corneal neuropathic pain. 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 comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating corneal neuropathic pain. As used herein, "modified NSAID" refers to a compound produced by modifying an NSAID molecule (i.e., the parent compound).

[0411] The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phosphate-modified NSAIDs (phospho-NSAIDs), phospho-amide-modified NSAIDs (phospho-amidated 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 a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib. In specific embodiments, the NSAID in the modified NSAID can be sulindac, ibuprofen, aspirin, or naproxen. Thus, the modified NSAID may be sulindac amide phosphate, Se-sulindac, HS-sulindac, NO-sulindac, or NOSH-sulindac. The modified NSAID may be aspirin phosphate, naproxen phosphate, flurbiprofen phosphate, or ibuprofen phosphate. The modified NSAID may be ibuprofen amide phosphate.

[0412] Pharmaceutical compositions of PS

[0413] The PS used in the methods of the present invention can be formulated into a suitable pharmaceutical composition 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. Pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of PS and may further comprise a pharmaceutically acceptable excipient. In specific embodiments, pharmaceutical compositions comprising PS can be formulated for use in the topical formulations of the present invention.

[0414] Pain associated with central sensitization can be systemic or occur in various locations throughout the body. Pain can be diffuse and widespread, or localized to the area where pain signaling initially originates. Pain often manifests in peripheral areas. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral location where pain is experienced. Thus, pharmaceutical compositions containing PS can be formulated for topical administration. Specifically, pharmaceutical compositions containing PS can be formulated for dermal administration.

[0415] The neuropathic pain associated with PTPN is felt within the damaged tissue, but the pain can also spread to the vicinity of the damaged area. Regardless, the pain is felt in the surrounding area. Therefore, particularly useful pharmaceutical compositions comprising PS are those that can be applied directly to the surrounding area experiencing neuropathic pain. In addition, pharmaceutical compositions comprising PS can also be applied to the location where one or more sensory symptoms of PTPN occur. Thus, pharmaceutical compositions comprising PS can be formulated for topical administration. Specifically, pharmaceutical compositions comprising PS can be formulated for dermal administration. A single application to the affected area may require less than about 5 ml of the pharmaceutical composition, for example, about 3 ml of the pharmaceutical composition.

[0416] Neuropathic pain associated with PHN most commonly occurs on the subject's trunk. As outlined above, PHN tends to affect one or two adjacent dermatomes and generally does not cross the midline of the body. Less commonly, PHN may be more widespread, affecting three or more dermatomes. Typically, neuropathic pain associated with PHN manifests in one or more thoracic dermatomes (i.e., the subject's trunk). Therefore, particularly useful pharmaceutical compositions comprising PS are those that can be applied directly to peripheral locations experiencing neuropathic pain, such as the thoracic dermatomes on the subject's trunk. In addition, pharmaceutical compositions comprising PS can also be applied to locations where one or more sensory symptoms of PHN occur. Therefore, pharmaceutical compositions comprising PS can be formulated for topical administration. Specifically, pharmaceutical compositions comprising PS can be formulated for dermal application, particularly application to the skin of the subject's thoracic dermatomes. A single application to one or more thoracic dermatomes may require up to about 15 ml of the pharmaceutical composition. A single application to an area affected by neuropathic pain associated with disseminated herpes zoster (i.e., three or more dermatomes) may require up to about 30 ml of the pharmaceutical composition.

[0417] Migraine pain (as well as pain caused by other headache disorders) manifests as pain in the head and face. Therefore, particularly useful pharmaceutical compositions comprising PS are those that can be applied directly to the surrounding area experiencing pain, such as the subject's head and / or neck. Thus, pharmaceutical compositions comprising PS can be formulated for topical administration. Specifically, pharmaceutical compositions comprising PS can be formulated for dermal application, particularly to the skin near the sensory branches of the trigeminal nerve. PS can be applied to the skin of the subject's head and / or neck. PS can be applied topically to the area where the neck meets the base of the skull. PS can be applied topically to one or both of the subject's temples. PS can be applied topically behind one or both of the subject's ears. For example, a single application to the temples or behind the ears 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).

[0418] Corneal neuropathic pain is similar to corneal pain in that it is felt in the eye. Therefore, a particularly useful pharmaceutical composition comprising PS is one that can be applied to the eyeball of a subject experiencing corneal neuropathic pain in a therapeutically relevant amount. Therefore, a pharmaceutical composition comprising PS can be applied directly to one or both eyeballs of a subject experiencing corneal neuropathic pain. Therefore, a pharmaceutical composition comprising PS can be formulated for topical application to the ocular surface (i.e., the eyeball), for example, to the cornea or the corner of the eye. In a preferred embodiment, a pharmaceutical composition comprising PS can be topically applied to the outer surface of one or more eyelids of a subject. Therefore, a pharmaceutical composition comprising PS can be formulated for skin application, in particular, application 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. For topical application to the outer surface of the eyelids, the PS is applied substantially entirely to the outer surface of the eyelids. In some cases, the lower eyelid may be preferred because the outer surface of the lower eyelid is less affected 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 adjacent to the skin of the orbit). In some cases, the upper eyelid may be preferred because its outer surface generally has a larger surface area suitable for topical application. 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.

[0419] In some embodiments, pharmaceutical compositions comprising PS can be formulated as semisolid or liquid forms. Thus, pharmaceutical compositions comprising 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, thereby imparting different densities to the compositions. Varying the density of the formulation is one way to control the exposure of the affected area to the pharmaceutical composition. For example, if the formulation has a low density and requires rubbing until it is absorbed, the exposure time may be shortened. Alternatively, if the formulation has a high density and is not readily absorbed, the exposure time of the area to the pharmaceutical composition may be extended. One skilled in the art will appreciate how to formulate topical pharmaceutical compositions to alter the relative exposure of the area to the active pharmaceutical ingredient.

[0420] In the treatment of corneal neuropathic pain, the pharmaceutical composition comprising PS for topical application to the ocular surface and / or the outer surface of the eyelid can be formulated as a gel (e.g., a hydrogel) or an ointment. For topical application to the ocular surface, the pharmaceutical composition comprising PS can be formulated as a gel (e.g., a hydrogel), an ointment, and / or an eye drop. For topical application to the outer surface of the eyelid, the pharmaceutical composition comprising PS can be formulated as a cream, a gel (e.g., a hydrogel), a lotion, an ointment, a foam, and / or a spray.

[0421] In other embodiments, the pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin. The patch can be manufactured in a manner that ensures controlled release of PS at the affected area.

[0422] In some embodiments for treating corneal neuropathic pain, a pharmaceutical composition comprising PS can be formulated in the form of 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, thereby allowing a therapeutically appropriate amount of PS to reach the ocular surface.

[0423] In a specific embodiment 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 suitable for application to the eye. A typical example of an eye drop composition is an ophthalmic solution applied dropwise to the eye. In some embodiments, the eye drop composition is an ophthalmic emulsion applied dropwise to the eye. In some embodiments, the droplet size is between about 10 and about 100 μL. The droplet size 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 size of the droplets 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.

[0424] Formulations suitable for topical administration and suitable pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO 2019 / 067919, which is incorporated herein by reference in its entirety.

[0425] In some embodiments, PS formulations suitable for topical administration may comprise PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, the concentration of PS may be 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 concentration of PS may be less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% w / w of the pharmaceutical composition, and particularly about 3% w / w of the pharmaceutical composition. As another illustrative example, when formulated as a gel, the concentration of PS can be less than or equal to 8% w / w of the pharmaceutical composition, such as less than or equal to 5% w / w of the pharmaceutical composition, particularly less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated as a hydrogel or ointment, the concentration of PS can be 5% w / w of the pharmaceutical composition.

[0426] In some embodiments for treating corneal neuropathic pain, PS formulations suitable for topical administration to the ocular surface and / or outer surface of the eyelid may comprise PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, the concentration of PS may be 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 concentration of PS can be less than or equal to 8% w / w of the pharmaceutical composition, such as about 5% w / w of the pharmaceutical composition, and particularly about 3% w / w of the pharmaceutical composition. As another illustrative example, when formulated as a gel, the concentration of PS can be less than or equal to 8% w / w of the pharmaceutical composition, such as less than or equal to 5% w / w of the pharmaceutical composition, and particularly less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated as a hydrogel or ointment, the concentration of PS can be 5% w / w of the pharmaceutical composition.

[0427] Alternatively, the pharmaceutical composition comprising PS can be formulated into any other form of administration suitable for treating pain associated with central sensitization. Alternatively, the pharmaceutical composition comprising PS can be formulated into any other form of administration suitable for treating and / or preventing neuropathic pain associated with PTPN. Alternatively, the pharmaceutical composition comprising PS can be formulated into any other form of administration suitable for treating and / or preventing migraine pain (or pain from other headache disorders). Alternatively, the pharmaceutical composition comprising PS can be formulated into any other form of administration suitable for treating and / or preventing neuropathic pain associated with PHN. For example, the composition can be formulated for transdermal administration or injection, such as subcutaneous injection.

[0428] In certain embodiments for treating corneal neuropathic pain, the composition may be formulated for intravitreal injection.

[0429] The formulations disclosed herein are also suitable for treating corneal pain, such as corneal pain caused by central sensitization and / or corneal pain generated at a central site of action.

[0430] As disclosed herein, in another aspect, the present invention provides a PS for use in therapy, wherein the PS is topically applied to the outer surface of one or more eyelids. The present invention also provides a method for treating and / or preventing an ocular disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a PS, thereby treating and / or preventing the ocular disease or disorder, wherein the PS is topically applied to the outer surface of one or more eyelids.

[0431] In some embodiments where the PS is topically applied to the outer surface of one or more eyelids, the pharmaceutical composition comprising the PS can be formulated as a gel (e.g., a hydrogel) or an ointment. For topical application to the outer surface of the eyelids, the pharmaceutical composition comprising the PS can be formulated as a cream, a gel (e.g., a hydrogel), a lotion, an ointment, a foam, and / or a spray.

[0432] In some embodiments where PS is topically administered to the outer surface of one or more eyelids, the 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 from the outer surface of the eyelids, thereby allowing a therapeutically appropriate amount of PS to reach the ocular surface.

[0433] In some embodiments where PS is topically applied to the outer surface of one or more eyelids, the PS formulation may comprise PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, the concentration of PS may be 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 concentration of PS may be less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% w / w of the pharmaceutical composition, and particularly about 3% w / w of the pharmaceutical composition. As another illustrative example, when formulated as a gel, the concentration of PS can be less than or equal to 8% w / w of the pharmaceutical composition, such as less than or equal to 5% w / w of the pharmaceutical composition, particularly less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated as a hydrogel or ointment, the concentration of PS can be 5% w / w of the pharmaceutical composition.

[0434] 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.

[0435] The observations presented here unexpectedly demonstrate that PS can have a direct effect on centrally generated neuronal pain signaling (e.g., through central sensitization) even after oral administration. Previous observations have suggested that, following topical administration, PS is transported along peripheral neurons to central sites, enabling PS to act directly on neurons involved in pain generation. Topical administration allows PS to be administered to areas with high concentrations of peripheral sensory neurons, allowing it to be absorbed and mobilized to the central site of action in sufficient quantities to achieve an analgesic effect. Oral administration of PS also produces analgesic effects in indications known to have central sites of pain generation, such as pain associated with central sensitization, pain associated with PTPN, pain associated with postherpetic neuralgia (PHN), and migraine pain, which was previously unexpected. In fact, typical NSAIDs have been shown to be ineffective for the treatment of 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 are not recommended for the treatment of neuropathic pain.

[0436] The observations herein indicate that following oral administration, PS reaches therapeutically relevant amounts in pain-sensing areas of the brain (e.g., the medulla oblongata and cerebellum). Evidence herein demonstrates that PS is taken up by neurons innervating the gastric mucosa and delivered along the vagus nerve to central brain sites. These observations are corroborated by the observation that PS is localized along the sciatic nerve and that therapeutic levels of PS are absent in the blood. Thus, without wishing to be bound by theory, PS may provide its direct analgesic effect to neurons within central pain-sensing areas of the brain, thereby providing a sophisticated mechanism that can alleviate centrally generated pain, regardless of its initial cause.

[0437] 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.

[0438] Thus, the present invention provides a method for treating pain associated with central sensitization, comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating pain associated with central sensitization, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing neuropathic pain associated with CIPN, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing neuropathic pain associated with DPN, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with PTPN, comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing neuropathic pain associated with PTPN, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing neuropathic pain associated with PHN, 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), the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing migraine pain (or pain associated with other headache disorders), wherein the PS is administered orally. The present invention provides a method for treating and / or preventing corneal neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing corneal neuropathic pain, wherein the PS is administered orally.

[0439] PS for oral administration can be formulated as a liquid or solid dosage form.

[0440] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.

[0441] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation art. The solid dosage forms such as capsules, tablets, and pills can be such that the PS is released only or preferentially in a certain portion of the intestinal tract (e.g., the stomach), optionally in a delayed manner.

[0442] In some embodiments, formulations for oral administration comprise one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or antistatic agents.

[0443] Formulations suitable for oral administration may comprise 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.

[0444] Even after oral administration, PS can reduce pain signaling in the CNS, particularly in pain-sensing areas of the brain. In some embodiments, oral administration of PS will reduce pain signaling in the brain. After oral administration, PS can accumulate (via the vagus nerve) 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 therapeutically relevant levels. In specific embodiments, after oral administration, PS accumulates in the medulla oblongata and / or cerebellum in therapeutically relevant levels. For example, after oral administration, PS can reduce pain signaling in the somatosensory cortex, such as the primary somatosensory cortex. Orally administered PS can reduce pain signaling in one or more of the following areas of the brain: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray. In specific embodiments, orally administered PS can reduce pain signaling in the medulla and / or cerebellum.

[0445] In some embodiments, PS is administered both orally and topically.

[0446] Pharmaceutical compositions of modified NSAIDs

[0447] The modified NSAIDs used in the methods of the present invention can be formulated into suitable pharmaceutical compositions for administration to subjects in need thereof, such as subjects suffering from CIPN or DPN or pain associated with central sensitization, subjects suffering from PTPN, subjects suffering from PHN, subjects suffering from migraine pain (and pain from other headache disorders), or subjects suffering from corneal neuropathic pain. Pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of the modified NSAID and may further comprise a pharmaceutically acceptable excipient. In specific embodiments, pharmaceutical compositions comprising the modified NSAID can be formulated into topical formulations for use in the present invention.

[0448] 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 extremities, and thus the extremities, which explains the "stocking and glove" distribution experienced by these patients. Therefore, particularly useful pharmaceutical compositions comprising modified NSAIDs are pharmaceutical compositions that can be applied directly to the peripheral locations experiencing neuropathic pain (e.g., the upper and lower extremities of a subject). In addition, pharmaceutical compositions comprising modified NSAIDs can also be applied to locations where one or more sensory symptoms of CIPN or DPN occur. Therefore, pharmaceutical compositions comprising modified NSAIDs can be formulated for topical administration. In particular, pharmaceutical compositions comprising modified NSAIDs can be formulated for dermal administration, particularly application to the skin of the upper and / or lower extremities of a subject.

[0449] In some embodiments, pharmaceutical compositions comprising modified NSAIDs can be formulated as semisolid or liquid forms. Thus, pharmaceutical compositions comprising modified NSAIDs can be formulated as creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. These compositions can have varying relative concentrations of oil and water, thereby imparting different densities to the compositions. Varying the density of the formulation is one way to control the exposure of the affected area to the pharmaceutical composition. For example, if the formulation has a low density and requires rubbing until it is absorbed, the exposure time may be shortened. Alternatively, if the formulation has a high density and is not readily absorbed, the exposure time of the area to the pharmaceutical composition may be extended. One skilled in the art will appreciate how to formulate topical pharmaceutical compositions to alter the relative exposure of the area to the active pharmaceutical ingredient.

[0450] In other embodiments, the pharmaceutical composition comprising the modified NSAID can be formulated as a patch that can be applied to the skin. The patch can be manufactured in a manner that ensures controlled release of the modified NSAID at the affected area.

[0451] Formulations suitable for topical administration and suitable pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO 2019 / 067919, which is incorporated herein by reference in its entirety.

[0452] In some embodiments, a modified NSAID formulation suitable for topical administration may comprise PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, the concentration of the modified NSAID may be 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 concentration of the modified NSAID may be less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% w / w of the pharmaceutical composition, and particularly about 3% w / w of the pharmaceutical composition. As other illustrative examples, when formulated as a gel, the concentration of the modified NSAID can be less than or equal to 8% w / w of the pharmaceutical composition, such as less than or equal to 5% w / w of the pharmaceutical composition, particularly less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated as a hydrogel or ointment, the concentration of the modified NSAID can be 5% w / w of the pharmaceutical composition.

[0453] 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 feet (i.e., stockings) 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).

[0454] The pharmaceutical composition comprising the modified NSAID may be formulated into any other form of administration 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, such as subcutaneous injection.

[0455] For example, a pharmaceutical composition for topical administration may comprise two or more modified NSAIDs disclosed herein. In certain embodiments, for example, a pharmaceutical composition for topical administration may comprise one or more modified NSAIDs disclosed herein other than PS in combination with PS.

[0456] The same areas of topical administration for PS are also suitable for topical administration of modified NSAIDs. For example, for the treatment of pain associated with central sensitization, a particularly useful pharmaceutical composition comprising a modified NSAID is one that can be applied directly to the peripheral location where pain is experienced. For the treatment and prevention of pain associated with PTPN, a particularly useful pharmaceutical composition comprising a modified NSAID is one that can be applied directly to the peripheral location where neuropathic pain is experienced. In addition, a pharmaceutical composition comprising a modified NSAID can also be applied to the location where one or more sensory symptoms of PTPN occur. For the treatment and / or prevention of pain associated with PHN, a particularly useful pharmaceutical composition comprising a modified NSAID is one that can be applied directly to the peripheral location where neuropathic pain is experienced (e.g., a thoracic dermatome on a subject's trunk). In addition, a pharmaceutical composition comprising a modified NSAID can also be applied to the location where one or more sensory symptoms of PHN occur. Furthermore, for the treatment and / or prevention of migraine pain (or pain from other headache disorders), particularly useful pharmaceutical compositions comprising a modified NSAID are those that can be applied directly to the peripheral location where pain is experienced (e.g., the head and / or neck of a subject).

[0457] In certain embodiments, the modified NSAID can be administered orally. The oral formulations disclosed herein for PS can also be used for oral formulations of other modified NSAIDs.

[0458] In specific embodiments, the orally administered modified NSAID is a phosphamidate NSAID, such as sulindac amide phosphate, such as Formula X; or ibuprofen amide phosphate, such as Formula XI. In some embodiments, the orally administered modified NSAID is ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; NO-sulindac, such as Formula XLIV; HS-sulindac, such as Formula XXXIV; or naproxen phosphate (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 sulindac amide phosphate (e.g., Formula X). In specific embodiments, the orally administered modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI, particularly ibuprofen amide phosphate, such as Formula XI.

[0459] As demonstrated herein, even after oral administration, modified NSAIDs (e.g., naproxen phosphate and sulindac amide phosphate) can be delivered along the vagus nerve in therapeutically relevant amounts to reach CNS regions, even in the brain. Therefore, in some embodiments, oral administration of a modified NSAID will reduce pain signaling occurring in the brain. After oral administration, the modified NSAID can accumulate (via the vagus nerve) in the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray (PAG) of the midbrain at therapeutically relevant levels. In specific embodiments, after oral administration, the modified NSAID accumulates in the medulla oblongata and / or cerebellum at therapeutically relevant levels. For example, after oral administration, the modified NSAID can reduce pain signaling in the somatosensory cortex, such as the primary somatosensory cortex. Orally administered modified NSAIDs can reduce pain signaling in one or more of the following areas of the brain: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray. In specific embodiments, orally administered modified NSAIDs can reduce pain signaling in the medulla oblongata and / or cerebellum.

[0460] In some embodiments, the modified NSAID can be administered both orally and topically.

[0461] PS dosing regimen

[0462] The appropriate dosage regimen of PS for the treatment of the indications 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 according to the World Health Organization's "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 excipient, the route of administration, and the judgment of the attending physician.

[0463] For topical administration, PS can be applied to cover one or more affected areas of a subject (i.e., those surrounding areas experiencing pain). In some embodiments, about 0.01 to about 5 g of PS can be applied to the affected area. Depending on the size of the affected area, PS can be administered at a rate of about 0.005–0.25 g / 10 cm 2 Apply to the affected area. Therefore, PS can be applied at a rate of about 0.005 g / 10 cm 2 , 0.01g / 10cm 2 , 0.05g / 10cm2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 Apply to the affected area.

[0464] For topical administration to treat and / or prevent neuropathic pain associated with PHN, the PS administered can cover one or more affected areas, such as one or more chest dermatomes of a subject. For example, PS can be topically administered to the site of a rash, or to a site experiencing sensory symptoms before the rash appears. Thus, PS can be topically administered during the prodromal phase or during a rash (e.g., administered to one or more chest dermatomes). Thus, PS can be prophylactically administered to prevent the occurrence of neuropathic pain associated with PHN after the rash subsides. In a specific embodiment, PS is administered (e.g., topically administered) to the site of the primary rash after the rash and / or skin lesions subside. Thus, PS can be topically administered (e.g., administered to one or more chest dermatomes) after the rash and / or skin lesions subside. In these cases, PS can prevent the occurrence of neuropathic pain associated with PHN, or treat neuropathic pain associated with PHN that has already established at the site of the original rash.

[0465] For topical administration to treat and / or prevent migraine pain (or pain associated with other headache disorders), the PS can be applied to cover one or more affected areas, such as the subject's temple or behind each ear.

[0466] For topical administration to the ocular surface, the PS can be applied to cover the affected area (i.e., the ocular surface). For topical administration to the outer surface of the eyelid, the PS can be applied to ensure that a therapeutically appropriate amount of the PS reaches the ocular surface after topical application to the outer surface of the eyelid. As described above, for topical administration to the outer surface of the eyelid, the PS is applied substantially entirely to the outer surface of the eyelid.

[0467] In embodiments where the PS is administered topically to the ocular surface, about 0.001 to about 1 mg of PS may be administered to the ocular surface. Depending on the size of the ocular surface, the PS may be administered at a dose of about 0.005-0.25 mg / cm 2 Thus, PS can be applied to the ocular surface at a dose of approximately 0.005 mg / cm 2 , 0.01mg / cm 2 , 0.05mg / cm 2 , 0.1mg / cm 2 , 0.15mg / cm 2 , 0.2mg / cm 2 or 0.25 mg / cm 2Applied to the ocular surface. Each eye drop can administer about 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, or 0.25 mg of PS.

[0468] In embodiments where topical administration is to the outer surface of the eyelid, about 0.1 to about 250 mg of PS may be applied to the outer surface of the eyelid. Depending on the size of the outer surface of the eyelid, PS may be applied at a dose of about 0.5-100 mg / cm 2 Apply to the outer surface of the eyelid. Thus, PS can be applied at a dose of approximately 0.5 mg / cm 2 , 5mg / cm 2 、10mg / cm 2 , 25mg / cm 2 , 50mg / cm 2 , 75mg / cm 2 or 100mg / cm 2 Apply to the outer surface of the eyelid.

[0469] In some cases, the PS used in the methods of the present invention for topical application can be applied, then removed from the affected area (e.g., by washing it off), and subsequently reapplied. In some cases, the PS is washed off after a period of time. Alternatively, because the analgesic effect may diminish over time and reapplication of the PS may be necessary, in some cases the PS is not washed off, but rather reapplied to the affected area after an appropriate administration period. For example, the PS can be applied to the affected area and left in place (before removal or reapplication) for about 0.5 to about 5 hours. Thus, the PS can be topically applied and left in place (before removal or reapplication) for about 0.5, about 1, about 2, about 3, about 4, or about 5 hours.

[0470] Because the analgesic effect may diminish over time, in some cases, a PS applied topically to the ocular surface and / or the outer surface of the eyelid may be reapplied to the ocular surface and / or the outer surface of the eyelid after an appropriate administration period. For embodiments involving topical application to the outer surface of the eyelid, the PS may be removed from the outer surface of the eyelid (e.g., by washing it off) before reapplication. In some cases, the PS is washed off after a period of time. In some cases, the PS is not washed off, but simply reapplied. For example, the PS may be applied to the ocular surface and / or the outer surface of the eyelid and left there (before removal or reapplication) for about 0.5 to about 5 hours. Thus, the PS may be topically applied to the ocular surface and / or the outer surface of the eyelid and left there (before removal or reapplication) for about 0.5, about 1, about 2, about 3, about 4, or about 5 hours.

[0471] Because 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, repeated topical administration of PS is necessary. Similarly, because migraine pain (and pain from other headache disorders) can be chronic, e.g., lasting up to 72 hours, and chronic migraines can last even longer, repeated topical administration of PS is necessary. Thus, PS can be applied topically one to four times a day. Thus, PS can be applied once, twice, three times, or four times a day. For certain formulations of PS, such as hydrogels or ointments having a PS concentration of approximately 5% w / w of the pharmaceutical composition, the formulation can be applied topically three times a day. In more severe cases, PS can be reapplied approximately 0.5 hours after each application.

[0472] 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 the outer surface of the eyelid one to four times a day. Thus, PS can be applied once, twice, three times, or four times a day. For specific formulations of PS, such as a hydrogel or ointment with a PS concentration of approximately 5% w / w of the pharmaceutical composition, the formulation can be topically applied to the ocular surface and / or the outer surface of the eyelid three times a day. In more severe cases, PS can be reapplied approximately 0.5 hours after each application. PS can have a long-lasting analgesic effect, thus allowing for reduced frequency of application. For example, PS can be applied topically less than once a day, for example, every other day. Indeed, for patients who experience long-term analgesia with a single application of PS, PS can be applied topically less than once a week, for example, once every two weeks.

[0473] In some embodiments where PS is topically administered to the ocular surface and / or the outer surface of the eyelid, the PS may have a long-lasting analgesic effect, thereby allowing for reduced frequency of administration. For example, PS may be topically administered to the ocular surface and / or the outer surface of the eyelid less than once a day (e.g., once every other day). In fact, for those patients who experience long-term analgesia with a single administration of PS, PS may be topically administered to the ocular surface and / or the outer surface of the eyelid less than once a week (e.g., once every two weeks).

[0474] For topical administration of some pharmaceutical compositions, it is useful to cover the affected area with, for example, a dressing (e.g., plastic wrap or film) after application of the pharmaceutical composition, for example to ensure that the appropriate amount of composition can be applied within the appropriate time. Thus, after topical application of the PS, the affected area may be bandaged.

[0475] In some embodiments, the PS can be topically administered in the form of a patch (e.g., plaster). The use of a patch can reduce the dosing interval and / or dosing frequency, for example, because the patch ensures controlled release of the PS. Thus, the patch can be applied to the affected area once a day.

[0476] In some embodiments of topical administration to the outer surface of the eyelid, the PS can be topically applied to the outer surface of the eyelid in the form of a patch (e.g., plaster). The use of a patch can reduce the dosing interval and / or dosing frequency, for example, because the patch ensures controlled release of the PS. Thus, the patch can be applied to the outer surface of the eyelid once a day.

[0477] The oral administration dosage level of PS can be 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 a specific embodiment, the administration dosage level of PS can be about 1 mg / mg / kg to about 5 mg / kg of the subject's body weight, for example about 3 mg / kg of the subject's body weight.

[0478] The oral dosage of PS can be from about 1 mg to about 2000 mg. In some embodiments, the oral dosage of PS can be from about 100 mg to 1500 mg, for example, from about 200 mg to about 1000 mg. In some embodiments, the oral dosage of PS can be from about 50 mg to about 400 mg, for example, from about 100 mg to about 350 mg, for example, from about 150 mg to about 300 mg, for example, from about 150 mg to about 250 mg. In specific embodiments, the oral dosage of PS is from about 250 mg to about 300 mg, preferably about 250 mg. In some embodiments involving multiple administrations, an equal amount of PS can be administered for each administration. In other embodiments, a higher initial dose can be administered, followed by a lower maintenance dose.

[0479] In some embodiments, PS can be administered orally once a day, or more frequently. For example, PS can be administered twice a day, three times a day, four times a day, or more frequently as needed. In specific embodiments, PS can be administered orally two or three times a day.

[0480] In a specific embodiment, PS is orally administered at a dose of about 150 mg to about 200 mg twice a day.Thus, a daily dose of about 300 mg to about 400 mg of PS can be orally administered to a subject.

[0481] In a specific embodiment, PS is orally administered at a dose of about 250 mg to about 300 mg (e.g., about 250 mg) twice or three times a day. Thus, a daily dose of about 500 mg to a maximum of about 900 mg of PS can be orally administered to a subject.

[0482] PS can be administered continuously for the desired duration. For example, PS can be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 28, 56, or 84 days. As described above, PS can be administered continuously over a long period of time to treat chronic conditions, for example, for at least 3 months. Thus, in some cases, continuous administration is achieved for the desired duration. PS can be administered intermittently based on the recurrence of pain and / or associated sensory symptoms associated with the indications described herein.

[0483] The PS can be used to treat (and prevent) pain in mammals associated with the indications described herein. For example, the subject can be a human.

[0484] As described above, PS can be formulated into a suitable pharmaceutical composition for administration to a subject suffering from any of the indications described herein (e.g., pain associated with central sensitization, PTPN, PHN, migraine (or other headache disorders), or corneal neuropathic pain). Thus, PS can be administered in a suitable pharmaceutical composition according to the above-described dosing regimen. In specific embodiments, PS or a suitable pharmaceutical composition of PS is administered as monotherapy.

[0485] The dosing regimens disclosed herein are suitable for treating corneal pain, such as corneal pain caused by central sensitization and / or corneal pain generated at a central site of action. In fact, the dosing regimens disclosed herein are suitable for any treatment method disclosed herein.

[0486] It will be understood by those skilled in the art that, in certain embodiments, the dosage of these compounds may be adjusted depending on the mammal being treated. For example, treatment of mice is described herein, and these dosages may or may not be modified when administering PS to humans. However, those skilled in the art may convert the dosages provided herein as needed, as described in the Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (published by the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005). The human equivalent dose (HED) can be determined from the animal dose, which can be multiplied by the following conversion factors to provide units of 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, miniature pig = 0.73 and minipig = 0.95.

[0487] Modified NSAID dosing regimen

[0488] The appropriate dosage regimen of the modified NSAID for the treatment and / or prevention of 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 according to the World Health Organization's "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 physician.

[0489] 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. Depending on the size of the affected area, the modified NSAID can be administered at a dose of about 0.005–0.25 g / 10 cm 2 Thus, the modified NSAID can be administered at a dose of about 0.005 g / 10 cm 2 , 0.01g / 10cm2 , 0.05g / 10cm 2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 Apply to the affected area.

[0490] In some cases, a modified NSAID for topical administration can be applied, then removed from the affected area (e.g., by washing it off), and subsequently reapplied. In some cases, the modified NSAID is washed off after a period of time. Alternatively, because the analgesic effect may diminish over time and reapplication of the modified NSAID may be necessary, in some cases, the modified NSAID is not washed off, but rather reapplied to the affected area after an appropriate administration time has elapsed. For example, a modified NSAID can be applied to the affected area and left in the affected area (before being removed or reapplied) for about 0.5 hours to about 5 hours. Thus, a modified NSAID can be topically applied and left in the affected area (before being removed or reapplied) for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0491] 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 may be necessary. Thus, the modified NSAID may be topically applied one to four times a day. Thus, the modified NSAID may be applied once a day, twice a day, three times a day, or four times a day. For specific 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 topically applied three times a day. In more severe cases, the modified NSAID may be reapplied approximately 0.5 hours after each application.

[0492] The modified NSAID may have a long-lasting analgesic effect, and thus the frequency of administration may be reduced. For example, the modified NSAID may be topically applied to the ocular surface and / or the outer surface of the eyelid less than once a day (e.g., once every other day). In fact, for patients who experience long-term analgesia with a single administration of the modified NSAID, the modified NSAID may be topically applied less than once a week, e.g., once every two weeks.

[0493] For topical administration of some pharmaceutical compositions, it may be useful to cover the affected area with, for example, a dressing (e.g., plastic wrap or film) after application of the pharmaceutical composition, e.g., to ensure that the appropriate amount of the composition is applied within the appropriate time. Thus, after topical application of the modified NSAID, the affected area may be bandaged.

[0494] In some embodiments, the modified NSAID can be topically administered in the form of a patch (e.g., plaster). Use of a patch can reduce dosing intervals and / or dosing 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.

[0495] The modified NSAID can be administered continuously for a desired period of time. For example, the modified NSAID can be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 28, 56, or 84 days. As described above, the modified NSAID can be administered continuously for a long period of time to treat chronic effects, for example, for at least 3 months. Thus, in some cases, continuous administration is achieved and maintained for a desired period of time. The modified NSAID can be administered intermittently based on the recurrence of neuropathic pain and / or related sensory symptoms.

[0496] Where appropriate, two or more modified NSAIDs disclosed herein can be administered, for example, topically. The two or more modified NSAIDs can be administered sequentially or simultaneously. In some cases, one or more modified NSAIDs disclosed herein other than a PS can be administered, for example, topically, in combination with a topically administered PS, for example, sequentially or simultaneously.

[0497] The modified NSAID can be used to treat and / or prevent CIPN in a mammal. For example, the subject can be a human.

[0498] As described above, the modified NSAID can be formulated into a suitable pharmaceutical composition for administration to a subject suffering from an indication described herein (e.g., CIPN or DPN). Thus, the modified NSAID can be administered in a suitable pharmaceutical composition according to the above-described dosing regimen.

[0499] Suitable oral dosage levels and regimens disclosed herein for PS may be equally applicable to oral dosage levels and regimens for other modified NSAIDs.

[0500] It will be understood by those skilled in the art that, in certain embodiments, the dosage of these compounds may be adjusted depending on the mammal being treated. For example, treatment of mice is described herein, and these dosages may or may not be modified when administering PS to humans. However, those skilled in the art may convert the dosages provided herein as needed, as described in the Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (published by the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005). The human equivalent dose (HED) can be determined from the animal dose, which can be multiplied by the following conversion factors to provide units of 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, miniature pig = 0.73 and minipig = 0.95.

[0501] Pharmaceutically acceptable forms of PS or modified NSAIDs

[0502] The pharmaceutical composition comprising PS may contain a pharmaceutically acceptable form of PS, which may be a solvate, a derivative and / or a prodrug.

[0503] Likewise, pharmaceutical compositions comprising the modified NSAID may contain a pharmaceutically acceptable form of the modified NSAID. The pharmaceutically acceptable form may be a solvate, derivative and / or prodrug.

[0504] Solvates

[0505] As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable forms of PS may include solvates of PS, such as solvates of PS-I and / or PS-II. Pharmaceutically acceptable forms of modified NSAIDs may include solvates of modified NSAIDs. In some embodiments, the solvate includes at least one solvent molecule. In some embodiments, the solvate includes less than one solvent molecule. In some embodiments, the solvate is a hydrate.

[0506] isotope

[0507] Pharmaceutically acceptable forms of PS may include isotope-labeled derivatives of PS-I. Pharmaceutically acceptable forms of PS may include isotope-labeled derivatives of PS-II. Isotope-labeled derivatives are compounds that are identical to PS, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. In some embodiments, isotope-labeled derivatives of PS include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, isotope-labeled derivatives of PS include one or more of the following isotopes, respectively: 2 H. 3 H. 13 C. 14 C. 18 O. 17 O. 31 P. 32 P. 35 S and 18 F. In some embodiments, the isotopically labeled derivative of PS includes one or more isotopes 2 H (e.g., deuterium). In some embodiments, the isotopically labeled derivative of PS includes one or more isotopes 3 H (eg, tritium). In some embodiments, the isotopically labeled derivative of PS includes one or more isotopes 14 C.

[0508] Pharmaceutically acceptable forms of modified NSAIDs may include isotopically labeled derivatives of the modified NSAID. Isotopically labeled derivatives are compounds that are identical to the modified NSAID, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. In some embodiments, the isotopically labeled derivatives of the modified NSAID include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, the isotopically labeled derivatives of the modified NSAID include one or more of the following isotopes, respectively: 2 H. 3 H. 13 C. 14 C. 18 O. 17 O. 31 P. 32 P. 35 S and 18 F. In some embodiments, the isotopically labeled derivative of a modified NSAID includes one or more isotopes 2 H (e.g., deuterium). In some embodiments, the isotopically labeled derivative of a modified NSAID includes one or more isotopes 3 H (e.g., tritium). In some embodiments, the isotopically labeled derivative of a modified NSAID includes one or more isotopes 14 C.

[0509] Derivatives and prodrugs

[0510] Pharmaceutically acceptable forms of PS may include derivatives of PS-I. Pharmaceutically acceptable forms of PS may include derivatives of PS-II. In some embodiments, the derivative of PS (e.g., PS-I or PS-II) is a metabolite. In other embodiments, the pharmaceutically acceptable form of PS is a prodrug of PS, such as a prodrug of PS-I or a prodrug of PS-II.

[0511] The structure of the sulfone group can be represented as: RS(=O)2-R'. In some embodiments, the derivative of PS is the sulfone form of PS.

[0512] PS contains an organophosphate functional group. The structure of the organophosphate functional group can be represented as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR"). For example, if R=CH2CH3 and R'=the rest of the molecule is PS according to Formula I or II (e.g., PS-I, PS-II, or a derivative thereof), then O=P(OR)2(OR') can represent PS.

[0513] In some embodiments, the derivative of PS is a PS in which one ethoxy (e.g., -OCH2CH3) group is replaced by an OH group, or a pharmaceutically acceptable salt thereof. In some embodiments, the derivative of PS is a PS in which two ethoxy (e.g., -OCH2CH3) groups are replaced by an OH group, or a pharmaceutically acceptable salt thereof.

[0514] The activities of PS demonstrated herein will be common to pharmaceutically acceptable forms thereof. Accordingly, the present invention provides pharmaceutically acceptable forms of PS for use in the methods of the present invention.

[0515] The pharmaceutically acceptable form of the modified NSAID may include a derivative of the modified NSAID. In some embodiments, the derivative of the modified NSAID is a metabolite. In other embodiments, the pharmaceutically acceptable form of the modified NSAID is a prodrug of the modified NSAID.

[0516] The activity of the modified NSAID may be shared by its pharmaceutically acceptable form. Accordingly, the present invention provides a pharmaceutically acceptable form of the modified NSAID for use in the methods of the invention.

[0517] Although preferred embodiments of the present invention are shown and described herein, these 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 invention.

[0518] Numbered implementation plan

[0519] The present invention further provides the following numbered embodiments.

[0520] 1. A method for treating pain associated with central sensitization, the method comprising administering a therapeutically effective amount of sulindac phosphate (PS) to a subject in need thereof, thereby treating pain associated with central sensitization.

[0521] 2. The method of embodiment 1, wherein treating the pain comprises reducing the pain.

[0522] 3. The method of any one of the preceding embodiments, wherein treating the pain comprises reducing one or more symptoms associated with central sensitization.

[0523] 4. The method of embodiment 3, wherein the one or more symptoms are selected from mood changes, fatigue, cognitive impairment, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia and / or phonophobia.

[0524] 5. The method of any one of the preceding embodiments, wherein PS reduces neuronal signaling involved in pain perception.

[0525] 6. The method of any one of the preceding embodiments, wherein PS reduces centrally occurring pain signaling.

[0526] 7. The method of any one of the preceding embodiments, wherein the PS reduces pain signaling occurring in the dorsal horn of the spinal cord.

[0527] 8. The method of any one of the preceding embodiments, wherein PS reduces pain signaling occurring in the CNS.

[0528] 9. The method of any one of the preceding embodiments, wherein the pain is allodynia.

[0529] 10. The method of embodiment 9, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0530] 11. The method of any one of the preceding embodiments, wherein the pain is hyperalgesia.

[0531] 12. 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 sulindac phosphate (PS) to a subject in need thereof, thereby treating and / or preventing neuropathic pain associated with PTPN.

[0532] 13. The method of embodiment 12, wherein treating the neuropathic pain comprises reducing the neuropathic pain.

[0533] 14. The method of embodiment 12 or 13, wherein preventing the neuropathic pain comprises reducing the incidence of the neuropathic pain.

[0534] 15. The method of any one of embodiments 12-14, wherein treating the neuropathic pain comprises reducing one or more sensory symptoms associated with PTPN.

[0535] 16. The method of any one of embodiments 12-15, wherein preventing the neuropathic pain comprises reducing the incidence of one or more sensory symptoms associated with PTPN.

[0536] 17. The method of embodiment 15 or 16, wherein the one or more sensory symptoms are selected from paresthesia, burning sensation, and stinging sensation.

[0537] 18. The method of embodiment 17, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or forking.

[0538] 19. The method of any one of embodiments 12-18, wherein PS reduces neuronal signaling involved in pain perception.

[0539] 20. The method of any one of embodiments 12-19, wherein the PS reduces pain produced by peripheral sensitization.

[0540] 21. The method of any one of embodiments 12-20, wherein PS reduces pain produced by central sensitization.

[0541] 22. The method of any one of embodiments 12-21, wherein PS reduces centrally occurring pain signaling.

[0542] 23. The method of any one of embodiments 12-22, wherein the PS reduces pain signaling occurring in peripheral nerves.

[0543] 24. The method of any one of embodiments 12-23, wherein PS reduces pain signaling occurring in the dorsal root ganglia.

[0544] 25. The method of any one of embodiments 12-24, wherein PS reduces pain signaling occurring in the dorsal horn of the spinal cord.

[0545] 26. The method of any one of embodiments 12-25, wherein the neuropathic pain is allodynia.

[0546] 27. The method of embodiment 26, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0547] 28. The method of any one of embodiments 12-27, wherein the neuropathic pain is hyperalgesia.

[0548] 29. The method of any one of embodiments 12-28, wherein the neuropathic pain associated with PTPN is caused by neuropraxia, such as a nerve compression injury.

[0549] 30. The method of any one of embodiments 12-29, wherein the neuropathic pain associated with PTPN is caused by axonal truncation, such as a nerve crush injury.

[0550] 31. The method of any one of embodiments 12-30, wherein the neuropathic pain associated with PTPN is caused by one or more of: 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); meralgia paresthesia; peroneal nerve compression; pudendal nerve entrapment syndrome; sciatica; tarsal tunnel syndrome; cervical disc herniation; thoracic disc herniation; and / or lumbar disc herniation.

[0551] 32. A method for treating and / or preventing migraine pain, the method comprising administering a therapeutically effective amount of sulindac phosphate (PS) to a subject in need thereof, thereby treating and / or preventing migraine pain.

[0552] 33. The method of embodiment 32, wherein treating the pain comprises reducing pain, such as a throbbing headache.

[0553] 34. The method of embodiment 32 or 33, wherein preventing the pain comprises reducing the incidence of the pain, e.g., throbbing headache.

[0554] 35. The method of any one of embodiments 32-34, wherein treating the pain comprises reducing one or more symptoms associated with a migraine.

[0555] 36. The method of any one of embodiments 32-35, wherein preventing the pain comprises reducing the incidence of one or more symptoms associated with migraine.

[0556] 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.

[0557] 38. The method of embodiment 37, wherein the aura comprises one or more sensory disturbances, such as visual symptoms, pins and needles (tingling), and / or numbness.

[0558] 39. The method of embodiment 37 or 38, wherein the cranial autonomic symptom is redness or tearing of the eyes.

[0559] 40. The method of any one of embodiments 32-39, wherein the subject experiences cutaneous allodynia.

[0560] 41. The method of any one of embodiments 32-40, wherein PS reduces neuronal signaling involved in pain perception.

[0561] 42. The method of any one of embodiments 32-41, wherein the PS reduces pain produced by peripheral sensitization.

[0562] 43. The method of any one of embodiments 32-42, wherein PS reduces pain produced by central sensitization.

[0563] 44. The method of any one of embodiments 32-43, wherein PS reduces centrally occurring pain signaling.

[0564] 45. The method of any one of embodiments 32-44, wherein the PS reduces pain signaling occurring in the trigeminal nerve.

[0565] 46. ​​The method of any one of embodiments 32-45, wherein PS reduces pain signaling occurring in the trigeminal ganglion.

[0566] 47. The method of any one of embodiments 32-46, wherein PS reduces pain signaling occurring in the caudate nucleus of the spinal trigeminal tract.

[0567] 48. The method of any one of embodiments 32-47, wherein PS reduces pain signaling occurring in higher order neurons and / or pain perception areas of the brain, such as trigeminothalamic neurons.

[0568] 49. The method of any one of embodiments 32-48, wherein the pain is allodynia, eg, cutaneous allodynia.

[0569] 50. The method of embodiment 49, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0570] 51. The method of any one of embodiments 32-50, wherein the pain is hyperalgesia.

[0571] 52. The method of any one of embodiments 32-51, wherein the migraine is episodic migraine or chronic migraine.

[0572] 53. The method of any one of embodiments 32-52, wherein the migraine is migraine with aura or migraine without aura.

[0573] 54. A method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), the method comprising administering to a subject in need thereof a therapeutically effective amount of sulindac phosphate (PS), thereby treating and / or preventing neuropathic pain associated with PHN.

[0574] 55. The method of embodiment 54, wherein treating the neuropathic pain comprises reducing the neuropathic pain.

[0575] 56. The method of embodiment 54 or 55, wherein preventing the neuropathic pain comprises reducing the incidence of the neuropathic pain.

[0576] 57. The method of any one of embodiments 54-56, wherein treating the neuropathic pain comprises reducing one or more sensory symptoms associated with PHN.

[0577] 58. The method of any one of embodiments 54-57, wherein preventing the neuropathic pain comprises reducing the incidence of one or more sensory symptoms associated with PHN.

[0578] 59. The method of any one of embodiments 54-58, wherein the neuropathic pain is sharp, burning, throbbing, or stabbing pain.

[0579] 60. The method of any one of embodiments 57-59, wherein the one or more sensory symptoms are selected from itching or numbness.

[0580] 61. The method of any one of embodiments 54-60, wherein PS reduces neuronal signaling involved in pain perception.

[0581] 62. The method of any one of embodiments 54-61, wherein the PS reduces pain produced by peripheral sensitization.

[0582] 63. The method of any one of embodiments 54-62, wherein PS reduces pain produced by central sensitization.

[0583] 64. The method of any one of embodiments 54-63, wherein PS reduces centrally occurring pain signaling.

[0584] 65. The method of any one of embodiments 54-64, wherein the PS reduces pain signaling occurring in a peripheral nerve, eg, a nerve innervating one or more dermatomes.

[0585] 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.

[0586] 67. The method of any one of embodiments 54-66, wherein PS reduces pain signaling occurring in the dorsal root ganglia.

[0587] 68. The method of any one of embodiments 54-67, wherein PS reduces pain signaling occurring in the dorsal horn of the spinal cord.

[0588] 69. The method of any one of embodiments 54-68, wherein the neuropathic pain is allodynia.

[0589] 70. The method of embodiment 69, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0590] 71. The method of any one of embodiments 54-70, wherein the neuropathic pain is hyperalgesia.

[0591] 72. The method of any one of the preceding embodiments, wherein the subject is a human.

[0592] 73. The method of any one of the preceding embodiments, wherein PS has Formula I (PS-I):

[0593]

[0594] 74. The method of any one of the preceding embodiments, wherein the PS has Formula II (PS-II):

[0595]

[0596] 75. The method of any one of the preceding embodiments, wherein the therapeutically effective amount of PS is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0597] 76. The method of embodiment 75, wherein the pharmaceutical composition comprising PS is formulated for topical administration.

[0598] 77. The method of embodiment 76, wherein the pharmaceutical composition comprising PS is formulated in a semisolid form.

[0599] 78. The method of embodiment 76, wherein the pharmaceutical composition comprising PS is formulated in liquid form.

[0600] 79. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a cream.

[0601] 80. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a gel, for example, wherein the gel is a hydrogel.

[0602] 81. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a lotion.

[0603] 82. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is an ointment.

[0604] 83. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a spray.

[0605] 84. The method of embodiment 76, wherein the pharmaceutical composition comprising PS is formulated in the form of a patch.

[0606] 85. The method of any one of embodiments 75-84, wherein the pharmaceutical composition comprises PS at a concentration of about 0.5% to about 15% w / w of the pharmaceutical composition.

[0607] 86. The method of embodiment 85, wherein the pharmaceutical composition comprises 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.

[0608] 87. The method of embodiment 86, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% or about 3% w / w of the pharmaceutical composition.

[0609] 88. The method of embodiment 86, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to about 3% w / w of the pharmaceutical composition, for example, about 2% or about 1% w / w of the pharmaceutical composition.

[0610] 89. The method of any one of embodiments 75-88, wherein the PS is at about 0.005 g / 10 cm 2 About 0.25g / 10cm 2 Apply to the affected area.

[0611] 90. The method of embodiment 89, wherein the PS is at about 0.005 g / 10 cm 2 Apply to the affected area.

[0612] 91. The method of embodiment 89, wherein the PS is at about 0.01 g / 10 cm 2 Apply to the affected area.

[0613] 92. The method of embodiment 89, wherein the PS is at about 0.05 g / 10 cm 2 Apply to the affected area.

[0614] 93. The method of embodiment 89, wherein the PS is at about 0.1 g / 10 cm 2 Apply to the affected area.

[0615] 94. The method of embodiment 89, wherein the PS is at about 0.15 g / 10 cm 2 Apply to the affected area.

[0616] 95. The method of embodiment 89, wherein the PS is at about 0.2 g / 10 cm 2 Apply to the affected area.

[0617] 96. The method of embodiment 89, wherein the PS is about 0.25 g / 10 cm 2 Apply to the affected area.

[0618] 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.

[0619] 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.

[0620] 99. The method of embodiment 97 or 98, wherein after the administration period, the PS is removed from the affected area, for example by washing it off.

[0621] 100. The method of embodiment 97 or 98, wherein after the administration period, PS is applied to the affected area a second or more times.

[0622] 101. The method of any one of embodiments 75-100, wherein the PS is administered once a day.

[0623] 102. The method of any one of embodiments 75-100, wherein the PS is administered twice a day.

[0624] 103. The method of any one of embodiments 75-100, wherein the PS is administered three times a day.

[0625] 104. The method of any one of embodiments 75-100, wherein the PS is administered four times a day.

[0626] 105. The method of any one of embodiments 75-104, wherein the PS is administered in the form of a pharmaceutical composition.

[0627] 106. A method of treating corneal neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of sulindac phosphate (PS), thereby treating corneal neuropathic pain.

[0628] 107. The method of embodiment 106, wherein treating the corneal neuropathic pain comprises reducing the corneal neuropathic pain.

[0629] 108. The method of embodiment 106 or 107, wherein treating the corneal neuropathic pain comprises reducing one or more symptoms associated with corneal neuropathic pain.

[0630] 109. The method of embodiment 108, wherein the one or more symptoms are selected from paresthesia, photosensitivity, photosalodynia, anxiety, depression, or apathy.

[0631] 110. The method of embodiment 109, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or forking.

[0632] 111. The method of any one of embodiments 106-110, wherein PS reduces pain produced by central sensitization.

[0633] 112. The method of any one of embodiments 106-111, wherein PS reduces centrally occurring pain signaling.

[0634] 113. The method of any one of embodiments 106-112, wherein PS reduces pain signaling occurring in the trigeminal ganglion.

[0635] 114. The method of any one of embodiments 106-113, wherein PS reduces pain signaling occurring in the caudate nucleus of the spinal trigeminal tract.

[0636] 115. The method of any one of embodiments 106-114, wherein PS reduces pain signaling occurring in higher order neurons and / or pain perception areas of the brain, such as trigeminothalamic neurons.

[0637] 116. The method of any one of embodiments 106-115, wherein the corneal neuropathic pain is allodynia.

[0638] 117. The method of embodiment 116, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0639] 118. The method of any one of embodiments 106-117, wherein the corneal neuropathic pain is hyperalgesia.

[0640] 119. The method of any one of embodiments 106-118, wherein the subject is human.

[0641] 120. The method of any one of embodiments 106-119, wherein PS is of Formula I (PS-I).

[0642] 121. The method of any one of embodiments 106-120, wherein the PS is of formula II (PS-II).

[0643] 122. The method of any one of embodiments 106-121, wherein the PS is administered to the ocular surface.

[0644] 123. The method of any one of embodiments 106-122, wherein the PS is applied to the outer surface of one or more eyelids, for example, wherein the one or more eyelids is one or both upper eyelids and / or one or both lower eyelids.

[0645] 124. The method of any one of embodiments 106-123, wherein the therapeutically effective amount of PS is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0646] 125. The method of embodiment 124, wherein the pharmaceutical composition comprising PS is formulated for topical administration.

[0647] 126. The method of embodiment 125, wherein the topical administration is to the ocular surface.

[0648] 127. The method of embodiment 125, wherein the topical administration is to the outer surface of one or more eyelids, for example, wherein the one or more eyelids is one or both upper eyelids and / or one or both lower eyelids.

[0649] 128. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is formulated in a semisolid form.

[0650] 129. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is formulated in liquid form.

[0651] 130. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is a cream.

[0652] 131. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is a gel, for example, wherein the gel is a hydrogel.

[0653] 132. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is a lotion.

[0654] 133. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is an ointment.

[0655] 134. The method of embodiments 125-127, wherein the pharmaceutical composition comprising PS is formulated as eye drops.

[0656] 135. The method of embodiment 134, wherein the eye drop composition is an ophthalmic solution or an ophthalmic emulsion for dropwise administration to the eye.

[0657] 136. The method of embodiment 134 or 135, wherein the droplet size is between about 10 and about 100 μL.

[0658] 137. The method of any one of embodiments 124-136, wherein the pharmaceutical composition comprises PS at a concentration of about 0.5% to about 15% w / w of the pharmaceutical composition.

[0659] 138. The method of embodiment 137, wherein the pharmaceutical composition comprises 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.

[0660] 139. The method of embodiment 138, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% or about 3% w / w of the pharmaceutical composition.

[0661] 140. The method of embodiment 139, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to about 3% w / w of the pharmaceutical composition, for example, about 2% or about 1% w / w of the pharmaceutical composition.

[0662] 141. The method of any one of embodiments 124-140, wherein the PS is at about 0.005 mg / cm 2 to about 0.25 mg / cm 2 Apply to the ocular surface.

[0663] 142. The method of embodiment 141, wherein the PS is at about 0.005 mg / cm 2, 0.01mg / cm 2 , 0.05mg / cm 2 , 0.1mg / cm 2 , 0.15mg / cm 2 , 0.2mg / cm 2 or 0.25 mg / cm 2 Apply to the ocular surface.

[0664] 143. The method of any one of embodiments 124-140, wherein the PS is at about 0.5 mg / cm 2 to about 100 mg / cm 2 Apply to the outer surface of the eyelid.

[0665] 144. The method of embodiment 143, wherein the PS is at about 0.5 mg / cm 2 , 5mg / cm 2 、10mg / cm 2 , 25mg / cm 2 , 50mg / cm 2 , 75mg / cm 2 or 100mg / cm 2 Apply to the outer surface of the eyelid.

[0666] 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 remains on the ocular surface and / or the outer surface of the eyelid for about 1 hour to about 5 hours.

[0667] 146. The method of embodiment 145, wherein the PS is applied to the ocular surface and / or the outer surface of the eyelid and remains 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.

[0668] 147. The method of embodiment 145 or 146, wherein after the administration period, the PS is removed from the outer surface of the eyelid, for example by washing it off.

[0669] 148. The method of any one of embodiments 145-147, wherein after the dosing period, PS is applied to the ocular surface and / or the outer surface of the eyelid a second or more times.

[0670] 149. The method of any one of embodiments 124-148, wherein the PS is administered once a day.

[0671] 150. The method of any one of embodiments 124-148, wherein the PS is administered twice a day.

[0672] 151. The method of any one of embodiments 124-148, wherein the PS is administered three times a day.

[0673] 152. The method of any one of embodiments 124-148, wherein the PS is administered four times a day.

[0674] 153. The method of any one of embodiments 141-152, wherein the PS is administered to the ocular surface and / or the outer surface of the eyelid in the form of a pharmaceutical composition.

[0675] 154. A method of treating and / or preventing an ocular disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of sulindac phosphate (PS), thereby treating and / or preventing the ocular disease or condition, wherein the PS is topically applied to the outer surface of one or more eyelids.

[0676] 155. The method of embodiment 154, wherein the one or more eyelids are one or both upper eyelids.

[0677] 156. The method of embodiment 154, wherein the one or more eyelids are one or both lower eyelids.

[0678] 157. The method of any one of embodiments 154-156, wherein the ocular disease or disorder is an inflammatory ocular disease or disorder.

[0679] 158. The method of any one of embodiments 154-157, wherein the ocular disease or condition is dry eye disease (DED).

[0680] 159. The method of any one of embodiments 154-158, wherein the ocular disease or condition is corneal pain, e.g., corneal neuropathic pain.

[0681] 160. A method for treating and / or preventing pain, said method comprising administering to a subject in need thereof a therapeutically effective amount of sulindac phosphate (PS), thereby treating and / or preventing said pain.

[0682] 161. PS for the treatment of pain associated with central sensitization.

[0683] 162. A PS for use in treating and / or preventing migraine pain in a subject.

[0684] 163. PS for use in the treatment and / or prevention of neuropathic pain associated with PTPN.

[0685] 164. PS for use in the treatment and / or prevention of neuropathic pain associated with PHN.

[0686] 165. PS for the treatment of corneal neuropathic pain.

[0687] 166. A PS for use in treating and / or preventing an ocular disease or disorder, wherein the PS is topically applied to the outer surface of one or more eyelids.

[0688] 167. PS for the treatment and / or prevention of pain.

[0689] 168. Use of PS for the manufacture of a medicament for treating pain associated with central sensitization.

[0690] 169. Use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PTPN.

[0691] 170. Use of PS for the manufacture of a medicament for treating and / or preventing migraine pain in a subject.

[0692] 171. Use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PHN.

[0693] 172. Use of PS for the manufacture of a medicament for treating corneal neuropathic pain.

[0694] 173. Use of a PS for the manufacture of a medicament for the treatment and / or prevention of an ocular disease or disorder, wherein the PS is topically applied to the outer surface of one or more eyelids.

[0695] 174. Use of PS for the manufacture of a medicament for the treatment and / or prevention of pain.

[0696] 175. The method of any one of embodiments 1-75, 106-121, and 154-160, wherein the PS is administered orally.

[0697] 176. The PS for use of any one of embodiments 161-167, wherein the PS is administered orally.

[0698] 177. The use of any one of embodiments 168-174, wherein the PS is administered orally.

[0699] 178. A method for treating and / or preventing neuropathic pain associated with CIPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing the neuropathic pain associated with CIPN, wherein the PS is administered orally.

[0700] 179. A method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering to a subject in need thereof a therapeutically effective amount of PS, thereby treating and / or preventing the neuropathic pain associated with DPN, wherein the PS is administered orally.

[0701] 180. The method, PS for use, or use of any one of embodiments 175-179, wherein the PS is formulated as a liquid or solid dosage form.

[0702] 181. The method, PS for use, or use of embodiment 180, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir.

[0703] 182. The method, PS for use, or use of embodiment 180, wherein the solid dosage form is a capsule, tablet, pill, powder, or granules.

[0704] 183. The method, PS for use, or use of any one of embodiments 175-182, 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 subject body weight, e.g., about 1 mg / kg to about 5 mg / kg of subject body weight, e.g., about 3 mg / kg of subject body weight.

[0705] 184. The method, PS for use, or use of any one of embodiments 175-183, wherein the PS is orally administered at a dose of about 1 mg to about 2000 mg, about 100 mg to about 1500 mg, about 200 mg to about 100 mg, 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.

[0706] 185. The method, PS for use, or use of any one of embodiments 175-184, wherein the PS is administered orally at a dose of about 250 mg to about 300 mg, preferably about 250 mg.

[0707] 186. The method, PS for use, or use of any one of embodiments 175-185, wherein the PS is administered orally once a day.

[0708] 187. The method, PS for use, or use of 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.

[0709] 188. The method, PS for use, or use of any one of embodiments 175-187, wherein the PS is administered orally two or three times a day.

[0710] 189. The method, PS for use, or use of any one of embodiments 175-188, wherein the PS is administered orally at a dose of about 150 mg to about 200 mg twice a day.

[0711] 190. The method, PS for use, or use of any one of embodiments 175-189, wherein the PS is orally administered at a daily dose of about 300 mg to about 400 mg.

[0712] 191. The method, PS for use, or use of any one of embodiments 175-190, wherein the PS is administered orally at a daily dose of about 250 mg to about 300 mg (e.g., about 250 mg) twice or three times a day.

[0713] 192. The method, PS for use, or use of any one of embodiments 175-191, wherein the PS is administered orally at a daily dose of about 500 mg to a maximum of about 900 mg a day.

[0714] 193. The method of any one of claims 175-192, wherein the PS is administered orally in the form of a pharmaceutical composition.

[0715] 194. A method of treating and / or preventing neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN), the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with CIPN, wherein the modified NSAID is not PS.

[0716] 195. A method of treating and / or preventing neuropathic pain associated with diabetic peripheral neuropathy (DPN), the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with DPN, wherein the modified NSAID is not PS.

[0717] 196. The method of embodiment 194 or 195, wherein treating the neuropathic pain comprises reducing the neuropathic pain.

[0718] 197. The method of any one of embodiments 194-196, wherein preventing the neuropathic pain comprises reducing the incidence of the neuropathic pain.

[0719] 198. The method of any one of embodiments 194-197, wherein treating the neuropathic pain comprises reducing one or more sensory symptoms associated with CIPN or DPN.

[0720] 199. The method of any one of embodiments 194-198, wherein preventing the neuropathic pain comprises reducing the incidence of one or more sensory symptoms associated with CIPN or DPN.

[0721] 200. The method of embodiment 198 or 199, wherein the one or more sensory symptoms are selected from paresthesia, burning sensation, and shooting pain.

[0722] 201. The method of embodiment 200, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or forking.

[0723] 202. The method of any one of embodiments 194-201, wherein the modified NSAID reduces neuronal signaling involved in pain perception.

[0724] 203. The method of any one of embodiments 194-202, wherein the modified NSAID reduces pain produced by peripheral sensitization.

[0725] 204. The method of any one of embodiments 194-203, wherein the modified NSAID reduces pain via central sensitization.

[0726] 205. The method of any one of embodiments 194-204, wherein the modified NSAID reduces centrally occurring pain signaling.

[0727] 206. The method of any one of embodiments 194-205, wherein the modified NSAID reduces pain signaling occurring in the sciatic nerve.

[0728] 207. The method of any one of embodiments 194-206, wherein the modified NSAID reduces pain signaling occurring in the dorsal root ganglion.

[0729] 208. The method of any one of embodiments 194-207, wherein the neuropathic pain is allodynia.

[0730] 209. The method of embodiment 208, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0731] 210. The method of any one of embodiments 194-209, wherein the neuropathic pain is hyperalgesia.

[0732] 211. The method of any one of embodiments 194 or 196-210, wherein the subject has cancer and is currently receiving or has previously been treated with one or more chemotherapeutic compounds.

[0733] 212. The method of embodiment 211, wherein the one or more chemotherapeutic compounds are selected from one or more of the following: platinum-based drugs, taxanes, immunomodulatory drugs, epothilones, vinca alkaloids, and proteasome inhibitors.

[0734] 213. The method of embodiment 212, wherein the one or more chemotherapeutic compounds are selected from one or more of the following: oxaliplatin, cisplatin, carboplatin, a taxane, paclitaxel, docetaxel, cabazitaxel, thalidomide and its analogs, vincristine, vinblastine, vinorelbine, vindesine, and bortezomib.

[0735] 214. The method of any one of embodiments 211-213, wherein the chemotherapeutic compound is a taxane, eg, paclitaxel.

[0736] 215. The method of any one of embodiments 211-213, wherein the chemotherapeutic compound is a vinca alkaloid, such as vincristine.

[0737] 216. The method of any one of embodiments 211-213, wherein the chemotherapeutic compound is a platinum-based antineoplastic drug, such as oxaliplatin.

[0738] 217. The method of any one of embodiments 211-216, wherein the subject has a solid tumor cancer.

[0739] 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.

[0740] 219. The method of any one of embodiments 194-218, wherein the subject is human.

[0741] 220. A method of treating pain associated with central sensitization, the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating pain associated with central sensitization.

[0742] 221. A method of treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with PTPN.

[0743] 222. A method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), the method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing neuropathic pain associated with PHN.

[0744] 223. A method of treating and / or preventing migraine pain, said method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing migraine pain.

[0745] 224. A method of treating and / or preventing corneal neuropathic pain, said method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing said corneal neuropathic pain.

[0746] 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: phosphate-modified NSAIDs, phosphoamide-modified NSAIDs, selenium-modified NSAIDs, metal complex-NSAIDs, HS-releasing NSAIDs, NO-releasing NSAIDs, and NOSH-releasing NSAIDs.

[0747] 226. The method of any one of embodiments 194-225, wherein the modified NSAID is a modified sulindac, a modified ibuprofen, a modified naproxen, a modified flurbiprofen, a modified aspirin, a modified ketoprofen, a modified tiaprofenic acid, a modified diclofenac sodium, a modified aceclofenac, a modified etodolac, a modified indomethacin, a modified mefenamic acid, a modified meloxicam, a modified nabumetone, a modified phenylbutazone, a modified piroxicam, a modified tenoxicam, a modified tolfenamic acid, a modified ketorolac tromethamine, a modified parecoxib, a modified etoricoxib, or a modified celecoxib.

[0748] 227. The method of embodiment 225 or 226, wherein the modified NSAID is sulindac amide phosphate, e.g., having formula X:

[0749]

[0750] 228. The method of embodiment 225 or 226, wherein the modified NSAID is Se-sulindac, for example, having Formula XIII:

[0751]

[0752] 229. The method of embodiment 225 or 226, wherein the modified NSAID is HS-sulindac, for example, having Formula XXXIV:

[0753]

[0754] 230. The method of embodiment 225 or 226, wherein the modified NSAID is NO-sulindac, for example, having formula XLIV or XLV:

[0755]

[0756] wherein R has the formula XLVI or XLVII:

[0757]

[0758] 231. The method of embodiment 225 or 226, wherein the modified NSAID is NOSH-sulindac, for example, having formula LVII:

[0759]

[0760] 232. The method of embodiment 225 or 226, wherein the modified NSAID is ibuprofen phosphate, for example, having formula III:

[0761]

[0762] 233. The method of embodiment 225 or 226, wherein the modified NSAID is aspirin phosphate, for example, having Formula V, VI, or VII:

[0763]

[0764]

[0765] 234. The method of embodiment 225 or 226, wherein the modified NSAID is flurbiprofen phosphate, for example, having formula IX:

[0766]

[0767] 235. The method of embodiment 225 or 226, wherein the modified NSAID is naproxen phosphate, for example, having Formula VIII:

[0768]

[0769] 236. The method of embodiment 225 or 226, wherein the modified NSAID is ibuprofenamide phosphate, for example, having formula XI:

[0770]

[0771] 237. The method of any one of embodiments 194-236, wherein the therapeutically effective amount of the modified NSAID is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0772] 238. The method of any one of embodiments 194-227, wherein the pharmaceutical composition comprising the modified NSAID is formulated for topical administration.

[0773] 239. The method of embodiment 238, wherein the pharmaceutical composition comprising the modified NSAID is formulated in a semisolid form.

[0774] 240. The method of embodiment 238, wherein the pharmaceutical composition comprising the modified NSAID is formulated in liquid form.

[0775] 241. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a cream.

[0776] 242. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a gel, eg, wherein the gel is a hydrogel.

[0777] 243. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a lotion.

[0778] 244. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is an ointment.

[0779] 245. The method of any one of embodiments 238-240, wherein the pharmaceutical composition comprising the modified NSAID is a spray.

[0780] 246. The method of embodiment 238, wherein the pharmaceutical composition comprising the modified NSAID is formulated as a patch.

[0781] 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.

[0782] 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.

[0783] 249. The method of embodiment 248, wherein the pharmaceutical composition comprises the modified NSAID at a concentration less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% or about 3% w / w of the pharmaceutical composition.

[0784] 250. The method of embodiment 249, wherein the pharmaceutical composition comprises the modified NSAID at a concentration less than or equal to 3% w / w of the pharmaceutical composition, for example, about 2% or about 1% w / w of the pharmaceutical composition.

[0785] 251. The method of any one of embodiments 237-250, wherein the modified NSAID is administered to the affected area at about 0.005 g / 10 cm2 to about 0.25 g / 10 cm2.

[0786] 252. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.005 g / 10 cm2.

[0787] 253. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.01 g / 10 cm2.

[0788] 254. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.05 g / 10 cm2.

[0789] 255. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.1 g / 10 cm2.

[0790] 256. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.15 g / 10 cm2.

[0791] 257. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.2 g / 10 cm2.

[0792] 258. The method of embodiment 251, wherein the modified NSAID is administered to the affected area at about 0.25 g / 10 cm2.

[0793] 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.

[0794] 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.

[0795] 261. The method of embodiment 259 or 260, wherein after the administration period, the modified NSAID is removed from the affected area, for example by washing it off.

[0796] 262. The method of embodiment 259 or 260, wherein after the administration period, the modified NSAID is applied to the affected area a second or more times.

[0797] 263. The method of any one of embodiments 237-262, wherein the modified NSAID is administered once a day.

[0798] 264. The method of any one of embodiments 237-262, wherein the modified NSAID is administered twice a day.

[0799] 265. The method of any one of embodiments 237-262, wherein the modified NSAID is administered three times a day.

[0800] 266. The method of any one of embodiments 237-262, wherein the modified NSAID is administered four times a day.

[0801] 267. The method of any one of embodiments 251-266, wherein the modified NSAID is administered as a pharmaceutical composition.

[0802] 268. The method of any one of claims 237-250 and 267, wherein the pharmaceutical composition comprises two or more of the modified NSAIDs.

[0803] 269. The method of any one of embodiments 194-268, wherein the method comprises administering, eg, topically administering, two or more modified NSAIDs to the subject.

[0804] 270. The method of embodiment 269, wherein the two or more modified NSAIDs are administered simultaneously or sequentially.

[0805] 271. A modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with CIPN, wherein the modified NSAID is not PS.

[0806] 272. Use of a modified NSAID for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with CIPN, wherein the modified NSAID is not PS.

[0807] 273. A modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with DPN, wherein the modified NSAID is not PS.

[0808] 274. Use of a modified NSAID for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with DPN, wherein the modified NSAID is not PS.

[0809] 275. The method of any one of embodiments 194-274, wherein the modified NSAID is selected from: naproxen phosphate, e.g., Formula VIII; ibuprofen phosphate, e.g., Formula III; glycerobuprofen phosphate, e.g., Formula LXXI; glycerophosphoaspirin II, e.g., Formula V; sulindac amide phosphate, e.g., Formula X; ibuprofen amide phosphate, e.g., Formula XI; glycerobuprofen amide phosphate, e.g., Formula XII; NO-sulindac, e.g., Formula XLIV; sulindac platinum, e.g., Formula LXVII; NO-aspirin, e.g., Formula XLIX; HS-sulindac, e.g., Formula XXXIV; or NOSH-aspirin, e.g., Formula LIX.

[0810] 276. The method of any one of embodiments 194-275, wherein the modified NSAID is a modified sulindac, such as NO-releasing sulindac (e.g., NO-sulindac, such as Formula XLIV), HS-releasing sulindac (e.g., HS-sulindac, such as Formula XXXIV), phosphamide-modified sulindac (e.g., sulindac amide phosphate, such as Formula X), or metal-chelated sulindac (e.g., sulindac platinum, such as Formula LXVII).

[0811] 277. A method as described in embodiment 276, wherein the modified sulindac is NO-releasing sulindac (e.g., NO-sulindac, such as Formula XLIV), H2S-releasing sulindac (e.g., HS-sulindac, such as Formula XXXIV), or preferably phosphoamide-modified sulindac (e.g., phosphosulinamide, such as Formula X).

[0812] 278. The method of any one of embodiments 194-275, wherein the modified NSAID is a phosphorylated NSAID, such as naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; glyceroprofen phosphate, such as Formula LXXI; or glycerophosphate aspirin II, such as Formula V.

[0813] 279. The method of any one of embodiments 194-275, wherein the modified NSAID is a phosphamidate NSAID, such as ibuprofenamide phosphate, such as Formula XII; ibuprofenamide phosphate, such as Formula XI; or sulindacamide phosphate, such as Formula X.

[0814] 280. The method of any one of embodiments 194-275, wherein the modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofen amide phosphate, such as Formula XI.

[0815] 281. The method of any one of embodiments 194-237, 268-270, and 275-280, wherein the modified NSAID is administered orally.

[0816] 282. The modified NSAID for use of embodiment 271 or 273, wherein the modified NSAID is administered orally.

[0817] 283. The use of any one of embodiments 272 or 274, wherein the modified NSAID is administered orally.

[0818] 284. The method, modified NSAID for use, or use of any one of embodiments 281-283, wherein the modified NSAID is formulated as a liquid or solid dosage form.

[0819] 285. The method, modified NSAID for use, or use of embodiment 284, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir.

[0820] 286. The method, modified NSAID for use, or use of embodiment 284, wherein the solid dosage form is a capsule, tablet, pill, powder, or granules.

[0821] 287. The method, modified NSAID for use, or use of any one of embodiments 281-286, wherein the modified NSAID is administered orally 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 subject body weight, e.g., about 1 mg / kg to about 5 mg / kg of subject body weight, e.g., about 3 mg / kg of subject body weight.

[0822] 288. The method, modified NSAID for use, or use of any one of embodiments 281-287, wherein the modified NSAID is administered orally at a dose of about 1 mg to about 2000 mg, about 100 mg to about 1500 mg, about 200 mg to about 100 mg, 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.

[0823] 289. The method, modified NSAID for use, or use of any one of embodiments 281-288, wherein the modified NSAID is administered orally at a dose of about 250 mg to about 300 mg, preferably about 250 mg.

[0824] 290. The method, modified NSAID for use, or use of any one of embodiments 281-289, wherein the modified NSAID is administered orally once a day.

[0825] 291. The method, modified NSAID for use, or use of 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.

[0826] 292. The method, modified NSAID for use, or use of any one of embodiments 281-291, wherein the modified NSAID is administered orally two or three times a day.

[0827] 293. The method, modified NSAID for use, or use of any one of embodiments 281-292, wherein the modified NSAID is administered orally at a dose of about 150 mg to about 200 mg twice a day.

[0828] 294. The method, modified NSAID for use, or use of any one of embodiments 281-293, wherein the modified NSAID is administered orally at a daily dose of about 300 mg to about 400 mg.

[0829] 295. The method, modified NSAID for use, or use of any one of embodiments 281-292, wherein the modified NSAID is administered orally at a daily dose of about 250 mg to about 300 mg (e.g., about 250 mg) twice or three times a day.

[0830] 296. The method, modified NSAID for use, or use of any one of embodiments 281-292 or 295, wherein the modified NSAID is administered orally at a daily dose of about 500 mg to about 900 mg a day.

[0831] 297. The method, modified NSAID for use, or use of any one of embodiments 281-296, wherein the modified NSAID is administered as a pharmaceutical composition.

[0832] 298. The method, modified NSAID for use, or use of any one of embodiments 281-297, wherein the modified NSAID is a phosphorylated NSAID, e.g., sulindac phosphate, such as Formula I or II; naproxen phosphate, such as Formula VIII; ibuprofen phosphate, such as Formula III; glyceroprofen phosphate, such as Formula LXXI; or glycerophosphate aspirin II, such as Formula V.

[0833] 299. The method, modified NSAID for use, or use of any one of embodiments 281-297, wherein the orally administered modified NSAID is a phosphamidate NSAID, such as sulindac amide phosphate, such as Formula X; or phosphoprofen amide, such as Formula XI.

[0834] 300. The method, modified NSAID for use, or use of any one of embodiments 281-297, wherein the orally administered modified NSAID is ibuprofen phosphate, e.g., Formula III; ibuprofen glycerol phosphate, e.g., Formula LXXI; NO-sulindac, e.g., Formula XLIV; or HS-sulindac, e.g., Formula XXXIV.

[0835] 301. The method, modified NSAID for use, or use of any one of embodiments 281-297, wherein the orally administered modified NSAID is a modified ibuprofen, such as ibuprofen phosphate, such as Formula III; ibuprofen glycerol phosphate, such as Formula LXXI; or ibuprofenamide phosphate, such as Formula XI, in particular ibuprofenamide phosphate, such as Formula XI.

[0836] 302. A method of treating and / or preventing pain, said method comprising administering to a subject in need thereof a therapeutically effective amount of a modified NSAID, thereby treating and / or preventing said pain.

[0837] 303. A modified NSAID for use in the treatment and / or prevention of pain.

[0838] 304. Use of a modified NSAID for the manufacture of a medicament for the treatment and / or prevention of pain.

[0839] Example

[0840] The embodiments encompassed herein will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as limited to these examples, but rather should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein.

[0841] Example 1 :Effects of PS in treating central sensitization-related pain in CIPN mouse model

[0842] method

[0843] Central sensitization was established by intraperitoneal administration of 10 mg / kg paclitaxel to C57 / BL mice. All study groups received paclitaxel once daily for 3 days. Figure 2 The results showed that paclitaxel significantly decreased PWT compared with untreated mice.

[0844] PS (8% hydrogel) or vehicle control was topically applied to both hind paws of mice 3 times a day for 10 days.The first dose was administered 2 days after the last administration of paclitaxel.

[0845] The research groups are as follows:

[0846] 1. Group 1: Paclitaxel only (n=9)

[0847] 2. Group 2: Paclitaxel plus vehicle (n=10)

[0848] 3. Group 3: Paclitaxel plus PS (n=10)

[0849] To determine treatment outcomes, pain threshold responses were measured using the well-established von Frey filament method. Specifically, a simplified up-down method using von Frey filaments to estimate paw withdrawal threshold (PWT) was used (as described in Bonin et al., Molecular Pain (2014); 10(26): 1–10). The results of the PWT test are expressed as applied force (gm). The PWT test was performed at baseline (i.e., 4 days after the first dose of paclitaxel (day -1)) and then on the last day of treatment with PS or vehicle (i.e., day 10), approximately 30 minutes after the last dose. Data are expressed as percentage change relative to the corresponding baseline value.

[0850] Figure 1 An outline of this study is provided.

[0851] result

[0852] like Figure 2 As shown in Table 1, vehicle administration on a background of paclitaxel had a limited effect on PWT compared to paclitaxel alone, whereas PS administration significantly increased PWT compared to vehicle and paclitaxel alone. Figure 2 The corresponding value.

[0853] Table 1-3 PWT of study groups

[0854]

[0855] in conclusion

[0856] Topical administration of PS significantly increased PWT in mice with confirmed pain associated with central sensitization. Therefore, PS treats pain associated with central sensitization.

[0857] In contrast to observations made with typical NSAIDs, PS exhibits analgesic effects in therapeutic models of pain associated with central sensitization. This striking activity of PS in specific animal models confirms the observation that, unlike typical NSAIDs, PS can effectively treat pain associated with central sensitization.

[0858] Example 2 PS effectively treats pain associated with central sensitization in a mouse model of CIPN induced by multiple different chemotherapeutic drugs

[0859] method

[0860] animal

[0861] Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from the Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in a facility certified by AAALAC. Food and water were available ad libitum. Mice in each cage were randomly assigned to treatment groups. All studies were conducted by an experimenter who was unaware of the identity of the treatment groups. The experiments were conducted during the light cycle (7:00 a.m. to 7:00 p.m.), and animals were euthanized by CO2 asphyxiation. The study was approved by the Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal study reports were in accordance with the ARRIVE guidelines.

[0862] Sulindac phosphate

[0863] PS was formulated into an 8% hydrogel ointment for topical application.

[0864] Pain induction associated with central sensitization

[0865] Central sensitization was induced in mice using three different chemotherapeutic compounds using established protocols (Carozzi et al., Exp Neurol (2010); 226: 301-309; Currie et al., PLoS Biol (2019); 17: e3000243; Eldridge et al., Toxicol Pathol (2020); 48: 190-201). The preparation and dosage of each of the three chemotherapeutic compounds are as follows.

[0866] Paclitaxel: Paclitaxel (purchased from MilliporeSigma (St. Louis, MO)) was dissolved in a mixture of 1 volume ethanol / 1 volume Cremophor EL (EMD Millipore Corp, Burlington, MA) / 18 volumes distilled water. Paclitaxel was administered every other day by four intraperitoneal injections of 8 mg / kg paclitaxel (in a volume of 1 ml / 100 g body weight) for a cumulative dose of 32 mg / kg.

[0867] Oxaliplatin: Oxaliplatin was dissolved in ddHO. 3 mg / kg of oxaliplatin was injected intraperitoneally daily for 5 days, followed by 5 days of no treatment, followed by 5 days of daily intraperitoneal injections of oxaliplatin as before, for a total of ten injections, for a cumulative dose of 30 mg / kg. All injections were administered intraperitoneally in a volume of 1 ml / 100 g body weight.

[0868] Vincristine: Vincristine was dissolved in PBS. 1.5 mg / kg of vincristine was injected intraperitoneally twice a week for a total cumulative dose of 3 mg / kg. All injections were administered intraperitoneally in a volume of 1 ml / 100 g body weight.

[0869] Protocol for using PS to treat established pain associated with central sensitization

[0870] After pain associated with central sensitization was established as demonstrated by a reduction in the mechanical allodynia threshold, 8% PS or placebo hydrogel ointment was applied to the hind paws of mice three times daily for the duration of the assessment period (see Figure 3-5 ). Mechanical allodynia was measured at the time points noted in the figures.

[0871] Mechanical allodynia assessment (von Frey test)

[0872] Mechanical allodynia thresholds were determined using von Frey filaments according to established methods (Chaplan et al., J Neurosci Methods (1994); 53:55-63; Bagdas et al., Biochem Pharmacol (2015); 97:590-600). Briefly, mice were placed in a quiet room for 30 minutes and then placed in a Plexiglas cage with a mesh metal floor to acclimate for 30 minutes before testing. A series of calibrated von Frey filaments (Stoelting, Wood Dale, IL) of increasing stiffness were applied vertically to the paw with a force sufficient to cause a slight bend in the filament and maintained for 2-3 seconds. This process was repeated 5 times at each stiffness level, with a few seconds between each. Paw withdrawal, licking, or shaking were considered positive responses. The mechanical threshold is expressed in g and represents the force required to cause the animal to respond to the von Frey filament.

[0873] Statistical analysis

[0874] Results are expressed as mean ± SEM. PK parameters were calculated using Microsoft Excel and PKSolver. Noncompartmental analysis was performed. Analysis of variance (ANOVA) was performed, followed by Bonferroni post hoc test. Differences were considered significant when P < 0.05.

[0875] result

[0876] The effect of PS was evaluated in mice with pain associated with central sensitization induced by three different chemotherapeutic compounds. This mirrors the clinical situation already considered in Example 1, where patients present with chronic pain associated with central sensitization. ...

Claims

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

2. The method of claim 1, wherein the modified sulindac is: (i) NO-releasing sulindac, such as NO-sulindac, optionally wherein the NO-sulindac has Formula XLIV: (ii) sulindac phosphate (PS), optionally wherein PS has Formula I (PS-I): or PS has the formula II (PS-II): (iii) sulindac amide phosphate, optionally wherein the sulindac amide phosphate has the formula X: or (iv) H2S-releasing sulindac, such as HS-sulindac, optionally wherein the HS-sulindac has Formula XXXIV:

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

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

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

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

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

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

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

10. The method of any one of the preceding claims, wherein the PS reduces pain produced by peripheral sensitization.

11. The method of any one of the preceding claims, wherein the PS reduces pain produced by central sensitization.

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

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

14. The method of claim 13, wherein the nerve innervating one or more dermatomes is 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. The method of any one of the preceding claims, wherein the PS reduces pain signaling occurring in the dorsal root ganglia and / or the dorsal horn of the spinal cord.

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

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

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

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

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

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

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

23. The method of claim 22, wherein the pharmaceutical composition comprising the modified NSAID is formulated in a semisolid form.

24. The method of claim 22, wherein the pharmaceutical composition comprising the modified NSAID is formulated in liquid form.

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

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

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

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

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

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

31. The method of any one of claims 21-30, 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. 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. The method of claim 32, wherein the pharmaceutical composition comprises the modified NSAID at a concentration less than or equal to 8% w / w of the pharmaceutical composition, such as about 5% or about 3% w / w of the pharmaceutical composition.

34. The method of claim 33, wherein the pharmaceutical composition comprises the modified NSAID at a concentration less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition.

35. The method of any one of claims 21-34, wherein the modified NSAID is administered at about 0.005 g / 10 cm 2 About 0.25g / 10cm 2 Apply to the affected area.

36. The method of claim 35, wherein the modified NSAID is administered at about 0.005 g / 10 cm 2 Apply to the affected area.

37. The method of claim 35, wherein the modified NSAID is administered at about 0.01 g / 10 cm 2 Apply to the affected area.

38. The method of claim 35, wherein the modified NSAID is administered at about 0.05 g / 10 cm 2 Apply to the affected area.

39. The method of claim 35, wherein the modified NSAID is administered at about 0.1 g / 10 cm 2 Apply to the affected area.

40. The method of claim 35, wherein the modified NSAID is administered at about 0.15 g / 10 cm 2 Apply to the affected area.

41. The method of claim 35, wherein the modified NSAID is administered at about 0.2 g / 10 cm 2 Apply to the affected area.

42. The method of claim 35, wherein the modified NSAID is administered at about 0.25 g / 10 cm 2 Apply to the affected area.

43. The method of any one of claims 21-42, 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. 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. The method of claim 43 or 44, wherein following the administration period, the modified NSAID is removed from the affected area, for example by washing it off.

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

47. The method of any one of claims 21-46, wherein the modified NSAID is administered once a day.

48. The method of any one of claims 21-46, wherein the modified NSAID is administered twice a day.

49. The method of any one of claims 21-46, wherein the modified NSAID is administered three times a day.

50. The method of any one of claims 21-46, wherein the modified NSAID is administered four times a day.

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

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

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

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

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

56. The method of any one of claims 52-55, wherein the modified NSAID is administered orally 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. The method of any one of claims 52-56, wherein the modified NSAID is administered orally at a dose of about 1 mg to about 2000 mg, about 100 mg to about 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, such as about 150 mg to about 300 mg, such as about 150 mg to about 250 mg.

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

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

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

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

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

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

65. The method of any one of claims 52-64, wherein the modified NSAID is administered orally at a daily dose of about 500 mg up to about 900 mg a day.

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

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

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

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

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

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