Oral administration of compounds for treating pain

Abstract

The invention features methods of treating and / or preventing pain and other disorders using orally administered compounds, for example modified NSAIDs, including phosphosulindac.

Description

[0001] ORAL ADMINISTRATION OF COMPOUNDS FOR TREATING PAIN This application claims the benefit of United States provisional application 63 / 601362, filed 21st November 2023, United States provisional application 63 / 650558, filed 22nd May 2024, and United States provisional application 63 / 601366, filed 21st November 2023, as well as PCT application PCT / US2023 / 080646, filed 21st November 2023, and PCT application PCT / US2023 / 080649, filed 21st November 2023, the complete contents of which are incorporated herein by reference for all purposes. FIELD OF THE INVENTION The invention relates to compounds, in particular modified non-steroidal anti-inflammatory drugs (NSAIDs), for example phosphosulindac (PS), and their use in the treatment of pain and other disorders via oral administration. BACKGROUND OF THE INVENTION Neuropathic pain can occur as a result of damage to the peripheral or central nervous system, for example due to the pathology of neuropathies. Neuropathies are diseases or abnormalities of the nervous system, which afflict more than 20 million Americans. Indeed, according to recent studies, it is observed that neuropathic pain affects about 1 in every 10 adults and the economic burden for treating this pain is increasing. Peripheral neuropathic pain is caused by damage to nerve structures such as peripheral nerve endings or nociceptors which become extremely sensitive to stimulation and which can generate pulses in the absence of stimulation. The damage can occur for many reasons, such as a traumatic injury (such as nerve compression, spinal cord injury and nerve damage following surgery), chemotherapy treatments, diseases such as diabetes, as well as advanced-stage cancers, or due to viruses (e.g., herpes zoster or HIV). The lesion of the peripheral nerve can result in pathological states characterized by the presence of continuous spontaneous pain often associated with hyperalgesia (increased response to harmful stimuli) and allodynia (pain induced by a non-painful stimulus). Hyperalgesia and allodynia are features of central sensitization, in which CNS nociceptive neurons display increased excitability due to a reduced stimulation threshold, triggered by persistent input or peripheral injury. As noted herein, central sensitization is implicated in the generation and maintenance of neuropathic pain. As central sensitization results from changes in the properties of the neurons in the CNS (i.e., central neuronal plasticity), the perception of pain is no longer coupled to the presence, intensity, or duration of a particular peripheral stimuli (noxious or otherwise). Accordingly, central sensitization is implicated in the generation and maintenance of pain in which the pain signalling is generated centrally (i.e., due to the hypersensitivity of central pain signalling neurons), even absent a peripheral stimulus. The dynamic changes in central neurons (i.e., plasticity) that occurs in the development and maintenance of pain associated with central sensitization are considered a major contributor of many clinical pain syndromes. Pain associated with central sensitization, sometimes referred to as centralised pain or central pain has both genetic and environmental influences that predispose patients, and occurs in patients with, for example, fibromyalgia, chronic pain syndromes, as well as neurological injuries such as stroke or a spinal cord injury. Although the pain may be experienced as originating from the periphery, the pain generation occurs at central sites of action, resulting in the symptoms of allodynia and hyperalgesia. From a symptomatic perspective, neuropathic pain and pain associated with central sensitization may cause sharp pains, dull aches, a sensation of painful burning or cold, paraesthesia, a loss of proprioception, numbness, or even a loss of the sensation of pain. Similarly, peripheral neuropathies may cause sharp pains, dull aches, a sensation of painful burning or cold, paraesthesia, a loss of proprioception, numbness, or even a loss of the sensation of pain. Neuropathic pain and pain associated with central sensitization has also developed into a major health problem in broad areas of the population. Treatment of neuropathic pain is often attempted using so-called unconventional analgesics such as antidepressants like duloxetine and amitriptyline, or anti-epileptics like gabapentin or pregabalin. Additionally, topical anaesthetics, including lidocaine, have been used for the treatment and management of neuropathic pain. Often, to achieve analgesic effects at central sites of action, administration into the central nervous system is required, for example via an epidural or spinal injection. Typically, oral NSAIDs are used to manage pain associated with chronic inflammatory conditions such as arthritis. Despite evidence to the contrary, oral NSAIDs are widely used in the management of neuropathic pain. However, oral administration of NSAIDs has been shown to be ineffective in the treatment of neuropathic pain. The lack of efficacy of typical NSAIDs in the context of neuropathic pain is likely because the pain is not caused by on-going peripheral inflammatory responses, but rather by pathological neuronal activity, for example linked to peripheral and central sensitization. In the absence of an ability to act as an analgesic directly on neuronal signalling, typical NSAIDs are ineffective in the treatment of such challenging pain indications such as neuropathic pain and pain associated with central sites of action (e.g., pain associated with central sensitization). Indeed, upon a review of recent clinical trials, there was no indication of any significant pain reduction with NSAIDs in neuropathic pain patients (Moore et al. Cochrane Database of Systematic Reviews (2015); 10: 1–25), with no clinical outcome showing a statistically significant difference between NSAIDs and placebo. The Cochrane Library concluded that NSAIDs should not be recommended for the treatment of neuropathic pain. Therefore, the anti-inflammatory activity of typical NSAIDs fails to generate an analgesic effect, certainly when the pain is generated via central sensitization occurring at central sites of action. Accordingly, there is a strong need for compounds that treat pain having a central site of action, for example neuropathic pain and pain associated with central sensitization. Furthermore, there is a strong need for centrally acting analgesic compounds with facile routes of administration. SUMMARY OF THE INVENTION The inventor has surprisingly found that oral administration of modified NSAIDs (for example PS) is effective in the treatment of a range of complex pain indications, including neuropathic pain and pain associated with central sensitization, both having central sites of action. Indeed, data from multiple distinct animal models demonstrates an ability of orally administered modified NSAIDs to treat allodynia, a manifestation of central sensitization generated by amplification of signals in centrally located neurons in response to typically innocuous stimuli. Furthermore strikingly, the inventor has observed that orally administered modified NSAIDs are able to reach pain sensing regions of the brain in therapeutically relevant amounts. In light of their instability in the blood, the data herein demonstrate the ability of the modified NSAIDs to traverse along the vagus nerve from the stomach to reach key areas of the brain, for example the medulla and cerebellum. To the inventor’s knowledge, this is the first demonstration of the ability of modified NSAIDs to access pain sensing regions deep in the central nervous system upon oral administration. This striking biodistribution, in combination with observations of the striking analgesic effects of orally administered modified NSAIDs (likely, but without wishing to be bound by theory, via direct action on centrally located pain generating neurons), points to a broad applicability of orally administered modified NSAIDs in the treatment of centrally generated pain. The ability of orally administered modified NSAIDs to achieve significant analgesia in challenging pain models builds on further data from the inventor demonstrating the efficacy of topically administered PS in the treatment and prevention of neuropathic pain associated with chemotherapy- induced peripheral neuropathy (CIPN) and diabetic peripheral neuropathy (DPN) (as demonstrated in WO2022 / 251805 and WO2022 / 251806, the contents of which are incorporated by reference in their entirety). Furthermore, the inventor has demonstrated the efficacy of PS and other modified NSAIDs in the treatment of other challenging pain conditions, including neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), neuropathic pain associated with post-herpetic neuralgia (PHN), pain associated with central sensitization, migraine pain and corneal neuropathic pain (as supported by WO2024 / 112725 and WO2024 / 112727, the contents of which are hereby incorporated by reference in their entirety). Previous observations exploited the topical administration of PS to peripheral regions, where peripheral pain sensing neurons are concentrated, permitting an accumulation of PS in central regions associated with the neurons responsible for the initial nociceptive signalling. Therefore, these observations failed to provide any indication that orally administered modified NSAIDs, for example PS, would be able to access central sites of action (i.e., in the absence of exposure to an abundance of peripherally located sensory neurons), let alone generate striking analgesic effects in multiple distinct animal models upon oral administration. The data presented herein demonstrate the surprising applicability of the modified NSAIDs in treating challenging pain indications even upon oral administration. Indeed, without wishing to be bound by theory, the observations herein suggest it may be possible to overcome evident failings of oral administration of typical NSAIDs in the treatment of challenging pain indications, by modifying the NSAIDs such that they may more readily access key sites of pain generation in the higher order pain sensing areas of the brain where they impart an unprecedented analgesic activity directly on neuronal signalling. Therefore, in a first aspect, the inventor provides a method of treating and / or preventing pain comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID is administered orally. The data herein demonstrate an unprecedented ability of orally administered modified NSAIDs, for example PS, to accumulate in the central nervous system, including in pain sensing regions of the brain, permitting a direct activity on pain signalling generated in central neurons, for example due to central sensitization. Therefore, in a further aspect, the inventor provides a method of administering a therapeutically effective amount of a modified NSAID, for example PS, to the central nervous system of a subject in need thereof, wherein the modified NSAID is administered orally. In some embodiments, the administration of the modified NSAID to the central nervous system leads to the treatment and / or prevention of pain. In a further aspect, the inventor provides a method of treating and / or preventing pain comprising administering a therapeutically effective amount of a modified NSAID to the central nervous system of a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID is administered orally. In some embodiments, the inventor provides a method of treating and / or preventing pain generated by neurons located in the central nervous system, for example in one or more areas of the brain involved in pain signalling and / or sensation, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID is administered orally. In some embodiments, the pain generated by neurons located in one or more areas of the brain involved in pain signalling and / or sensation is caused by central sensitization. In some embodiments, the modified NSAID targets neuronal pain signalling in one or more areas of the brain involved in pain signalling and / or sensation. In some embodiments, the modified NSAID acts directly on neurons in one or more areas of the brain involved in pain signalling and / or sensation. Upon oral administration, the modified NSAID, for example PS, may accumulate (via the vagus nerve) at therapeutically relevant levels in the central nervous system, for example in one or more of the areas of the brain involved in pain signalling and / or sensation. For example, the modified NSAID may accumulate in the brainstem (e.g., the midbrain, medulla oblongata and the pons) or the cortical regions (e.g., the cerebral cortext). The modified NSAID may accumulate in one or more of the following areas of the brain: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter (PAG). In particular embodiments, upon oral administration, the modified NSAID accumulates at therapeutically relevant levels in the medulla and / or cerebellum. Accordingly, in particular embodiments, the orally administered modified NSAID translocates along neurons (e.g., the vagus nerve) to accumulate in the central nervous system, for example the regions of the brain implicated in pain signalling described herein. Therefore, in some embodiments, the orally administered modified NSAID is delivered to one or more of the areas of the brain involved in pain sensation described herein. In some embodiments, the orally administered modified NSAID is administered to one or more of the areas of the brain involved in pain sensation, for example one or more of the areas of the brain disclosed herein (e.g., the medulla and / or cerebellum). Given the ability to access central sites of action in therapeutically relevant amounts, in some embodiments, the orally administered modified NSAID may reduce pain signalling occurring centrally. For example, the PS may reduce pain signalling occurring in the central nervous system, for example in one or more of the areas of the brain involved in pain signalling and / or sensation. The orally administered modified NSAID may reduce pain signalling in the somatosensory cortex, for example the primary somatosensory cortex. The orally administered modified NSAID may reduce pain signalling 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 matter. In particular embodiments, the orally administered modified NSAID may reduce pain signalling in the medulla and / or cerebellum. Therefore, the orally administered modified NSAID may target neuronal pain signalling in the central nervous system, for example in one or more of the areas of the brain involved in pain sensation described herein. Accordingly, in particular embodiments, the orally administered modified NSAID acts directly on neuronal signalling generated in centrally located neurons. This activity is distinct to reducing pain generating triggers (e.g., inflammation) in the periphery or reducing signalling in peripheral neurons (i.e., any impact on centrally located nerve signalling via reducing peripheral pain signalling would be an indirect impact on the activity of centrally located neurons). Here, without wishing to be bound by theory, the orally administered modified NSAID accesses the pain sensing regions of the central nervous system, in particular the brain, and impart their analgesic activity directly on pain sensing neurons in this central location. Accordingly, in particular embodiments, the orally administered modified NSAID, for example PS, acts directly on centrally located neurons, for example neurons located in one or more of the areas of the brain involved in pain sensation disclosed herein. Therefore, the modified NSAID acts centrally. In some embodiments, the modified NSAID treats and / or prevents pain associated with neuronal signalling generated by neurons in the central nervous system, for example neurons located in one or more areas of the brain implicated in pain signalling and / or sensation. In some embodiments, the modified NSAID reduces signalling generated by neurons in the central nervous system, for example neurons in one or more areas of the brain implicated in pain signalling and / or sensation disclosed herein. In some embodiments, the pain is neuropathic pain. The neuropathic pain may be neuropathic pain associated with CIPN. The neuropathic pain may be neuropathic pain associated with DPN. The neuropathic pain may be neuropathic pain associated with PTPN. The neuropathic pain may be neuropathic pain associated with PHN. The neuropathic pain may be corneal neuropathic pain. In some embodiments, the pain is migraine pain. The pain may be pain associated with central sensitization. The pain may be a consequence of central sensitization resulting in allodynia and / or hyperalgesia. Accordingly, the pain may be centrally generated pain, for example central pain or chronic pain. In some embodiments, the orally administered modified NSAID may reduce pain generated via central sensitization. In particular, given its ability to traverse towards key sites of pain generation, the orally administered modified NSAID may reduce pain generated via central sensitization. In some instances, the reduction may be complete such that the pain generation is eliminated. Thus, the orally administered modified NSAID may reduce pain signalling occurring centrally. In another aspect, the inventor provides a method of treating and / or preventing pain associated with central sensitization comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that the pain associated with central sensitization is treated and / or prevented, wherein the modified NSAID is administered orally. 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. Furthermore, evidence accumulated by the inventor indicates the efficacy of orally administered modified NSAIDs, for example PS, in the treatment and / or prevention of neuropathic pain associated with CIPN, neuropathic pain associated with DPN, neuropathic pain associated with PTPN, migraine pain, neuropathic pain associated with PHN, and corneal neuropathic pain. Accordingly, in another aspect, the inventor provides a method of treating and / or preventing neuropathic pain associated with CIPN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with CIPN is treated and / or prevented, wherein the modified NSAID is administered orally. In another aspect, the inventor provides a method of treating and / or preventing neuropathic pain associated with DPN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with DPN is treated and / or prevented, wherein the modified NSAID is administered orally. In another aspect, the inventor provides a method of treating and / or preventing neuropathic pain associated with PTPN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PTPN is treated and / or prevented, wherein the modified NSAID is administered orally. In another aspect, the inventor provides a method of treating and / or preventing neuropathic pain associated with PHN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PHN is treated and / or prevented, wherein the modified NSAID is administered orally. In another aspect, the inventor provides a method of treating and / or preventing migraine pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that migraine pain is treated and / or prevented, wherein the modified NSAID is administered orally. In another aspect, the inventor provides a method of treating and / or preventing corneal neuropathic pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that corneal neuropathic pain is treated and / or prevented, wherein the modified NSAID is administered orally. The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramide-modified NSAIDs (phosphoramide-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, H2S-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs) and NO-, SH-releasing NSAIDs (NOSH-NSAIDs, which release both NO and H2S). The modified NSAID may be modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indometacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib, or modified celecoxib. In particular embodiments, the NSAID of the modified NSAID may be sulindac, ibuprofen, or naproxen. In some embodiments, the orally administered modified NSAID is PS, such as formula I or II; phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; NO- sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; platinum-sulindac, such as formula LXVII; phosphosulindac amide, such as formula X; phospho-ibuprofen amide, such as formula XI; NOSH1, such as formula LIX; or phosphonaproxen, such as formula VIII. In particular embodiments, the modified NSAID is PS. In some embodiments, the PS is the sulfoxide form of PS. Therefore, the PS may have the formula I (PS-I): (I) .

[0002] In other embodiments, the PS is the sulfide form of PS. Therefore, the PS may have the formula II (PS-II): . Herein, references to II. The sulfoxide form of the compound is preferred. The compounds of formulae I and II are described in U.S. Patent No.8,236,820, which is hereby incorporated by reference in its entirety. In particular embodiments, the orally administered modified NSAID is a phosphoramide NSAID, for example phosphosulindac amide, such as formula X; or phospho-ibuprofen amide, such as formula XI. In some embodiments, the orally administered modified NSAID is a phospho-NSAID, for example PS, such as formula I or II; phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; or phosphonaproxen, such as formula VIII. In particular embodiments, the orally administered modified NSAID is a modified sulindac, for example a phospho-sulindac, (e.g., phosphosulindac (PS), such as formula I or II); an NO-releasing sulindac (e.g., NO-sulindac, such as formula XLIV); a H2S-releasing sulindac (e.g., HS-sulindac, such as formula XXXIV); a platinum-sulindac (e.g., Pt-sulindac, such as formula LXVII); or a phosphoramide modified sulindac (e.g., phosphosulindac amide, such as formula X). In some embodiments, the orally administered modified NSAID is a modified ibuprofen, for example phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen-amide, such as formula XI, in particular phospho-ibuprofen-amide, such as formula XI. The modified NSAID, for example PS, may be formulated into a pharmaceutical composition for use in the invention. In some embodiments, the pharmaceutical composition comprises a modified NSAID and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be a gastro-retentive pharmaceutical composition. Accordingly, the modified NSAID, for example PS, may be formulated into a gastro-retentive pharmaceutical composition. In a further aspect, the inventor provides a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS. The gastro-retentive pharmaceutical composition is for oral administration. The gastro-retentive pharmaceutical composition may comprise one or more gastro-retentive agents (e.g., one or more gastro-retentive excipients). The inventor also provides a pharmaceutical composition comprising or consisting of a modified NSAID, for example PS, and one or more gastro-retentive agents. The inventor also provides a pharmaceutical combination comprising or consisting of a modified NSAID, for example PS, and one or more gastro-retentive agents. In another aspect, the inventor provides a kit comprising a modified NSAID, for example PS, and one or more gastro-retentive agents. The gastro-retentive agent may be a gastro-retentive excipient, as disclosed herein. The gastro- retentive excipient may be an effervescent excipient, a low density excipient, and / or a mucoadhesive excipient. Without wishing to be bound by theory, a mucoadhesive excipient might maximise the amount of modified NSAID adhering to the stomach lining enabling increased absorption to the vagus nerve and thus increased concentration of the modified NSAID at key sites of action in the brain. Accordingly, in particular embodiments, the gastro-retentive excipient is a mucoadhesive excipient. In those embodiments exploiting separate (e.g., sequential) oral administration of the modified NSAID, for example PS, and a gastro-retentive agent, the gastro-retentive agent may be a compound or composition which extends the length of time for which the modified NSAID, for example PS, is retained in the stomach (e.g., Ensure® or EnsurePlus®). The gastro-retentive agent may be a composition comprising fatty acids (e.g., unsaturated fatty acids), for example triglycerides. The inventor further provides a method comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof. The inventor further provides a method of treating and / or preventing pain comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the pain is treated and / or prevented. The gastro-retentive pharmaceutical composition is administered orally. In some embodiments, the pain is associated with one or more of the indications disclosed herein, for example neuropathic pain or pain associated with central sensitization. The inventor further provides a method comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. The inventor further provides a method of treating and / or preventing pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro- retentive agents are administered orally. In some embodiments, the pain is associated with one or more of the indications disclosed herein, for example neuropathic pain or pain associated with central sensitization. The modified NSAID, for example PS, and one or more gastro-retentive agents may be administered simultaneously, separately or sequentially. In particular embodiments, the one or more gastro-retentive agents is administered prior to administration of the modified NSAID, for example PS. In some embodiments, the modified NSAID, for example PS, is formulated as a gastro-retentive pharmaceutical composition. In some embodiments, the modified NSAID, for example PS, is administered in combination with one or more gastro-retentive agents, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. The inventor further provides a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, for use in therapy. The gastro-retentive pharmaceutical composition is administered orally. The inventor also provides a modified NSAID, for example PS, and one or more gastro-retentive agents as a combined preparation for simultaneous, separate or sequential use in therapy. Also provided is a modified NSAID, for example PS, for use with one or more gastro-retentive agents in therapy. Furthermore, provided is one or more gastro-retentive agents for use with a modified NSAID, for example PS, in therapy. The inventor further provides a modified NSAID, for example PS, and one or more gastro-retentive agents for use in therapy, wherein the modified NSAID, for example PS, and the one or more gastro- retentive agents are administered orally. In some embodiments, the one or more gastro-retentive agents is administered prior to administration of the modified NSAID, for example PS. In a further aspect, the inventor provides a modified NSAID, for example PS, for use in therapy, wherein the use further comprises administering one or more gastro-retentive agents, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. In a further aspect, the inventor provides one or more gastro-retentive agents for use in therapy, wherein the use further comprises administering a modified NSAID, for example PS, wherein the one or more gastro- retentive agents and the modified NSAID, for example PS, are administered orally. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 – effect of PS, with or without pre-treatment with EnsurePlus®, in treating neuropathic pain associated with CIPN. D0, D7, and D10 indicate day 0 (pre-treatment), day 7 and day 10 of treatment, respectively. Figure 2 – effect of PI, with or without pre-treatment with EnsurePlus®, in treating neuropathic pain associated with CIPN. D0, and D7 indicate day 0 (pre-treatment), and day 7 of treatment, respectively. Figure 3 – effect of sulindac, with or without pre-treatment with EnsurePlus®, in treating neuropathic pain associated with CIPN. D0, and D7 indicate day 0 (pre-treatment), and day 7 of treatment, respectively. Figure 4 – comparative effects of PS, sulindac, and PI, with or without pre-treatment with EnsurePlus®, in treating neuropathic pain associated with CIPN. D0, and D7 indicate day 0 (pre- treatment), and day 7 of treatment, respectively. Figure 5 – effect of PS, with or without pre-treatment with EnsurePlus®, in treating migraine pain. DETAILED DESCRIPTION OF THE INVENTION Definitions The following definitions of types of pain are according to the International Association for the Study of Pain (IASP). “Pain” is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. “Central sensitization” refers to increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. “Peripheral sensitization” refers to increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields. The precise etiology of central and peripheral sensitization differs between neuropathic pain and other forms of pain, such as inflammatory pain. “Allodynia” is pain due to a stimulus that does not normally provoke pain. “Hyperalgesia” is increased pain from a stimulus that normally provokes pain. Pain associated with central sensitization can be either generalized or in multiple locations in the body. Given the related nervous system involvement, pain associated with central sensitization displays symptoms corresponding to those observed with neuropathic pain. Accordingly, patients with pain associated with central sensitization may experience one or more sensations described as heat, burning, throbbing, shooting, stabbing, sharpness, cramping, aching, tingling, numbness, or pins and needles. Pain associated with central sensitization is also associated with mood changes, fatigue, cognitive disturbances, sleep changes, and pain catastrophizing. Additionally, patients with pain associated with central sensitization may have multifocal pain, memory complaints, and comorbidities including major depressive disorder or generalized anxiety disorder. “Neuropathic pain” is caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. Patients with neuropathic pain may experience one or more sensations described as heat, burning, throbbing, shooting, stabbing, sharpness, cramping, aching, tingling, numbness, or pins and needles. The term “lesion of the somatosensory nervous system” is commonly used when diagnostic investigations (e.g., imaging, neurophysiology, biopsies, lab tests) reveal an abnormality or when there was obvious trauma. The term “disease of the somatosensory nervous system” is commonly used when the underlying cause of the lesion is known (e.g., stroke, vasculitis, diabetes mellitus, genetic abnormality). “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. The following definitions of types of headache are according to the International Classification of Headache Disorders (ICHD) 3rd Edition (ICHD-3). Migraine has two major types: “migraine without aura”, a clinical syndrome characterized by headache with specific features and associated symptoms; and “migraine with aura”, primarily characterized by the transient focal neurological symptoms that usually precede or sometimes accompany the headache. “Migraine without aura” (i.e., common migraine; hemicrania simplex) is a recurrent headache disorder manifesting in attacks lasting 4-72 hours. The headache typically has a unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and / or photophobia and phonophobia. “Migraine with aura” (i.e., classic or classical migraine) involves recurrent attacks, lasting miniutes, of unilateral fully reversible visual, sensory or other CNS symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms. “Episodic migraine” commonly involves about 1-2 migraine / headaches per month. “Chronic migraine” is a headache occurring on 15 or more days / month for more than three months, which, on at least 8 days / month, has features of migraine headache. In general, the term “disease” refers to a state of being or health status of a patient or subject capable of being treated using the methods provided herein. The term “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application. Accordingly, when the intended application is treating the disease, the “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to treat the disease. When the intended application is treating and / or preventing the disease, the “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to treat and / or prevent the disease. “Pharmaceutically acceptable excipient” is 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. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with PS, its use in the therapeutic compositions of the invention is contemplated. 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 variability (or within statistical experimental error), and thus the number may vary accordingly. The term “comprising” encompasses “including” as well as “consisting”, e.g., a composition “comprising” X may consist exclusively of X or may include something additional (e.g., X + Y). Pain associated with central sensitization As noted above, pain associated with central sensitization is generated as a result of over-activity of centrally located neurons, which display reduced stimulation thresholds and can depolarise even in the absence of a peripheral stimulus. Indeed, the perception of pain is no longer coupled to the presence, intensity, or duration of a particular peripheral stimulus (noxious or otherwise). Accordingly, subjects having pain associated with central sensitization, may experience spontaneous pain, pain induced by a non-painful stimulus (allodynia) or experience heightened pain in response to a harmful stimulus (hyperalgesia). Central sensitization is associated with chronic pain states in which the pain is generated or amplified by hyperexcitability of higher order neurons. The pain can manifest as a widespread or diffuse pain, sometimes localised in the vicinity of the site of the original trigger of nociception. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect, for example by reducing the neuronal signalling involved in the sensation of pain at central sites of action. Accordingly, the modified NSAID may reduce pain signalling occurring centrally. In some embodiments, the pain associated with central sensitization is allodynia. The allodynia may be in response to mechanical and / or thermal stimuli. In addition, in some embodiments, the pain associated with central sensitization is hyperalgesia. In some embodiments, the inventor provides a method of treating pain associated with central sensitization, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that pain associated with central sensitization is treated, wherein the modified NSAID is administered orally. A subject experiencing pain associated with central sensitization would benefit from an analgesic which can both reduce the pain generated by central sensitization and prevent generation of further pain associated with central sensitization. Therefore, in some embodiments, the modified NSAID, for example PS, can be used in the treatment and prevention of pain associated with central sensitization, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID, for example PS, for use in the treatment of pain associated with central sensitization, wherein the modified NSAID is administered orally. Furthermore, the inventor provides the use of a modified NSAID, for example PS, for the manufacture of a medicament for the treatment of pain associated with central sensitization, wherein the medicament is administered orally. 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). The pain associated with central sensitization is not acute nociceptive pain (i.e., that relieves when the harmful stimulus is removed). Accordingly, 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 particular embodiments, the pain is sensed in the absence of peripheral nociceptor input, for example to noxious or innocuous stimuli. The pathogenesis of the central sensitization may vary, depending on the initial pathology triggering peripheral input and contributing to the central sensitization. For example, the central sensitization may be as result of inflammatory pain mechanisms – that is to say, the initial trigger was an inflammatory response, but the central sensitization that is generated causes pain even in the absence of on-going inflammation. In particular instances, the central sensitization is a result of neuropathic pain mechanisms. Central sensitization is a feature of a number of chronic pain conditions. The pain associated with central sensitiation may be the pain associated with one or more of the following: inflammatory pain; neuropathic pain; fibromyalgia; chronic pain; chronic regional pain syndrome; rheumatoid arthritis; psoriatic arthritis; osteoarthritis; spondyloarthritis; lupus; temporomandibular disorders; and / or idiopathic low back pain. The pain associated with central sensitization resulting from inflammatory pain is not due to on-going peripheral inflammatory responses. In particular 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 disorders; and / or idiopathic low back pain. In some embodiments, pain associated with central sensitization occurs following 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 post- herpetic neuralgia. In some embodiments, the pain associated with central sensitization may be migraine pain. In some embodiments, the pain associated with central sensitization may be pain of other headache disorders. In some embodiments, the pain associated with central sensitization may be pain associated with corneal neuropathic pain. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on pain associated with central sensitization. In treating pain associated with central sensitization, the modified NSAID may reduce the pain. In some instances, the reduction is complete such that the pain is eliminated. In treating the pain associated with central sensitization, the modified NSAID may also reduce one or more of the symptoms associated with central sensitization. In treating and preventing pain associated with central sensitization, the modified NSAID may decrease the incidence of the pain. In treating and preventing pain associated with central sensitization, the modified NSAID may also decrease the incidence of one or more of the symptoms associated with central sensitization. The pain associated with central sensitization may be a diffuse pain. The pain may be widespread. In some embodiments, the pain may be diffuse around the region of initial injury. In some embodiments, the pain associated with central sensitization may have features of neuropathic pain, and therefore may result in one or more sensations described as heat, burning, throbbing, shooting, stabbing, sharpness, cramping, aching, tingling, numbness, or pins and needles. Patients suffering from pain associated with central sensitization may experience a range of symptoms. The symptoms include mood changes, fatigue, cognitive disturbances, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia, and / or phonophobia. Even if the symptoms experienced by a subject experiencing pain associated with central sensitization are not considered painful (or do not reach a threshold necessary to be considered pain per se), modified NSAID may reduce any one or more of the symptoms experienced by the subject. In some instances, the reduction is complete such that one or more of the symptoms experienced by the subject are eliminated. Indeed, the resolution of the underlying pain associated with central sensitization would remedy many of the symptoms associated therewith. As noted above, the pain associated with central sensitization may be allodynia and / or hyperalgesia. In particular embodiments, the pain associated with central sensitization is allodynia (e.g., mechanical or thermal allodynia). The modified NSAID may reduce the neuronal signalling involved in the sensation of pain generated via central sensitization. In some instances, the reduction may be complete such that the pain generation is eliminated. Thus, the modified NSAID may reduce pain signalling occurring centrally. The modified NSAID may reduce pain signalling occurring in the CNS, for example in one or more of the areas of the brain involved in pain sensation disclosed herein. In some instances, the reduction may be complete such that pain signalling is eliminated. The pain associated with central sensitization in a subject may be neuropathic pain. In some embodiments, the modified NSAID does not prevent the development of central sensitization. Pain associated with central sensitization in a patient can be measured on a visual analogue pain scale or using any other appropriate method in the art. In particular embodiments, the orally administered modified NSAID may be one or more of the following: PS, such as formula I or II; phosphosulindac amide, such as formula X; phospho- ibuprofen amide, such as formula XI; phospho-ibuprofen, such as formula III; phospho-glycerol- ibuprofen, such as formula LXXI; NO-sulindac, such as formula XLIV; or HS-sulindac, such as formula XXXIV; Pt-sulindac, such as formula LXVIII; or phosphonaproxen, such a formula VIII. In particular embodiments, the orally administered modified NSAID is a phospho-NSAID, for example, PS, such as formula I or II; phosphonaproxen, such as formula VIII; phospho-ibuprofen, such as formula III; or phospho-glycerol ibuprofen, such as formula LXXI. In preferred embodiments, the orally administered modified NSAID is a phosphoramide NSAID, for example phosphosulindac amide, such as formula X; or phospho-ibuprofen amide, such as formula XI. In particular embodiments, the orally administered modified NSAID may be a modified sulindac, for example PS, such as formula I or II; phosphosulindac amide, such as formula X; NO-sulindac, such as formula XLIV; or HS-sulindac, such as formula XXXIV. In particular embodiments, the orally administered NSAID is a modified ibuprofen, for example phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen-amide, such as formula XI, in particular phospho-ibuprofen-amide, such as formula XI. In particular embodiments of treating pain associated with central sensitization, the orally administered modified NSAID is phosphosulindac amide, such as formula X. The inventor provides a method of treating pain associated with central sensitization, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that pain associated with central sensitization is treated. The inventor further provides a method of treating pain associated with central sensitization, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that pain associated with central sensitization is treated, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Pain associated with chemotherapy-induced peripheral neuropathy (CIPN) CIPN, and the associated neuropathic pain, is a frequent, dose-dependent side effect of commonly used chemotherapies. Peripheral nerve damage represents the majority of neurological damage associated with chemotherapy toxicity and represents the most frequent limiting factor for chemotherapy after hematological toxicity. The pain has been thought to be due to a direct toxic effect on the sensory axon, demyelination, or an impairment of calcium metabolism. The neuropathic pain associated with CIPN is particularly difficult to treat. It is currently managed with antidepressants (e.g., duloxetine) and / or antiepileptics (e.g., gabapentin and pregabalin). Unfortunately, pain control is not very satisfactory and these systemic treatments induce major side effects leading to poor treatment adherence. Indeed, to date, there are no satisfactory means of preventing or even treating the pain associated with CIPN: the only approved drug (duloxetine) is generally considered ineffective. As outlined above, chemotherapy can cause damage to neurons resulting in peripheral neuropathy and associated neuropathic pain. The pain can arise during or after a patient has undergone chemotherapy and can manifest for example as shooting, burning, or stabbing pain associated with other sensory symptoms. Accordingly, in some embodiments, the inventor provides a method of preventing neuropathic pain associated with CIPN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with CIPN is prevented, wherein the modified NSAID is administered orally. In other embodiments, the inventor provides a method of treating neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with CIPN is treated, wherein the modified NSAID is administered orally. A subject may experience neuropathic pain caused by one or more previous doses of chemotherapy in advance of one or more subsequent doses and so the subject would benefit from an analgesic which can both treat existing neuropathic pain and prevent generation of further neuropathic pain. Therefore, in some embodiments, the modified NSAID can be used in the treatment and prevention of neuropathic pain associated with CIPN, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID, for example PS, for use in the treatment and / or prevention of neuropathic pain associated with CIPN, wherein the modified NSAID is administered orally. Furthermore, the inventor provides the 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 medicament is administered orally. As CIPN develops in light of chemotherapy, the subject may be a human patient with cancer, who is about to receive treatment, is receiving treatment, has previously received treatment with one or more chemotherapeutic compounds. In general, a chemotherapeutic compound refers to an agent having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. The prevalence of CIPN is agent-dependent, with reported rates varying from 19% to more than 85% in patients on different medications, and is the highest in the case of platinum-based drugs, taxanes, immunomodulatory drugs, and epothilones, although it is also observed in patients on other common cancer chemotherapies, including vinca alkaloids and proteasome inhibitors. Therefore, the one or more chemotherapeutic compounds may be a platinum-based antineoplastic (for example oxaliplatin, cisplatin, or carboplatin), a taxane (for example paclitaxel, docetaxel, or cabazitaxel), a vinca alkaloid (for example vincristine, vinblastine, vinorelbine, or vindesine), or a proteasome inhibitor (for example, bortezomib). The one or more chemotherapeutic compounds may be one or more immunomodulatory drugs, including thalidomide and / or its analogues. The one or more chemotherapeutic compounds may be a platinum-based antineoplastic, for example oxaliplatin, a taxane, for example paclitaxel, and a vinca alkaloid, for example vincristine. The subject may have any cancer which is treated with a chemotherapeutic compound associated with the occurrence of CIPN and the associated neuropathic pain. In some embodiments, the subject with CIPN has a solid tumor cancer. The subject may have ovarian cancer, breast cancer, lung cancer (for example non- small cell lung cancer), Kaposi sarcoma, and / or pancreatic cancer. Alternatively, the subject may have melanoma, esophageal cancer, prostate cancer (for example hormone-refractory prostate cancer), head and neck cancer, stomach cancer, and / or cervical cancer. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on neuropathic pain associated with CIPN. The neuropathic pain associated with CIPN may be a burning pain. A subject undergoing or following chemotherapy may experience neuropathic pain constantly present and symmetric in the lower and upper limbs. In treating neuropathic pain associated with CIPN, the modified NSAID may reduce the neuropathic pain. In some instances, the reduction is complete such that the neuropathic pain is eliminated. In treating the neuropathic pain associated with CIPN, the modified NSAID may also reduce one or more of the sensory symptoms associated with CIPN. In preventing neuropathic pain associated with CIPN, the modified NSAID may decrease the incidence of the neuropathic pain. In preventing neuropathic pain associated with CIPN, the modified NSAID may also decrease the incidence of one or more of the sensory symptoms associated with CIPN. Patients suffering from CIPN describe a range of sensory, bilateral symptoms, for example in hands and feet (also described as the ‘stocking and glove’ distribution). The sensory symptoms include paresthesia (e.g., numbness, tingling, pricking, and / or formication), burning sensations, or shooting (i.e., electric shock-like) sensations. Even if the sensory symptoms experienced by a subject undergoing or following chemotherapy are not considered painful (or do not reach a threshold necessary to be considered pain per se), the modified NSAID may reduce any one or more of the sensory symptoms experienced by a subject undergoing or following chemotherapy, including those listed above. The modified NSAID can be used to reduce the stocking and glove distribution in a subject undergoing or following chemotherapy. In some instances, the reduction is complete such that the one or more sensory symptoms are eliminated. As noted above, the neuropathic pain associated with CIPN may be a consequence of central sensitization resulting in allodynia and / or hyperalgesia. The modified NSAID may reduce the neuronal signalling involved in the sensation of pain in a subject undergoing or following chemotherapy. The modified NSAID may reduce pain generated via central sensitization. In some instances, the reduction may be complete such that the pain generation is eliminated. Thus, the modified NSAID may reduce pain signalling occurring centrally, for example in one or more of the areas of the brain involved in pain sensation disclosed herein. In some instances, the reduction may be complete such that pain signalling is eliminated. The neuropathic pain in a subject undergoing or following chemotherapy CIPN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject undergoing or following chemotherapy CIPN may be hyperalgesia. Neuropathic pain in a patient undergoing or following chemotherapy can be measured on a visual analogue pain scale or using any other appropriate method in the art. In particular embodiments of treating and / or preventing CIPN upon oral administration, the modified NSAID may be one or more of the following: PS, such as formula I or II; phosphosulindac amide, such as formula X; phospho-naproxen, such as formula VIII; phospho-ibuprofen, such as formula III; phospho-glycerol ibuprofen, such as formula LXXI; phospho-ibuprofen amide, such as formula XI; NO-sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; Pt-sulindac, such as formula LXVII; NOSH-aspirin, such as formula LIX; or a compound having formula LXIX. In particular embodiments of treating and / or preventing CIPN upon oral administration, the modified NSAID may be a phospho-NSAID, for example phosphosulindac (PS), such as formula I or II; phospho-naproxen, such as formula VIII; phospho-ibuprofen, such as formula III; or phospho- glycerol ibuprofen, such as formula LXXI. In particular embodiments of treating and / or preventing CIPN upon oral administration, the modified NSAID may be a phosphoramide NSAID, for example phospho-ibuprofen amide, such as formula XI or phosphosulindac amide, such as formula X. In particular embodiments of treating and / or preventing CIPN upon oral administration, the modified NSAID may be a NO-releasing NSAID, for example NO-sulindac, such as formula XLIV; a HS- releasing NSAID, for example HS-sulindac, such as formula XXXIV; or a NOSH-releasing NSAID, such as NOSH-aspirin, such as formula LIX. In particular embodiments of treating and / or preventing CIPN upon oral administration, the modified NSAID may be a modified sulindac, for example PS, such as formula I or II; phosphosulindac amide, such as formula X; NO-sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; Pt- sulindac, such as formula LXVII; or phosphosulindac amide, such as formula X. In particular embodiments of treating and / or preventing CIPN upon oral administration, the modified NSAID may be a modified ibuprofen, for example phospho-ibuprofen, such as formula III; phospho- glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen-amide, such as formula XI, in particular phospho-ibuprofen-amide, such as formula XI. The inventor provides a method of treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the neuropathic pain associated with CIPN is treated and / or prevented. The inventor further provides a method of treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that the neuropathic pain associated with CIPN is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Pain associated with diabetic peripheral neuropathy (DPN) DPN is the peripheral nerve damage caused by diabetes, and represents one of the most serious complications of the disease. About half of all people with diabetes have some form of nerve damage, with hyperglycaemia being a main cause of peripheral neuropathy in DPN. DPN can affect both small nerves and large nerves, which protect the human body by sending signals about pain and temperature changes to brain, and which detect touch, pressure, and help to keep balance. Clinical guidelines recommend pain relief in painful diabetic neuropathy through the use of antidepressants (e.g., duloxetine) and / or antiepileptics (e.g., gabapentin and pregabalin), as well as opioids and topical agents such as capsaicin. The current treatments for the pain associated with DPN have limited efficacy and may cause significant side effects. The pathology occurring in diabetic patients, in particular hyperglycaemia, can cause damage to neurons resulting in peripheral neuropathy and associated neuropathic pain. The neuropathic pain in these patients develops over time and is often worse in patients with long-standing disease, and may include stabbing pain, burning pain, and / or drilling pain. In some embodiments, the inventor provides a method of preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with DPN is prevented, wherein the modified NSAID is administered orally. In other embodiments, the inventor provides a method of treating neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with DPN is treated, wherein the modified NSAID is administered orally. As DPN develops in diabetes patients over time, a subject may experience worsening neuropathic pain over time and so the subject would benefit from an analgesic which can both treat the ongoing neuropathic pain and prevent generation of further neuropathic pain. Therefore, in some embodiments, the modified NSAID, for example PS, can be used in the treatment and prevention of neuropathic pain associated with DPN, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with DPN, wherein the modified NSAID is administered orally. Furthermore, the inventor provides the 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 medicament is administered orally. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on neuropathic pain associated with DPN. The neuropathic pain associated with DPN may be a stabbing pain, burning pain, and / or drilling pain. A subject with DPN may experience neuropathic pain constantly present and symmetric in the lower and upper limbs. In treating neuropathic pain associated with DPN, the modified NSAID may reduce the neuropathic pain. In some instances, the reduction is complete such that the neuropathic pain is eliminated. In treating the neuropathic pain associated with DPN, the modified NSAID may also reduce one or more of the sensory symptoms associated with DPN. In preventing neuropathic pain associated with DPN, the modified NSAID may decrease the incidence of the neuropathic pain. In preventing neuropathic pain associated with DPN, the modified NSAID may also decrease the incidence of one or more of the sensory symptoms associated with DPN. The sensory symptoms of DPN include paraesthesia (e.g., numbness, tingling, pricking, or formication), burning sensations, or shooting (i.e., electric shock-like) sensations. DPN usually affects extremities like feet, hands, legs, and arms, where nerve fibres are the longest and most numerous, and patients often have a ‘stocking and glove’ distribution. Even if the sensory symptoms experienced by a subject with DPN are not considered painful (or do not reach a threshold necessary to be considered pain per se), the modified NSAID may be used to reduce any one or more of the sensory symptoms experienced by a subject with DPN, including those listed above. The modified NSAID may be used to reduce the stocking and glove distribution in a subject with DPN. In some instances, the reduction is complete such that the one or more sensory symptoms are eliminated. As noted above, the neuropathic pain associated with DPN may be a consequence of central sensitization, resulting in allodynia and / or hyperalgesia. The modified NSAID may reduce the neuronal signalling involved in the sensation of pain in a subject with DPN. The modified NSAID may reduce pain generated via central sensitization. In some instances, the reduction may be complete such that the pain generation is eliminated. Accordingly, the modified NSAID may reduce pain signalling occurring centrally. In some instances, the reduction may be complete such that the pain signalling is eliminated. The neuropathic pain in a subject with DPN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject with DPN may be hyperalgesia. Neuropathic pain in a patient with DPN can be measured on a visual analogue pain scale or using any other appropriate method in the art. In particular embodiments of treating and / or preventing DPN upon oral administration, the modified NSAID may be one or more of the following: PS, such as formula I or II; phosphosulindac amide, such as formula X; phospho-naproxen, such as formula VIII; phospho-ibuprofen, such as formula III; phospho-glycerol ibuprofen, such as formula LXXI; phospho-ibuprofen amide, such as formula XI; NO-sulindac, such as formula XLIV; or NOSH-aspirin, such as formula LIX. In particular embodiments of treating and / or preventing DPN upon oral administration, the modified NSAID may be a phospho-NSAID, for example phosphosulindac (PS), such as formula I or II; phospho-naproxen, such as formula VIII; phospho-ibuprofen, such as formula III; or phospho- glycerol ibuprofen, such as formula LXXI. In particular embodiments of treating and / or preventing DPN upon oral administration, the modified NSAID may be a phosphoramide NSAID, for example phospho-ibuprofen amide, such as formula XI or phosphosulindac amide, such as formula X. In particular embodiments of treating and / or preventing DPN upon oral administration, the modified NSAID may be a NO-releasing NSAID, for example NO-sulindac, such as formula XLIV; or a NOSH-releasing NSAID, such as NOSH-aspirin, such as formula LIX. In particular embodiments of treating and / or preventing DPN upon oral administration, the modified NSAID may be a modified sulindac, for example PS, such as formula I or II; phosphosulindac amide, such as formula X; or NO-sulindac, such as formula XLIV. In particular embodiments of treating and / or preventing DPN upon oral administration, the modified NSAID may be a modified ibuprofen, for example phospho-ibuprofen, such as formula III; phospho- glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen-amide, such as formula XI, in particular phospho-ibuprofen-amide, such as formula XI. The inventor provides a method of treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the neuropathic pain associated with DPN is treated and / or prevented. The inventor further provides a method of treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that the neuropathic pain associated with DPN is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Pain associated with post-traumatic peripheral neuropathy Post-traumatic peripheral neuropathy (PTPN) can arise from a range of traumatic peripheral nerve injuries and is associated with neuropathic pain that can cause mild discomfort to life-long impairment. Traumatic nerve injuries may be classified into categories (Seddon and Sunderland’s Grade I-VI) based on the presence of demyelination and the extent of damage to the axons and the connective tissues of the nerve (see Menorca et al., Hand Clin. (2013); 29(3):317-330). The main classifications, in order of severity, are neurapraxia (Grade I), axonotmesis (encompassing Grades II- IV), and neurotmesis (Grade V). Grade VI (a later addition to the Seddon and Sunderland classification) involves different levels of damage (Grade III-V) along the nerve. Of course, such peripheral nerve trauma can be associated with chronic neuropathic pain. The trauma may result in a tangle of neural fibers and connective tissue that develops following the nerve injury (a traumatic neuroma), with the area associated with paresthesia. The damaged nerve and any surrounding nerves may show altered gene expression that renders them hypersensitive, with development of spontaneous discharges. Therefore, the trauma results in painful hypersensitivity to non-noxious stimuli (allodynia) or an exaggerated pain response to noxious stimuli (hyperalgesia), reflective of central sensitization. Traumatic neuropathic pain can cause the patient to feel burning, stabbing, raw, gnawing or sickening sensations as well as numbness, and tingling and prickling sensations. The neuropathic pain associated with PTPN is particularly difficult to treat. It is currently managed by 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 can be employed including nerve blocks, ablation, and neurostimulation, designed to interfere with, interrupt, or modulate pain pathways. Unfortunately, pain control is not very satisfactory and many of the systemic treatments induce major side effects leading to poor treatment adherence. The neuropathic pain associated with PTPN may be due to traumatic nerve injuries falling into any one or more of Seddon and Sunderland’s classes (i.e., Grade I-VI). For example, the traumatic nerve injury may be neurapraxia (Grade I, defined by focal demyelination (causing asynchronous conduction or even conduction block) without damage to the axons or the connective tissues). The neurapraxis may be caused by mild compression or traction of the nerve. The compression injury may occur in locations where nerves pass through narrow anatomical openings, for example those in the upper extremities including the carpal tunnel and cubital tunnel. Nerves may also be compressed by displaced fragments of fractures, disclocation of joints, or expanding hematoma. The traumatic nerve injury may be axonotmesis (Grade II-IV, with increasing severity, involving axon damage with intact endoneurium (Grade II); involving axon and endoneurium damage with intact perineurium (Grade III); and involving axon, endoneurium, and perineurium damage with intact epineurium (Grade IV)). The axonotmesis may be caused by crush injuries that do not result in a complete transection of the nerve. Such crush injuries, with varying degrees of neural damage, may occur from an acute traumatic compression of the nerve from a blunt object, such as a bat, surgical clamp or other crushing object. In some instances, the traumatic nerve injury may be neurotmesis (Grade V, defined by full transection of the axons and connective tissue layers wherein complete discontinuity of the nerve is observed). Injuries involving complete discontinuation of the nerve may occur due to a laceration from a knife, gunshot, glass shard or as a consequence of a car accident or surgical complication. Finally, the traumatic nerve injury may be a combination of any one of these classes (Grade VI). In some embodiments, the traumatic nerve injury is a compression injury. In particular embodiments, the traumatic nerve injury is a crush injury. In certain embodiments, the neuropathic pain associated with PTPN is pain caused by a nerve compression injury and / or a nerve crush injury. The nerve compression injury may be caused by accidents and trauma; joint sprains (e.g., ankle, knee or wrist); arthritis; broken bones; bone spurs; dislocated joints (e.g., elbow or shoulder); herniated disc; hypothyroidism; surgical complications; tumours and / or cysts. The traumatic nerve injury may affect one or more of the following nerves: median nerve; radial nerve; suprascapular nerve; ulnar nerve; lateral femoral cutaneous nerve; peroneal nerve; pudendal nerve; sciatic nerve; tibial nerve; and / or the 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. Accordingly, 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’s canal syndrome); meralgia paresthetica; peroneal nerve compression; pudendal nerve entrapment syndrome; sciatica; tarsal tunnel syndrome; herniated cervical disc; herniated thoracic disc; and / or herniated lumbar disc. In certain embodiments, the neuropathic pain associated with PTPN may be pain caused by a herniated spinal disc. The neuropathic pain associated with PTPN may be caused by a herniated disc in the vertebrae of the spinal column. A herniated disc (prolapsed disc or slipped disc) occurs when the fibrous outer portion of the disc ruptures or tears, resulting in the disc bulging out of the spinal vertebrae. Such a herniated disc may result in the compression of nerves located between adjacent vertebrae or even of the spinal cord itself. This can cause pain, numbness, tingling or weakness in the arms or legs. Long- term compression of the disc can result in symptoms associated with neuropathic pain (e.g., allodynia and hyperalgesia). A bulging disc is less severe than a herniated disc but is also a cause of neuropathic pain associated with PTPN. The herniated (or bulging) disc may be a herniated (or bulging) cervical disc, for example causing pain in the neck, shoulders or arms. The herniated (or bulging) disc may be a herniated (or bulging) thoracic disc, for example causing pain in the mid-back around the level of the disc herniation (or bulge). The herniated (or bulging) disc may be a lumbar herniated (or bulging) disc, for example causing intermittent or continuous back pain and / or sciatica. The neuropathic pain associated with post-traumatic peripheral neuropathy, for example due to traumatic injury to peripheral neurons, can arise immediately after injury and can manifest for example as burning, stabbing, raw, gnawing, sickening pain, poorly localized and sometimes diffuse, and is associated with other sensory symptoms. Accordingly, in some embodiments, the inventor provides a method of treating neuropathic pain associated with PTPN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PTPN is treated, wherein the modified NSAID is administered orally. The pain can also arise with delayed onset after injury. Accordingly, the inventor provides a method of preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PTPN is prevented, wherein the modified NSAID is administered orally. Given that the pain can be experienced both immediately and with delayed onset, a subject may experience pain immediately on injury which develops into a different pain sensation occurring with delayed onset. Therefore, in some embodiments, the modified NSAID can be used in the treatment and prevention of neuropathic pain associated with PTPN, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID, for example PS, for use in the treatment and / or prevention of neuropathic pain associated with PTPN, wherein the modified NSAID is administered orally. Furthermore, the inventor provides the use of a modified NSAID, for example PS, for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PTPN, wherein the modified NSAID is administered orally. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on neuropathic pain associated with PTPN. The neuropathic pain associated with PTPN may be a stabbing or burning pain. In treating neuropathic pain associated with PTPN, the modified NSAID may reduce the neuropathic pain. In some instances, the reduction may be complete such that the neuropathic pain associated with PTPN is eliminated. In treating the neuropathic pain associated with PTPN, the modified NSAID may also reduce one or more of the sensory symptoms associated with PTPN. In preventing neuropathic pain associated with PTPN, the modified NSAID may decrease the incidence of the neuropathic pain. In preventing neuropathic pain associated with PTPN, the modified NSAID may also decrease the incidence of one or more of the sensory symptoms associated with PTPN. Patients suffering from PTPN describe a range of sensory symptoms. The sensory symptoms include paresthesia (e.g., numbness, tingling, pricking, and / or formication), burning sensations, or stabbing sensations. Even if the sensory symptoms experienced by a subject with traumatic nerve injury are not considered painful (or do not reach a threshold necessary to be considered pain per se), the modified NSAID may reduce any one or more of the sensory symptoms experienced by the subject, including those listed above. In some instances, the reduction may be complete such that the one or more of the sensory symptoms associated with PTPN are eliminated. As noted above, nerve damage associated with PTPN may result in over-activation of pain signalling pathways resulting in sensitization of peripheral and / or central neurons, which display reduced stimulation thresholds. Accordingly, subjects having PTPN may experience pain as a consequence of this sensitization, for example, experiencing pain induced by a non-painful stimulus (allodynia) or experiencing heightened pain in response to a harmful stimulus (hyperalgesia). On the basis of observations herein, the modified NSAID may have a direct analgesic effect, for example by reducing the neuronal signalling involved in the sensation of pain. Accordingly, the neuropathic pain associated with PTPN may be a consequence of central sensitization resulting in allodynia and / or hyperalgesia. PS may reduce the neuronal signalling involved in the sensation of pain in a subject with traumatic peripheral nerve injury. The PS may reduce pain generated via central sensitization. In particular, given the ability to traverse towards key sites of pain generation, the modified NSAID may reduce pain generated via central sensitization. In some instances, the reduction may be complete such that the pain generation is eliminated. Thus, the modified NSAID may reduce pain signalling occurring centrally, for example in the brain, for example in one or more of the areas of the brain involved in pain sensation disclosed herein. In some instances, the reduction may be complete such that pain signalling is eliminated. The neuropathic pain in a subject with PTPN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject with PTPN may be hyperalgesia. Neuropathic pain in a patient can be measured on a visual analogue pain scale or using any other appropriate method in the art. In particular embodiments of treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is selected from one or more of the following: phosphosulindac (PS), such as formula I or II; phospho-ibuprofen, such as formula III; phosphosulindac amide, such as formula X; or phospho-ibuprofen amide, such as formula XI. In particular embodiments, the orally administered modified NSAID is a phopsho-NSAID, for example phosphosulindac (PS), such as formula I or II; or phospho-ibuprofen, such as formula III. In particular embodiments, the orally administered modified NSAID is a phosphoramide NSAID, for example phosphosulindac amide, such as formula X; or phospho-ibuprofen amide, such as formula XI. In certain embodiments, the orally administered modified NSAID is modified sulindac, for example phosphosulindac (PS), such as formula I or II; or phosphosulindac amide, such as formula X. In certain emdobiments of treating and / or preventing neuropathic pain associated with PTPN, the orally administered modified NSAID is a modified ibuprofen, for example phospho-ibuprofen, such as formula III; or preferrably phospho-ibuprofen amide, such as formula XI. In certain embodiments, the modified NSAID does not have formula LXIX and / or LXX. The inventor provides a method of treating and / or preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the neuropathic pain associated with PTPN is treated and / or prevented. The inventor further provides a method of treating and / or preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that the neuropathic pain associated with PTPN is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Pain associated with post-herpetic neuralgia PHN is a common complication of herpes zoster, which results from the reactivation of varicella zoster virus (VZV). VZV is a highly virulent neurotropic virus, which can cause varicella (chickenpox) as the primary infection in susceptible individuals. The virus can be retrogradely transported along axons of sensory neurons from the skin to establish a latent infection within sensory ganglia in the peripheral nervous system. In the even of the previously infected subject becoming immune suppressed, the virus can reactivate, presenting as acute herpes zoster (AHZ, “shingles”). Recovery from AHZ is frequently complicated by the development of post-herpetic neuralgia, a neuropathic pain syndrome characterized by persisting pain arising in areas affected by herpes zoster. PHN is typically defined as pain lasting 90 days or more after the initial presentation of the rash or at least three months after the healing of skin lesions. AHZ is diagnosed more than 1 million times a year in the US alone. Approximately 20% of patients with AHZ will experience PHN and will continue to suffer intermittent neuropathic symptoms, including itchiness and pain. The pain is characterized as sharp, stabbing, throbbing or burning, often localized to the site of the original rash. The long-pasting pain is associated with painful hypersensitivity to non-noxious stimuli (allodynia) or an exaggerated pain response to noxious stimuli (hyperalgesia), reflective of central sensitization. Without treatment, the incidence of pain persisting three months after the development of the rash is reported to be about 8-15%, a figure which increases rapidly in the elderly. The pain associated with PHN is linked to peripheral and particularly central sensitization (Hadley et al., Curr Pain Headache Rep. (2016); 20:17). During reactivation of VZV, the virus replicates and spreads from the dorsal root ganglion to the periphery. The propagation of the virus causes nerve damage (e.g., due to an immune reaction against the neurons) which results in more frequent depolarization of nociceptors. The reduction in the threshold for nociceptor signalling results in peripheral sensitization. On-going peripheral signalling results in central sensitization, characterized by a heightened state of activation of centrally located neurons (e.g. in the dorsal root horn and higher order neurons). Further pathological mechanisms resulting in altered gene expression in centrally located neurons, loss of co-inhibitory signalling or altered neuronal signalling networks (e.g., deafferentiation) all contribute to the hypersensitivity experienced in subjects with pain associated with PHN. The persistent pain, linked to central sensitization, manifests as hyperalgesia (increased response to harmful stimuli) and / or allodynia (pain induced by a non-painful stimulus). The neuropathic pain associated with PHN is particularly difficult to treat. Current treatments for neuropathic pain associated with PHN include systemic tricyclic antidepressants, anticonvulsants and opiods, as well as topical lidocaine and capsaicin. Additionally, there are interventional therapies including subcutaneous botulinum toxin injections, nerve blocks and nerve stimulations. However, these therapies are not aways effective. Indeed, even with the most effective drugs, only 30-50% of patients obtain more than 50% pain relief, often with significant side-effects. The neuropathic pain associated with PHN causes significant suffering and a financial burden, manifested in both healthcare costs and lost of quality-adjusted life years, and given the lack of efficacy of current treatments, pain associated with PHN represents an area of largely unmet medical need. As outlined above, reactivation of varicella zoster virus can cause acute herpes zoster, manifesting as a rash, and subsequently neuropathic pain associated with post-herpetic neuralgia (PHN). As noted above, neuropathic pain associated with PHN persists for 90 days or more after the initial presentation of the rash or at least three months after the resolution of skin lesions. The pain may manifest for example as sharp, burning, throbbing or stabbing pain. The neuropathic pain associated with PHN typically arises after herpes zoster reactivation and resolution of the rash, allowing the subject to take preventative measures to avoid generation of neuropathic pain after resolution of the rash and skin lesions. Accordingly, in some embodiments, the inventor provides a method of preventing neuropathic pain associated with PHN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PHN is prevented, wherein the modified NSAID is administered orally. In other embodiments, the inventor provides a method of treating neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PHN is treated, wherein the modified NSAID is administered orally. As the pain associated with PHN develops during manifestation of the rash and persists after the rash has resolved, a subject would benefit from an analgesic which can both treat existing neuropathic pain and prevent generation of further neuropathic pain associated with PHN. Therefore, in some embodiments, the modified NSAID can be used in the treatment and prevention of neuropathic pain associated with PHN, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID for use in the treatment and / or prevention of neuropathic pain associated with PHN, wherein the modified NSAID is administered orally. Furthermore, the inventor provides the use of a modified NSAID for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PHN, wherein the modified NSAID is administered orally. As explained herein, the pain associated with PHN is typically localized to the site of the rash. The rash (e.g., a maculopapular rash) may manifest in one or more adjacent dermatomes (an area of skin that is mainly supplied by a single spinal nerve). The spinal nerve may be a cervical nerve, a thoracic nerve, a lumbar nerve, and / or a sacral nerve. Accordingly, the neuropathic pain associated with PHN may be experienced in one or more adjacent dermatomes. The neuropathic pain associated with PHN may be experienced in one or more dermatomes, wherein each dermatome is supplied by a cervical nerve, a thoracic nerve, a lumbar nerve, or a sacral nerve. Typically, the neuropathic pain associated with PHN manifests on the subject’s trunk, along a thoracic dermatome. In certain instances, for example in immune compromised individuals, the rash, and thus the associated neuropathic pain, may be more widespread, affecting three or more dermatomes (i.e., due to disseminated zoster). On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on neuropathic pain associated with PHN. The neuropathic pain associated with PHN may be a sharp, throbbing, stabbing or burning pain. In treating neuropathic pain associated with PHN, the modified NSAID may reduce the neuropathic pain. In some instances, the reduction is complete such that the neuropathic pain is eliminated. In treating the neuropathic pain associated with PHN, the modified NSAID may also reduce one or more of the sensory symptoms associated with PHN. In preventing neuropathic pain associated with PHN, the modified NSAID may decrease the incidence of the neuropathic pain. In preventing neuropathic pain associated with PHN, the modified NSAID may also decrease the incidence of one or more of the sensory symptoms associated with PHN. Patients suffering from PHN describe a range of sensory symptoms. The sensory symptoms include itching and numbness. Even if the sensory symptoms experienced by a subject with PHN are not considered painful (or do not reach a threshold necessary to be considered pain per se), PS may reduce any one or more of the sensory symptoms experienced by the subject. In some instances, the reduction is complete such that the one or more sensory symptoms experienced by the subject are eliminated. As noted above, nerve damage associated with PHN may result in over-activation of pain signalling pathways resulting in sensitization of peripheral and / or central neurons, which display reduced stimulation thresholds. Accordingly, subjects having PHN may experience pain as a consequence of this sensitization, for example, experiencing pain induced by a non-painful stimulus (allodynia) or experiencing heightened pain in response to a harmful stimulus (hyperalgesia). On the basis of observations herein, the modified NSAID may have a direct analgesic effect, for example by reducing the neuronal signalling involved in the sensation of pain. Accordingly, the neuropathic pain associated with PHN may be a consequence of central sensitization resulting in allodynia and / or hyperalgesia. The modified NSAID may reduce the neuronal signalling involved in the sensation of pain in a subject with PHN. In some instances, the reduction may be complete such that the pain is eliminated. The modified NSAID may reduce pain generated via central sensitization. In some instances, the reduction may be complete such that the pain generation is eliminated. In particular, given its ability to traverse towards central sites of pain generation, the modified NSAID may reduce pain generated via central sensitization. Thus, the modified NSAID may reduce pain signalling occurring centrally. Given that the modified NSAIDs are shown to accumulate in the CNS, the modified NSAIDs may reduce pain signalling occurring in the CNS. In some instances, the reduction may be complete such that pain signalling is eliminated. The neuropathic pain in a subject with PHN may be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject with PHN may be hyperalgesia. Neuropathic pain in a patient can be measured on a visual analogue pain scale or using any other appropriate method in the art. In another aspect, the modified NSAID may also be useful for treating other herpes zoster associated pain, for example prodomal pain (in advance of the manifestation of the rash) or acute herpes zoster pain (coinciding with the manifestation of the rash). The damage incurred to peripheral neurons from the translocation of the virus causes increased signalling from centrally located neurons. This may drive neuronal sensitization in advance of the onset of persistent pain characteristic of neuropathic pain associated with PHN. Therefore, the modified NSAID may be useful in treating pain at these stages of the pathology of the infection. The inventor thus also provides a method of treating pain experienced by subjects as a result of herpes zoster comprising administering a therapeutically effective amount of the modified NSAID to a subject in need thereof such that the pain is treated, wherein the modified NSAID is administered orally. The inventor also provides a method of treating acute herpes zoster pain comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that the acute herpes zoster pain is treated, wherein the modified NSAID is administered orally. The inventor also provides a method of treating herpes zoster prodromal pain comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that the herpes zoster prodromal pain is treated, wherein the modified NSAID is administered orally. In particular embodiments of treating and / or preventing neuropathic pain associated with PHN, the orally administered modified NSAID is selected from one or more of the following: phosphosulindac (PS), such as formula I or II; or NO-sulindac, such as formula XLIV. In particular embodiments, the orally administered modified NSAID is a phopsho-NSAID, for example phosphosulindac (PS), such as formula I or II; or an NO-releasing NSAID, for example NO- sulindac, such as formula XLIV. In certain embodiments, the orally administered modified NSAID is modified sulindac, for example phosphosulindac (PS), such as formula I or II; phosphosulindac amide, such as formula X; or NO- sulindac, such as formula XLIV. The inventor provides a method of treating and / or preventing neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the neuropathic pain associated with PHN is treated and / or prevented. The inventor further provides a method of treating and / or preventing neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that the neuropathic pain associated with PHN is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Migraine pain Migraine is a disabling neurological disorder affecting over 1 billion people worldwide, with a one- year prevalence of 15%. Its prevalence peaks in those aged 35-39, and it is the leading cause of disability in people younger than 50, and thus has a significant socioeconomic burden. Migraine is typically characterized by a recurrent unilateral, pulsating headache, with moderate to severe intensity, accompanied by nausea, vomiting, and sensory hypersensitivity symptoms. The pathophysiology of migraine has been a matter of debate and is now classified as a neuronal disorder (Goadsby et al., Physiol Rev (2017); 97:553-622). Previous theories of pain generation via dilation of cranial arteries lost traction given the failure of effective therapies (e.g., sumatriptan) to reverse the slight dilation of these arteries observed during a migraine attack. Furthermore, the suggestion that migraine is triggered by so-called neurogenic inflammation (local dural release of endogenous inflammatory mediators) has also been rendered implausible, not least in light of the clinical failure of compounds designed to inhibit this process. Indeed, evidence of inflammatory pathology in migraineurs is lacking. Accordingly, migraine is considered a purely neuronal disorder resulting from changes or dysfunction in brain stem and hypothalamic regions, which contribute to changes in cellular and vascular function in many regions of the brain. These changes cause neurons to fail to normally modulate or gate sensory inputs. Dysfunction of these regions can lead to the perception of head pain through normal vessels throbbing, and continued dysfunction can lead to central sensitization of trigeminovascular neurons and the exacerbation of pain to normal physical activity as well as cutaneous allodynia. Indeed, peripheral and central sensitization of trigeminal neurons is considered a fundamental component of the pathophysiology, being clinically observed in migraine patients. This neuronal mechanism would explain the longevity of migraine attack, and the transition to chronic migraine as well as specific related symptoms (e.g., cutaneous allodynia). Central sensitization occurs when the function of neuronal circuits in sensory pathways are enhanced or inappropriately modulated, and results in abnormal sensitivity, manifested as, for example, the presence of continuous spontaneous pain often associated with hyperalgesia (increased response to harmful stimuli) and allodynia (pain induced by a non-painful stimulus). As central sensitisation results from changes in the properties of the neurons in the CNS, the perception of pain is no longer coupled to the presence, intensity, or duration of a particular peripheral stimuli (noxious or otherwise). Accordingly, central sensitisation is implicated in the generation and maintenance of pain in which the pain signalling is generated centrally (i.e., due to the hypersensitivity of central pain signalling neurons), even absent a peripheral stimulus. As suggested above, sensitization in migraine is the pain that develops as a consequence of failure of integration and filtering of sensory signalling, ultimately resulting in the perception of activation of sensory systems under normal conditions, for example the cutaneous allodynia experienced by migraineurs. Such symptoms are experienced in both episodic and chronic migraine, although pain amplification is thought to be more involved in chronic migraine. There is currently a worldwide need for additional pain therapy for the treatment of migraine and other headache disorders. A variety of pharmacologic interventions have been postulated for treating migraine reflecting the diverse nature of this disorder. Indeed, relatively non-selective drugs such as ergot alkaloids have been used for decades. Other treatments include opiates (e.g., oxycodone), beta-blockers (e.g., propranolol), anticonvulsants (e.g., topiramate), or serotonin receptor agonists (e.g., sumatriptan). Patients with milder symptoms may be able to control those symptoms with non-steroidal anti- inflammatory agents (NSAIDs), although, as noted above, inflammatory responses are considered of limited relevance when considering migraine pathophysiology. Indeed, studies have demonstrated that particular NSAIDs, for example naproxen, are not clinically useful for treating migraine (see, for example, Law et al. Cochrane Database of Systematic Reviews (2013); 10: 1–45). As outlined above, migraine is characterized by moderate to severe attacks of unilateral pulsating head pain, associated with photophobia, phonophobia, nausea and / or vomiting. Accordingly, in some embodiments, the inventor provides a method of treating migraine pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that migraine pain is treated, wherein the modified NSAID is administered orally. Typically, a migraine attack is comprised of three phases: a premonitory phase, the migraine headache itself, and a postdrome phase. The premonitory phase occurs about 24-48 hours prior to the headache phase and is typically characterized by symptoms such as mood alterations, fatigue and neck discomfort, and in some individuals experiences of aura, a transient focal neurological symptom of visual, sensory or motor disturbances. A subject within the premonitory phase, and in advance of the onset of the headache phase, may be able to administer a therapeutic that prevents the onset of the headache phase. Accordingly, in other embodiments, the inventor provides a method of preventing migraine pain, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that migraine pain is prevented, wherein the modified NSAID is administered orally. A subject may experience repeated migraine attacks, in particular if they have a short interictal period between attacks, and so administration of the therapeutic may treat the pain of an ongoing attack and prevent pain of subsequent attacks. Therefore, in some embodiments, the modified NSAID can be used in the treatment and prevention of migraine pain, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID for use in the treatment and / or prevention of migraine pain, wherein the modified NSAID is administered orally. Furthermore, the inventor provides the use of a modified NSAID for the manufacture of a medicament for the treatment and / or prevention of migraine pain, wherein the modified NSAID is administered orally. In some embodiments, when treating and / or preventing migraine pain, the modified NSAID may be administered during the premonitory phase, the headache phase and / or the postdrome phase. In particular, for preventing migraine pain, the modified NSAID may be administered during the premonitory phase. For treating migraine pain, the modified NSAID may be administered during the headache phase. The migraine may be episodic migraine. In certain instances, the migraine may be chronic migraine. The migraine may be migraine without aura or migraine with aura. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on migraine pain. The migraine pain may be a pulsating head pain. A subject with migraine, in particular chronic migraine, may experience a persistent migraine headache and / or premonitory-like phase, with limited neurological recovery and baseline restoration between attacks. Subjects suffering from migraine may experience a number of associated symptoms, including aura, nausea, vomiting, photophobia and / or phonophobia. The sensory disturbances associated with aura may include visual symptoms, pins and needles (tingling), and / or numbness. Furthermore, subjects may experience cranial autonomic symptoms such as eye redness or tearing. Additionally, subjects may experience cutaneous allodynia. The migraine with aura may be migraine with typical aura or migraine with brainstem aura. The migraine may be hemiplegic migraine (e.g., familial hemiplegic migraine or sporadic hemiplegic migraine); retinal migraine; chronic migraine; or probable migraine (with and without aura). In treating migraine pain, the modified NSAID may reduce the pain. In some instances, the reduction may be complete such that the migraine pain is eliminated. In treating the migraine pain, the modified NSAID may also reduce one or more of the symptoms associated with migraine. In preventing migraine pain, the modified NSAID may decrease the incidence of the pain. In preventing migraine pain, the modified NSAID may also decrease the incidence of one or more of the symptoms associated with migraine. The modified NSAID may reduce cutaneous allodynia. In certain embodiments, the modified NSAID may reduce chronic migraine pain. As noted above, the reduction may be complete such that the pain is eliminated. Even if the symptoms experienced by a subject with migraine, for example aura or cranial autonomic symptoms, are not considered painful (or do not reach a threshold necessary to be considered pain per se), in treating and / or preventing migraine pain, the modified NSAID may reduce any one or more of the symptoms experienced by a subject with migraine. In some instances, the reduction may be complete such that the one or more of the symptoms experienced by a subject with migraine are eliminated. Central sensitization is features of migraine pain. Migraine pain may be a consequence of central sensitisation resulting in allodynia, for example cutaneous allodynia, and / or hyperalgesia. Accordingly, subjects having migraine may experience pain as a consequence of this sensitisation, for example, experiencing pain induced by a non-painful stimulus (allodynia) or experiencing heightened pain in response to a harmful stimulus (hyperalgesia). On the basis of observations herein, the modified NSAID may have a direct analgesic effect, for example by reducing the neuronal signalling involved in the sensation of pain. Accordingly, the modified NSAID may reduce the neuronal signalling involved in the sensation of pain in a subject with migraine. In some instances, the reduction may be complete such that the pain is eliminated. Furthermore, the modified NSAID may reduce pain generated via central sensitisation. In particular, given its ability to traverse towards central sites of pain generation, the modified NSAID may reduce pain generated via central sensitisation. The reduction may be complete such that the pain generation is eliminated. Accordingly, the modified NSAID may reduce pain signalling occurring centrally. Given that the modified NSAIDs herein are shown to ascend neurons towards the CNS, the preliminary observations of an analgesic activity of modified NSAIDs in migraine indicate that the modified NSAIDs may reduce pain signalling occurring in higher order neurons and / or pain sensing regions of the brain (e.g., trigeminothalamic neurons or other pain sensing areas of the brain disclosed herein). The reduction may be complete such that the pain signalling is eliminated. In some embodiments, the pain is allodynia, for example, cutaneous allodynia. The allodynia may be in response to mechanical and / or thermal stimuli. In addition, in some embodiments, the pain is hyperalgesia. The migraine pain may be neuropathic pain. A patient with migraine can be diagnosed using the well-known ICHD-3 guidelines. Migraine pain can be measured on a visual analogue pain scale or using any other appropriate method in the art. In particular embodiments, the orally administered modified NSAID for treating and / or preventing migraine pain is selected from one or more of the following: PS, such as formula I or II; or phosphonaproxen, such as formula VIII. In other embodiments of treating and / or preventing migraine pain, the orally administered modified NSAID may be a phosphoramide NSAID, for example phosphosulindac amide, such as formula X; or phospho-ibuprofen amide, such as formula XI. In some embodiments, the orally modified NSAID may be a phospho-NSAID, for example PS, such as formula I or II; or phosphonaproxen, such as formula VIII. In some embodiments, the orally administered NSAID is a modified sulindac, for example PS, such as formula I or II; NO-sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; or platinum sulindac, such as formula LXVII. In certain embodiments, the modified NSAID does not have formula LXIX and / or LXX. The inventor provides a method of treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the migraine pain is treated and / or prevented. The inventor further provides a method of treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, in combination with one or more gastro-retentive agents, to a subject in need thereof, such that the migraine pain, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Pain of other headache disorders In light of the observations herein of the efficacy of modified NSAIDs in treating migraine pain, the modified NSAID may treat and / or prevent pain of other headache disorders, in particular headache disorders with pathophysiology manifesting in dysfunction of the trigeminal system. For example, the modified NSAID may treat and / or prevent chronic headache pain, tension-type headache pain and / or trigeminal autonomic cephalalgia pain. The trigeminal autonomic cephalalgia may be cluster headache, hemicrania continua, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms. In some embodiments, the modified NSAID may treat and / or prevent trigeminal neuralgia pain, for example head and facial pain. The inventor provides a method of treating and / or preventing pain of other headache disorders, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the pain of other headache disorders is treated and / or prevented. The inventor further provides a method of treating and / or preventing pain of other headache disorders, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that the pain of other headache disorders is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Corneal neuropathic pain Corneal discomfort affects 5-30% of the population aged over 50 years. Corneal neuropathic pain is a condition in which corneal pain is experienced in response to normally non-painful stimuli (e.g., a wind or draught). This is a reflection of the sensitization of centrally acting neurons after prolonged and repeated nociceptive signalling from peripheral neurons in response to direct damage to corneal nerves. Any mechanical or chemical injury to the corneal nerve endings can result in ectopic sprouts and neuroma formation which show spontaneous activity. The central sensitization, manifesting as painful hypersensitivity to non-noxious stimuli (allodynia) or an exaggerated pain response to noxious stimuli (hyperalgesia), or indeed spontaneous signalling, results in sustained chronic corneal pain even in the absence of peripheral stimuli or clinical signs. In this way, corneal neuropathic pain is distinct in its mechanism of pain generation compared to, for example, inflammatory eye disorders which trigger acute peripheral pain signalling from the cornea in response to ongoing inflammation. Patients with corneal neuropathic pain experience severe corneal pain, as well as irritation such as burning, photophobia and grittiness, even without peripheral signs. Accordingly, this indication inevitably negatively impacts the quality of life of patients. The chronic pain sensation, accompanied by light sensitivity and irritation results in impaired functioning and inability to perform routine daily activities. Corneal neuropathic pain is particularly difficult to treat. For corneal neuropathic pain patients, experiencing corneal pain in the absence of any ongoing corneal pathology, anti-inflammatory drugs are ineffective. Instead, centrally acting neuromodulators are often recommended. For example, anticonvulsants (e.g., gabapentin and pregabalin) can be considered as the first line treatment; serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine) as the second line treatment; and tricyclic antidepressants (e.g., nortriptyline, amitriptyline) as third-line agents. Combination therapy or weak opioids (tramadol) can also be used in the case of resistance to treatment in the setting of a broad neurologic pain. Unfortunately, pain control is not very satisfactory and many of the systemic treatments induce major side effects leading to poor treatment adherence. Corneal neuropathic pain is also known as ocular neuropathic pain. Accordingly, herein the terms ‘corneal neuropathic pain’ and ‘ocular neuropathic pain’ may be used interchangeably. As explained above, corneal neuropathic pain is a persistent chronic pain which occurs in light of neuroplastic changes in centrally located neurons due to persistent nociceptive signalling from the periphery. Such changes result in hyperexcitability of nociceptors in the CNS, so-called central sensitization, which manifests, for example as allodynia. The pain persists even in the absence of an on-going peripheral trigger, rendering corneal neuropathic pain, like other neuropathic pains, particularly difficult to treat as resolving peripheral pathology does not affect the sensation of pain. In this way, the corneal neuropathic pain may be chronic corneal pain. Corneal neuropathic pain can develop as a result of a number of peripheral drivers of nociception. Typically, corneal neuropathic pain develops in light of consistent pain signalling generated from the cornea (one of the most densely innervated tissues). As noted above, persistent peripheral signalling through corneal nerves ultimately results in central sensitization, a key feature of corneal neuropathic pain, which can result in the sensation of pain even in the absence of peripheral triggers. Therefore, corneal neuropathic pain may be caused by any peripheral stimulus that causes chronic stimulation of corneal nerves. For example, the corneal neuropathic pain may be caused by chronic corneal surface diseases or conditions, for example recurrent corneal erosions, corneal surface neoplasia, and / or inflammatory eye conditions. The corneal neuropathic pain may be caused by surgical interventions, for example kerato-refractive surgery (e.g., photorefractive keratectomy (PRK), laser in-situ keratomileusis (LASIK), Small Incision Lenticule Extraction (SMILE) and corneal inlay procedures), cataract surgery (e.g., laser-assisted cataract surgery), corneal transplant surgeries, and / or laser retinopexy. The corneal neuropathic pain may be caused by laser procedures for the treatment of retinal conditions (e.g., diabetic macular oedema; proliferative diabetic retinopathy; macular oedema due to retinal vein occlusions; neovascularisation secondary to retinal vein occlusions; peripheral retinal degenerations, holes, and / or tears; Eales’ disease and other retinal vasculitis; central serious retinopathy; retinopathy of prematurity; extrafoveal polyps of polypoidal choroidal vasculopathy (PCV)). The corneal neuropathic pain may be caused by an infection, for example herpes simplex keratitis and / or herpes zoster keratitis. The corneal neuropathic pain may be caused by toxic keratopathy, for example due to topical or systemic agents (e.g., preservatives containing benzalokium chloride or isotretinoin, respectively). The corneal neuropathic pain may be caused by radiation or ultraviolet light exposure. The corneal neuropathic pain may be a result of systemic neuropathies, for example small fiber neuropathy or multiple sclerosis. Furthermore, the corneal neuropathic pain may be caused by trauma, for example causing damage to the corneal nerves, for example chemical burns. The initial trigger of the pain may be air pollution or dry weather, which triggers persistent corneal inflammation and ultimately corneal neuropathic pain. Accordingly, the corneal neuropathic pain may be caused by allergens, for example causing allergic conjunctivitis. The corneal neuropathic pain may be caused by one or more chalazions, for example due to the persistent irritation of the cornea caused by the chalazion during blinking. Persistent peripheral nociceptor signalling in response to these peripheral triggers results in increased sensitivity of centrally located neurons resulting in the generation of pain even once the initial clinical presentation has resolved. Indeed, even local anaesthesia cannot relieve the pain given the dysregulation of centralised neuronal signalling. Additionally, in some embodiments, the corneal neuropathic pain is caused by direct damage to centrally located neurons, for example by ischemia, hemorrhage, mechanical compression, infection, and / or degenerative processes. Furthermore, the corneal neuropathic pain may be a result of injury to adjacent tissues or nerves, for example the conjunctiva, eye muscles, globe, optic nerve, and or autonomic or sympathetic nerves. Corneal neuropathic pain arises as a result of perisitent peripheral nociceptive signalling resulting in neuronal sensitization, manifested as hypersensitivity to innocuous peripheral triggers and associated long-lived pain. Therefore, central sensitization is a feature of corneal neuropathic pain. The pain can manifest for example as shooting, burning, or stabbing pain associated with other sensory symptoms. Accordingly, in some embodiments, the inventor provides a method of treating corneal neuropathic pain comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that corneal neuropathic pain is treated, wherein the modified NSAID is administered orally. A subject experiencing corneal neuropathic pain would benefit from an analgesic which can both treat existing corneal neuropathic pain and prevent generation of further corneal neuropathic pain (i.e., prevent further central sensitization). Therefore, in some embodiments, the modified NSAIDs can be used in the treatment and prevention of corneal neuropathic pain, wherein the modified NSAID is administered orally. In line with the above, the inventor provides a modified NSAID for use in the treatment of corneal neuropathic pain, wherein the modifed NSAID is administered orally. Furthermore, the inventor provides the use of a modified NSAID for the manufacture of a medicament for the treatment of corneal neuropathic pain, wherein the modified NSAID is administered orally. On the basis of the observations herein, the modified NSAID may have a direct analgesic effect on corneal neuropathic pain. The corneal neuropathic pain may be a stabbing or burning pain. In treating corneal neuropathic pain, the modified NSAID may reduce the corneal neuropathic pain. In some instances, the reduction may be complete such that the corneal neuropathic pain is eliminated. In treating the corneal neuropathic pain, the the modified NSAID may also reduce one or more of the associated sensory symptoms. Patients suffering from corneal neuropathic pain describe a range of sensory symptoms. The sensory symptoms include paresthesia (e.g., numbness, tingling, pricking, and / or formication), photosensitivity, or photoallodynia. Even if the sensory symptoms experienced by the subject are not considered painful (or do not reach a threshold necessary to be considered pain per se), the modified NSAID may reduce any one or more of the sensory symptoms experienced by the subject, including those listed above. In some instances, the reduction may be complete such that the one or more of the associated sensory symptoms are eliminated. Furthermore, in treating corneal neuropathic pain the modified NSAID may improve other related symptoms in the subject, for example anxiety, depression, and / or apathy. As noted above, corneal neuropathic pain is generated as a result of over-activity of centrally located neurons, which display reduced stimulation thresholds and can depolarise even in the absence of a peripheral stimulus. Indeed, the perception of pain is no longer coupled to the presence, intensity, or duration of a particular peripheral stimulus (noxious or otherwise). Thus, the corneal neuropathic pain may be a consequence of central sensitization. Accordingly, subjects having corneal neuropathic pain may experience pain induced by a non-painful stimulus (allodynia) and / or may experience heightened pain in response to a harmful stimulus (hyperalgesia). On the basis of preliminary observations, the modified NSAID may have a direct analgesic effect, for example by reducing the neuronal signalling involved in the sensation of pain. Thus, the modified NSAID may reduce the neuronal signalling involved in the sensation of pain in a subject with corneal neuropathic pain. Given its ability to traverse towards central sites of pain generation, the modified NSAID may reduce pain generated via central sensitization. Accordingly, the modified NSAID may reduce pain signalling occurring centrally. the modified NSAID. Given that the modified NSAIDs are shown herein to ascend peripheral neurons towards the CNS, the modified NSAID may reduce pain signalling occurring in higher order neurons and / or one or more of the areas of the brain involved in pain sensation (e.g., trigeminothalamic neurons or other pain sensing areas of the brain). In some instances, the reduction may be complete such that the pain signalling is eliminated. In some embodiments, the corneal neuropathic pain is allodynia. The allodynia may be in response to mechanical and / or thermal stimuli. Additionally or alternatively, the corneal neuropathic pain in a subject may be hyperalgesia. In some embodiments, the corneal neuropathic pain is chronic corneal neuropathic pain. In some embodiments, the corneal neuropathic pain is not acute corneal pain. Corneal neuropathic pain in a patient can be measured on a visual analogue pain scale or using any other appropriate method in the art. Given the observations herein, the modified NSAIDs show direct activity on neurons associated with the generation of pain caused by central sensitization. Therefore, the modified NSAID may also be useful for treating particular forms of corneal pain. Corneal pain is also known as ocular pain, and so these terms may be used interchangeably herein. For example, the modified NSAID may treat corneal pain caused by central sensitization. Therefore, the inventor also provides a method of treating corneal pain caused by central sensitization comprising administering a therapeutically effective amount of the modified NSAID to a subject in need thereof such that corneal pain caused by central sensitization is treated, wherein the modified NSAID is administered orally. Indeed, the modified NSAID may treat corneal pain manifesting as allodynia. The modified NSAID may treat corneal pain manifesting as hyperalgesia. As the pain is caused by central sensitization, it is experienced in the absence of ongoing noxious peripheral triggers (e.g., corneal inflammation). The corneal pain may be chronic pain (i.e., pain persisting for 3 months or more). In certain embodiments, the corneal pain is not acute pain, for example acute pain associated with DED (i.e., pain experienced as a result of ongoing corneal inflammation). The modified NSAID may be useful for treating corneal pain generated at central sites of (i.e., those sites responsible for central pain signalling in the absence of ongoing peripheral triggers). Therefore, the inventor provides a method of treating corneal pain generated at central sites of action comprising administering a therapeutically effective amount of the modified NSAID to a subject in need thereof such that corneal pain generated at central sites of action is treated, wherein the modified NSAID is administered orally. Indeed, given the observations herein, the modified NSAID may treat corneal pain in light of its ability to traverse towards central sites of action. For example, the modified NSAID may reduce corneal pain by accumulating within higher order neurons within the CNS. Accordingly, the modified NSAID may be acting directly on the pain generating centers within higher order neurons within the CNS. Therefore, the inventor provides a method of treating corneal pain comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that corneal pain is treated, wherein the modified NSAID reduces pain signalling occurring within higher order neurons within the CNS, wherein the modified NSAID is administered orally. In some instances, the reduction may be complete such that the pain signalling is eliminated. The inventor provides a method of treating and / or preventing corneal neuropathic pain, comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof such that the corneal neuropathic pain is treated and / or prevented. The inventor further provides a method of treating and / or preventing corneal neuropathic pain, comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, such that the corneal neuropathic pain is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. Modified NSAIDs Herein, ‘modified NSAID’ refers to a compound resulting from the modification of an NSAID molecule (i.e., 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. The modified NSAID may be selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramide-modified NSAIDs (phosphoramide-NSAIDs), selenium-modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs (metal-NSAIDs), H2S-releasing NSAIDs (HS-NSAIDs), NO-releasing NSAIDs (NO-NSAIDs) and NOSH-releasing NSAIDs (NOSH-NSAIDs). Phospho-NSAIDs The phospho-NSAID may be PS, for example having the formula I or II. The phospho-NSAID may be phospho-ibuprofen, for example having the formula III: . The phospho-NSAID IV: (IV). The PEG may to about 15000, for example about 200 to 3000, or about 200 to 1000. The phospho-ibuprofen-PEG may be in its anionic form, as shown in formula IV and / or in its protonated form. The phospho-NSAID may be phospho-aspirin, for example having the formula V, VI or VII:

[0003] I), Accordingly, the phospho-aspirin may be glycero-phospho-aspirin I (for example having the formula VI), or particularly glycero-phospho-aspirin II (for example having the formula V). The phospho- aspirin may be: 2-acetoxy-benzoic acid 4-(diethoxy-phosphoryloxymethyl)-phenyl ester or 2- acetoxybenzoic acid 3-(diethoxy-phosphoryloxymethyl)-phenyl ester. The phospho-NSAID may be phospho-naproxen, for example having the formula VIII: (VIII). The phospho-NSAID may be phospho-flurbiprofen, for example having the formula IX: (IX). Phosphoramid The phosphoramide-NSAID may be phosphosulindac-amide, for example having the formula X: . The the formula XI: . The example having the formula XII: (XII). Selenium-modified NSAIDs For Se-NSAIDs, the Se may be incorporated as selenocyanates, sulfur selenide, selenazolidine or selenoesters. The Se-NSAID may be Se-sulindac, for example having the formula XIII: . The Se-NSAID may be Se- XIV or XV: , , wherein R is SeCN or The Se-NSAID may be Se-aspirin, for example having the formula XVI, XVII, or XVIII: , I), wherein R is SeCN or SeCF3. The Se-NSAID may be Se-celecoxib, for example having the formula XIXI or XX: (XX). The Se-NSAID (XXI). The Se-NSAID may XXII: (XXII). The Se-NSAID may be Se-ketoprofen, for example having the formula XXIII: . Metal-NSAIDs The metal-NSAIDs , , , (Zn), iridium (Ir), ruthenium (Ru), nickel (Ni), silver (Ag), manganese (Mn), or organotin. The Cu complexes may be four- or six-coordinate. The Co complexes may be six-coordinate. The organotin may be tretabutyltin, teibutyltin oxide, triphenyltin acetate, triphenyltin chloride, trimethyltin chloride, triphenyltin hydroxide, azocyclotin, cyhexatin, heamethylditin, tetraethyltin. The metal-NSAID may be Cu(II)-naproxen, for example having the formula XXIV: (XXIV). The metal-NSAID the formula XXV: . The metal-NSAID may be Cu(II)-indomethacin, for example having the formula XXVI, XXVII, XXVIII, or XXIX: , ,

[0004] X). The metal-NSAI X: (XXX). The metal-NSAID may be the formula XXXI: . The metal-NSAID

[0005] (XXXII). The metal-NSAID formula XXXIII: (XXXIII). H2S-releasing NSAIDs The H2S-releasing NSAID may be HS-sulindac, for example having the formula XXXIV: . The H2S-releasing XXXV: (XXXV). The H2S-releasing the formula XXXVI: I). The H2S-releasing NSAID e formula XXXVII, XXXVIII, XXXIX, or XL , , The H2S- XLI: (XLI). The H2S-releasing the formula XLII, or XLIII: II), . NO-releasing NSAIDs The NO-releasing NSAID may be NO-sulindac, for example having the formula XLIV or XLV: , (XLV), wherein R has formula (XLVI), (XLVII). The NO-releasing NSAID may be NO-aspirin, for example having the formula XLVIII or XLIX: , . The NO-releasing NSAID formula L: (L). The NO-releasing the formula LI: (LI). The NO-releasing having the formula LII: (LII). The NO-releasing NSAID having the formula LIII, LIV, or LV: (LIII), ), V). The NO-releasing NSAID m ving the formula LVI: (LVI). NO-, SH-releasing A NO-, SH-releasing NSAID releases both NO and H2S. Accordingly a NOSH-NSAID is a NO and H2S-releasing NSAID. This terminology is well-established in the art. The NO-, SH-releasing NSAID may be NOSH-sulindac, for example having the formula LVII: (LVII). The NO-, SH- having the formula LVIII: (LVIII). The NO-, the formula LIX, LX, LXI, or LXII: X), Other modified NSAIDs The modified NSAID may be a modified NSAID which does not fall within one of the classes disclosed above. For example, the modified NSAID may be nitroxide-aspirin, for example having the formula LXIII: (LXIII). The modified NSAID may be triazole-thioether-naproxen, for example having the formula LXIV: (LXIV). The modified having the formula LXV: (LXV). The modified NSAID may having the formula LXVI: (LXVI). The modified NSAID may example an erlotinib-NSAID conjugate, a riboflavin-NSAID conjugate, a podophyllotoxin-NSAID conjugate, a chalcone-NSAID conjugate, a ursolic acid-NSAID conjugate or a camptothecin-NSAID conjugate. The modified NSAID may be platinum-sulindac, for example having the formula LXVII: (LXVII) The modified NSAID may be Q922, for example having the formula LXVIII: . In another aspect, composition comprising a The modified NSAID may have the formula LXIX: (LXIX). The modified (LXX). In certain LXIX and / or LXX. In some embodiments, the modified NSAID is a phospho-NSAID, for example phospho-glycerol- ibuprofen, for example having formula LXXI: Generation of The skilled person could generate the modified NSAIDs disclosed herein using routine methods, for example via modification of the carboxylic acid group. Pharmaceutical compositions of modified NSAIDs The modified NSAID, for example PS, for use in the methods of the invention can be formulated into an appropriate pharmaceutical composition for administering to subjects in need thereof, for example subjects with pain associated with central sensitization, subjects with PTPN, subjects with PHN, subjects with migraine pain (and pain of other headache disorders), or subjects with corneal neuropathic pain. Pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the modified NSAID and may further comprise a pharmaceutically acceptable excipient. In particular embodiments, the pharmaceutical composition comprising the modified NSAID for use in the invention may be formulated for oral administration. The modified NSAID, for example PS, for oral administration may be formulated as a liquid or solid dosage form. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Solid dosage forms for oral administration include but are not limited to capsules, tablets, pills, powders, and granules. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. The solid dosage forms of capsules, tablers and pills, may be such that they release the modified NSAID only, or preferentially, in a certain part of the intestinal tract, for example the stomach, optionally, in a delayed manner. In some embodiments, the formulation for oral administration comprises one or more fillers, disintigrants, lubricants, glidants, anti-adherents and / or anti-statics. The formulations suitable for oral adminsitration may comprise the modified NSAID 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. In some embodiments, the pharmaceutical composition may be a gastro-retentive pharmaceutical composition as disclosed herein. Accordingly, the modified NSAID, for example PS, may be formulated into a gastro-retentive pharmaceutical composition as disclosed herein. Dosing regimens of the modified NSAID The appropriate dosage regimen for the modified NSAID for treating 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 such variables as the type and extent of progression of the pain (e.g., as determined by the “Pain Ladder” guideline from the World Health Organization), the severity of the pain (e.g., acute, subacute, or chronic), the age, weight, and general condition of the particular patient, formulation of the excipient, and the judgment of the attending clinician. The modified NSAID, for example PS, may be administered orally at dosage levels 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. In particular embodiments, the modified NSAID, for example PS, may be administered at dosage levels of about 1 mg / kg to about 5 mg / kg, for example about 3 mg / kg of subject body weight. The modified NSAID may be administered orally at a dosage of about 1 mg to about 2000 mg. In some embodiments, the modified NSAID may be administered orally at a dosage of about 100 mg to 1500 mg, for example about 200 mg to about 1000 mg. In some embodiments, the modified NSAID may be administered orally at a dosage of about 50 mg to about 400 mg, for example about 100 mg to about 350 mg, for example about 150 mg to about 300 mg, for example about 150mg to about 250 mg. In particular embodiments, the modified NSAID is administered orally at a dosage of about 250 mg to about 300 mg, preferably about 250 mg. In some embodiments of multiple dosing, equal amount of the modified NSAID may be administered in each dose. In other embodiments, a higher initial dose may be administered, followed by low maintenance doses. In some embodiments, the modified NSAID may be administered orally once a day, or more frequently. For example, the modified NSAID may be administered twice a day, three times a day, four times a day, or more often as necessary. In particular embodiments, the modified NSAID may be administered orally two or three times a day. In particular embodiments, the modified NSAID is administered orally at a dosage of about 150 mg to about 200 mg twice a day. Accordingly, a subject may be administered the modified NSAID orally at a daily dosage of about 300 mg to about 400 mg. In particular embodiments, the modified NSAID, for example PS, is administered orally at a dosage of about 250 mg to about 300 mg (for example, about 250 mg) two or three times a day. Accordingly, a subject may be administered the modified NSAID, for example PS, orally at a daily dosage of about 500 mg to up to about 900 mg a day. The administration of the modified NSAID may continue as long as necessary. For example, the modified NSAID may be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 28, 56, or 84 days. As noted above, the modified NSAID can be administered chronically on an ongoing basis for the treatment of chronic effects, for example for at least 3 months. Accordingly, in some cases, continuous dosing is achieved and maintained as long as necessary. The modified NSAID may be administered intermittently according to the recurrence of the pain associated with the indications described herein and / or associated sensory symptoms. The modified NSAID can be used for the treatment (and prevention) of pain associated with the indications described herein in mammals. For example the subject may be a human. As noted above, the modified NSAID can be formulated into an appropriate pharmaceutical composition for administering to subjects with any one of the indications described herein (e.g., pain associated with central sensitization, PTPN, PHN, migraine (other other headache disorders), or corneal neuropathic pain). Accordingly, the modified NSAID may be administered according to the dosing regimens above in an appropriate pharmaceutical composition. In particular embodiments, the modified NSAID or the appropriate pharmaceutical composition of the modified NSAID is administered as a monotherapy. A person having ordinary skill in the art understands that, in certain embodiments, dosages of such compounds may be adjusted depending upon the mammal to be treated. For example, the treatment of mice is described herein and such dosages may or may not be revised upon the administration of PS to a human. However, a person having ordinary skill in the art may, if necessary, convert the dosages provided herein as set forth in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. A human equivalent dose (HED) may be determined from an animal dose, the animal dose may be multiplied by the following conversion factors, to provide units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, micro-pig = 0.73, and mini-pig = 0.95. Gastro-retentive pharmaceutical compositions and uses thereof As demonstrated herein, modified NSAIDs, for example PS, bind to the stomach lining and are taken up by the vagus nerve along which they can traverse to reach key sites of action in the brain in therapeutically relevant amounts. Accordingly, pharmaceutical compositions of the invention may advantageously include an adaptation that can help to retain the modified NSAID in the stomach. In this way, without wishing to be bound by theory, the modified NSAID is retained in the stomach for longer periods, permitting higher concentrations of the modified NSAID to traverse along the vagus nerve towards the brain, for example pain sensing regions of the brain. Therefore, gastro-retentive pharmaceutical compositions of the invention may be exploited to provide an advantageous pharmacokinetic profile, for example an increased Cmaxor improved AUC0-24hin the tissues of the brain, for example pain sensing regions of the brain. Pharmaceutical compositions of the invention may be gastro-retentive pharmaceutical compositions. A gastro-retentive pharmaceutical composition is formulated such that it extends the length of time for which the pharmaceutical composition is retained in the stomach, with the overall goal of gastric retention being to delay the progress of the modified NSAID, for example PS, from the stomach into the small intestine. Accordingly, the gastro-retentive formulation extends the time for which the modified NSAID, for example PS, is exposed to the stomach lining enabling higher concentrations of the modified NSAID to adhere to the stomach lining and thus be taken up by the vagus nerve. Therefore, the inventor also provides a gastro-retentive pharmaceutical composition comprising a modified NSAID, for example PS. The gastro-retentive pharmaceutical composition may comprise one or more gastro-retentive agents, for example one or more gastro-retentive excipients. The skilled person is aware of mechanisms by which increased gastric retention can be achieved. For example, the gastric retention may be achieved by oral administration of the modified NSAID, for example PS, in combination with physical blockade of stomach emptying, for example by exploiting techniques that form plug-like devices which resist stomach emptying. The increased gastric retention may be achieved by specific formulation of the pharmaceutical composition comprising the modified NSAID, for example PS. For example, gastro-retentive drug delivery systems, such as low- density / floating systems, high density systems, expandable systems, bioadhesive systems, raft forming systems, super-porous hydrogel systems, magnetic systems, and ion-exchange resin systems, may be used (see Tripathi J et al., (2019) Pharmaceutics; 11:193). Various adaptations to help retain a pharmaceutical composition of the invention in the stomach include, but are not limited to: (i) inclusion of an effervescent excipient, which can provide buoyancy during gaseous release in stomach acid; (ii) rapid gastric dispersal into multiple granules or pellets, thereby avoiding expulsion of the complete pharmaceutical composition from the stomach in a single event; (iii) the use of low density excipients to provide a buoyant or floating pharmaceutical composition; and / or (iv) the inclusion of a mucoadhesive in the pharmaceutical composition. These four approaches inter alia, for example, the further approaches discussed herein, can be used individually or together to provide advantageous pharmaceutical compositions for delivery of modified NSAIDs. The gastric retention may increase the Cmaxof the modified NSAID, for example PS, in the brain, for example in pain sensing regions of the brain, compared to oral administration without gastric retention. The gastric retention may increase the AUC0-24h of the modified NSAID, for example PS, in the brain, for example in pain sensing regions of the brain, compared to oral administration without gastric retention. The gastric retention may increase the Cmax and / or AUC0-24h, of the modified NSAID, for example PS, in the vagus nerve, compared to oral administration without gastric retention. A first approach may be to include an effervescent excipient in the pharmaceutical composition, for example tablet, and in particular an excipient that will effervesce on contact with gastric acid e.g. a carbonate or a bicarbonate or hydrogen carbonate salt, such as sodium bicarbonate. As the pharmaceutical composition effervesces it tends to float due to the release of gas, and thus the progress of the pharmaceutical composition towards the pyloric sphincter at the base of the stomach is delayed (e.g. see Wei et al. (2001) Drug Dev Ind Pharm 27:469-74, Ray & Prusty (2010) Int J Appl Pharmaceutics 2:12-16). Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, and an effervescent excipient. A second approach may be to formulate the pharmaceutical composition, for example tablet, so that on contact with gastric contents it disperses into a large number of granules or pellets, which in turn provide extended release. A similar approach was disclosed by Aburahma & Hamza Yel (2011) Pharm Dev Technol 16(4):316-30, who compressed extended-release beads with a fast-disintegrating component. Accordingly, the gastro-retentive pharmaceutical composition comprising the modified NSAID, for example PS, may be formulated as a tablet comprising dispersable granules or pellets. A third approach may be to use low density excipients that thereby provide a buoyant or floating pharmaceutical composition, for example tablet. By using adequate amounts of low density excipients, it is possible to provide a pharmaceutical composition with an overall density below that of gastric contents, thereby permitting it to float in the stomach and thus delay its transit to the pyloric sphincter without needing effervescence (e.g. Srikanth Meka et al. (2014) Acta Pharm 64:485-494). Gastric contents have a density of about 1.004-1.010 g / cm3and so the pharmaceutical composition, for example tablet, should have a density below this, ideally such that it can float. Buoyancy, and the length of time that a pharmaceutical composition, for example tablet, remains buoyant as it degrades, can be assessed in vitro in simulated gastric fluids maintained at 37 °C. The density of a pharmaceutical composition, for example tablet, can be determined by the displacement method using analytical grade benzene as a displacing medium. Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, and a low density excipient. The gastro-retentive pharmaceutical composition may be a floating pharmaceutical composition, for example tablet, comprising the modified NSAID, for example PS. A fourth approach may be to include a mucoadhesive excipient in the pharmaceutical composition, for example tablet. Mucoadhesives permit the pharmaceutical composition to interact with the mucosal surfaces of the gastrointestinal tract, for example of the stomach lining. This approach is discussed in, for instance, Jha & Nanda (2013) Asian J Biomed Pharm Sci 3:44-49. Various mucoadhesive excipients suitable for inclusion in pharmaceutical compositions are known in the art, and these are often hydrophilic polymers. In general, good mucoadhesives have strong hydrogen bonding groups (-OH, -COOH), strong anionic charges, sufficient flexibility to penetrate the extended glycan network of the cell glycocalyx, surface tension characteristics suitable for wetting mucus / mucosal tissue surface, and / or a high molecular weight (see Yadav et al. (2010) J Chem Pharm Res 2:418-32). Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, and a mucoadhesive excipient. A fifth approach may be to include a magnetic excipient in the pharmaceutical composition. Application of an external magnetic field can be used to retain such compositions within the stomach. Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, and a magnetic excipient. A sixth approach may be to include a high-density excipient in the pharmaceutical composition. High-density systems, with a density greater than gastric fluid, which enable sinking of the pharmaceutical formulation in the stomach, such as in the stomach folds, may better withstand expulsion by gastric peristaltic movements. Accordingly, the gastro-retentive pharmaceutical compositions may comprise the modified NSAID, for example PS, and a high-density excipient. A seventh approach may be to include an expandable excipient in the pharmaceutical composition. Expandable systems achieve longer retention time in the stomach due to their ability to swell and, through their increased size, withstand mechanical explusion by the contractions of the pyloric sphincter. After sustained release of the drug has been completed, these systems reduce in size to enable their expulsion. Super-porous hydrogel systems are a type of expandable system, which can swell up to 100 times or more in the stomach due to the absorption of water through numerous pores. Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, formulated in an expandable system. Furthermore, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, formulated in a super-porous hydrogel system. The gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, and an expandable excipient, for example a super-porous hydrogel excipient. An eighth approach may be to exploit ion-exchange resin systems. Ion-exchange resin systems involve loading resin particles with drugs based on ionic interaction. Since the gastric environment is acidic, the resin systems used for release in the stomach would be cationic. Positively-charged ions from the drug formulation are bound to the resin and are subsequently displaced by the protons in gastric fluid, resulting in the release of the drug into the stomach. Different parameters of the resin system can be adjusted to prolong the release of drugs, such as particle size, cross-linking density and chemistry of the ionogenic group. Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, and an ion-exchange resin. Resins can also be combined with low-density systems or bioadhesive systems to prolong the gastric retention time. Accordingly, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, an ion-exchange resin and a low-density excipient. Furthermore, the gastro-retentive pharmaceutical composition may comprise the modified NSAID, for example PS, an ion-exchange resin and a mucoadhesive. One or more of these approaches can be employed individually or in combination to maximise the gastric retention of the pharmaceutical composition. Also provided herein is a pharmaceutical composition comprising or consisting of a modified NSAID, for example PS, and one or more gastro-retentive agents. The invention also provides a pharmaceutical combination comprising or consisting of a modified NSAID, for example PS, and one or more gastro-retentive agents. In another aspect, the invention provides a kit comprising a modified NSAID, for example PS, and one or more gastro-retentive agents. The gastro-retentive agent may be a gastro-retentive excipient as described herein. In those embodiments exploiting separate (e.g., sequential) oral administration of the modified NSAID, for example PS, and a gastro-retentive agent, the gastro-retentive agent may be a compound or composition which extends the length of time for which the modified NSAID, for example PS, is retained in the stomach (e.g., Ensure® or EnsurePlus®). The gastro-retentive agent may be a composition comprising fatty acids (e.g., unsaturated fatty acids), for example triglycerides. As noted above, the pharmaceutical composition comprising the modified NSAID, for example PS, may additionally comprise one or more gastro-retentive agents, for example one or more gastro- retentive excipients. For example, the pharmaceutical composition comprising the modified NSAID, for example PS, may additionally comprise one or more of an effervescent excipient, a tablet comprising granules or pellets, a low density excipient, a mucoadhesive excipient, a magnetic excipient, a high density excipient, an expandable excipient, and / or an ion-exchange resin system. In particular embodiments, the pharmaceutical composition comprises a modified NSAID, for example PS, and a low density excipient and a mucoadhesive excipient. In particular embodiments, the pharmaceutical composition is a floating tablet comprising a modified NSAID, for example PS, and a mucoadhesive excipient. The skilled person is aware of routine experiments by which to determine the extent of gastric retention. For example, gastric retention can be measured by including a radionuclide in the formulation and directly recording the fraction of the formulation that remains in the stomach as a function of time following dosing using an appropriate scintillation camera. Although this approach has relatively high precision, it has two principal drawbacks: (i) the radionuclide itself is typically not found in the commercial article and hence the formulation departs in its constitution from the intended commercial form, and (ii) the conduct of such experiments is difficult and expensive and subjects the participants to the additional risk of exposure to radioactivity. Thus, gastric retention can instead be determined by inference from other properties of a gastro-retentive pharmaceutical composition, for example by comparison of the Cmax(or AUC0-24h) produced by the gastro-retentive pharmaceutical composition to the Cmax(or AUC0-24h) produced by a pharmaceutical composition not comprising gastro-retentive agents, or by comparison of the Cmax(or AUC0-24h) in the fasted state to the Cmax(or AUC0-24h) in the fed state. Gastric retention can be measured using magnetic resonance imaging (MRI) to monitor stomach volume. The gastro-retentive pharmaceutical compositions comprising the modified NSAID, for example PS, as disclosed herein, may be used as a medicament. Medical uses of gastro-retentive pharmaceutical compositions of the invention are described throughout the specification. Accordingly, the inventor provides a method comprising administering a therapeutically effective amount of a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof. The inventor further provides, a gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, for use in therapy. The inventor provides the use of a modified NSAID, for example PS, in the manufacture of a gastro-retentive medicament. Combination therapy comprising a modified NSAID and one or more gastro-retentive agents The experiments herein demonstrate, for the first time, the therapeutic utility of combining a modified NSAID, for example PS, with one or more gastro-retentive agents. Accordingly, the inventor further provides a method comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, wherein the modified NSAID, for example PS, and the one or more gastro- retentive agents are administered orally. The inventor further provides a method of treating and / or preventing pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. The inventor also provides, a modified NSAID, for example PS, and one or more gastro-retentive agents as a combined preparation for simultaneous, separate or sequential use in therapy. Also provided is a modified NSAID, for example PS, for use with one or more gastro-retentive agents in therapy. Furthermore, provided is one or more gastro-retentive agents for use with a modified NSAID, for example PS, in therapy. The modified NSAID, for example PS, and the gastro-retentive agent are administered orally. The inventor further provides a modified NSAID, for example PS, and one or more gastro-retentive agents for use therapy, for example in treating and / or preventing pain, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. In some embodiments, the one or more gastro-retentive agents is administered prior to administration of the modified NSAID, for example PS. In a further aspect, the inventor provides a modified NSAID, for example PS, for use in therapy, for example in treating and / or preventing pain, wherein the use further comprises administering one or more gastro-retentive agents, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally. In a further aspect, the inventor provides one or more gastro-retentive agents for use in therapy, for example in treating and / or preventing pain, wherein the use further comprises administering a modified NSAID, for example PS, wherein the one or more gastro-retentive agents and the modified NSAID, for example PS, are administered orally. The inventor further provides the use of a modified NSAID, for example PS, and one or more gastro- retentive agents in the manufacture of a medicament. In some embodiments, the pain is associated with one or more of the indications disclosed herein, for example neuropathic pain or pain associated with central sensitization. The modified NSAID, for example PS, and one or more gastro-retentive agents may be administered simultaneously, separately or sequentially. In particular embodiments, the gastro-retentive agent is administered prior to administration of the modified NSAID, for example PS. The gastro-retentive agent may be a gastro-retentive excipient, as disclosed herein. The gastro- retentive agent may be a compound or composition which extends the length of time for which the modified NSAID, for example PS, is retained in the stomach (e.g., Ensure® or EnsurePlus®). The gastro-retentive agent may be a composition comprising fatty acids (e.g., unsaturated fatty acids), for example triglycerides. Pharmaceutically acceptable forms of the modified NSAID The pharmaceutical composition comprising the modified NSAID, for example PS, can contain a pharmaceutically acceptable form of the modified NSAID. The pharmaceutically acceptable form may be a solvate, derivative, and / or prodrug. Solvates As used herein, the term “solvate” refers to a compound that further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. For example, the pharmaceutically acceptable form of the modified NSAID may include a solvate. In some embodiments, the solvate includes at least 1 molecule of solvent. In some embodiments, the solvate includes less than 1 molecule of solvent. In some embodiments, the solvate is a hydrate. Isotopes The pharmaceutically acceptable form of the modified NSAID may include an isotopically labelled derivative of the modified NSAID. An isotopically labelled derivative is a compound that is identical to the modified NSAID, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, the isotopically labelled derivative of the modified NSAID includes one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, the isotopically labelled derivative of the modified NSAID includes one or more isotopes of2H,3H,13C,14C,18O,17O,31P,32P,35S, and18F, respectively. In some embodiments, the isotopically labelled derivative of the modified NSAID includes one or more isotopes of2H (e.g., deuterium). In some embodiments, the isotopically labelled derivative of the modified NSAID includes one or more isotopes of3H (e.g., tritium). In some embodiments, the isotopically labelled derivative of the modified NSAID includes one or more isotopes of14C. Derivatives and prodrugs The pharmaceutically acceptable form of the modified NSAID may include a derivative of the modified NSAIDI. In some embodiments, the derivative is a metabolite. In other embodiments, the pharmaceutically acceptable form is a prodrug of the modified NSAID. A sulfone group can be structurally expressed as: R−S(=O)2−R'. In some embodiments, the derivative of PS is a sulfone form of PS. PS contains an organophosphate functional group. An organophosphate functional group can be structurally expressed as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR''). For example, O=P(OR)2(OR') can represent PS if R = CH2CH3 and R' = the remainder of the molecule is as per PS in formula I or II (e.g., PS-I, PS-II, or a derivative thereof). In some embodiments, the derivative of PS is PS wherein one of the ethoxy (e.g. -OCH2CH3) groups is an OH group, or a pharmaceutically acceptable salt thereof. In some embodiments, the derivative of PS is PS wherein both ethoxy (e.g. -OCH2CH3) groups are OH groups, or a pharmaceutically acceptable salt thereof. The activity of the modified NSAID demonstrated herein would be shared by pharmaceutically acceptable forms thereof. Therefore, the inventor provides pharmaceutically acceptable forms of the modified NSAID for use in the methods of the invention. While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practising the invention. NUMBERED EMBODIMENTS The invention further provides the following numbered embodiments. 1. A method of treating pain associated with central sensitization comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that pain associated with central sensitization is treated, wherein the modfieid NSAID is administered orally. 2. The method of embodiment 1, wherein treating the pain comprises reducing the pain. 3. The method of any one of the preceding embodiments, wherein treating the pain includes reducing one or more of the symptoms associated with central sensitization. 4. The method of embodiment 3, wherein the one or more symptom is selected from mood changes, fatigue, cognitive disturbances, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia, and / or phonophobia. 5. The method of any one of the preceding embodiments, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain. 6. The method of any one of the preceding embodiments, wherein the modified NSAID reduces pain signalling occurring centrally. 7. The method of any one of the preceding embodiments, wherein the modified NSAID reduces pain signalling occurring in the CNS. 8. The method of any one of the preceding embodiments, wherein the pain is allodynia. 9. The method of embodiment 8, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 10. The method of any one of the preceding embodiments, wherein the pain is hyperalgesia. 11. A method of treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN) comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PTPN is treated and / or prevented, wherein the modified NSAID is administered orally. 12. The method of embodiment 11, wherein treating the neuropathic pain comprises reducing the neuropathic pain. 13. The method of embodiment 11 or 12, wherein preventing the neuropathic pain comprises decreasing the incidence of the neuropathic pain. 14. The method of any one of embodiments 11-13, wherein treating the neuropathic pain includes reducing one or more of the sensory symptoms associated with PTPN. 15. The method of any one of embodiments 11-15, wherein preventing the neuropathic pain includes decreasing the incidence of one or more of the sensory symptoms associated with PTPN. 16. The method of embodiment 14 or 15, wherein the one or more sensory symptom is selected from paresthesia, burning sensations and stabbing sensations. 17. The method of embodiment 16, wherein the paresthesia includes one or more of numbness, tingling, pricking, or formication. 18. The method of any one of embodiments 11-17, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain. 19. The method of any one of embodiments 11-18, wherein the modified NSAID reduces pain generated via central sensitization. 20. The method of any one of embodiments 11-19, wherein the modified NSAID reduces pain signalling occurring centrally. 21. The method of any one of embodiments 11-20, wherein the neuropathic pain is allodynia. 22. The method of embodiment 21, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 23. The method of any one of embodiments 11-22, wherein the neuropathic pain is hyperalgesia. 24. The method of any one of embodiments 11-23, wherein the neuropathic pain associated with PTPN is caused by neurapraxia, for example a nerve compression injury. 25. The method of any one of embodiments 11-24, wherein the neuropathic pain associated with PTPN is caused by axonotmesis, for example a nerve crush injury. 26. The method of any one of embodiments 11-25, wherein the neuropathic pain associated with PTPN is caused by one or more of the following: carpal tunnel syndrome; pronator teres syndrome; radial tunnel syndrome; suprascapular nerve entrapment; thoracic outlet syndrome; ulnar nerve entrapment (cubital tunnel syndrome or Guyon’s canal syndrome); meralgia paresthetica; peroneal nerve compression; pudendal nerve entrapment syndrome; sciatica; tarsal tunnel syndrome; herniated cervical disc; herniated thoracic disc; and / or herniated lumbar disc. 27. A method of treating and / or preventing migraine pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that migraine pain is treated and / or prevented, wherein the modified NSAID is administered orally. 28. The method of embodiment 27, wherein treating the pain comprises reducing the pain, for example pulsating head pain. 29. The method of embodiment 27 or 28, wherein preventing the pain comprises decreasing the incidence of the pain, for example pulsating head pain. 30. The method of any one of embodiments 27-29, wherein treating the pain includes reducing one or more of the symptoms associated with migraine. 31. The method of any one of embodiments 27-30, wherein preventing the pain includes decreasing the incidence of one or more of the symptoms associated with migraine. 32. The method of embodiment 27 or 31, wherein the one or more symptom is selected from aura, nausea, vomiting, photophobia, phonophobia and / or cranial autonomic symptoms. 33. The method of embodiment 32, wherein the aura includes one or more sensory disturbances, for example visual symptoms, pins and needles (tingling), and / or numbness. 34. The method of embodiment 32 or 33, wherein the cranial autonomic symptom eye redness or tearing. 35. The method of any one of embodiments 27-34, wherein the subject experiences cutaneous allodynia. 36. The method of any one of embodiments 27-35, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain. 37. The method of any one of embodiments 27-36, wherein the modified NSAID reduces pain generated via central sensitisation. 38. The method of any one of embodiments 27-37, wherein the modified NSAID reduces pain signalling occurring centrally. 39. The method of any one of embodiments 27-38, wherein the modified NSAID reduces pain signalling occurring in higher order neurons and / or one or more of the areas of the brain involved in pain sensation, for example trigeminothalamic neurons. 40. The method of any one of embodiments 27-39, wherein the pain is allodynia, for example cutaneous allodynia. 41. The method of embodiment 40, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 42. The method of any one of embodiments 27-41, wherein the pain is hyperalgesia. 43. The method of any one of embodiments 27-42, wherein the migraine is episodic migraine or chronic migraine. 44. The method of any one of embodiments 27-43, wherein the migraine is migraine with aura or migraine without aura. 45. A method of treating and / or preventing neuropathic pain associated with post-herpetic neuralgia (PHN) comprising administering a therapeutically effective amount of a modified NSAID, for example phosphosulindac, to a subject in need thereof such that neuropathic pain associated with PHN is treated and / or prevented, wherein the modified NSAID is administered orally. 46. The method of embodiment 45, wherein treating the neuropathic pain comprises reducing the neuropathic pain. 47. The method of embodiment 45 or 46, wherein preventing the neuropathic pain comprises decreasing the incidence of the neuropathic pain. 48. The method of any one of embodiments 45-47, wherein treating the neuropathic pain includes reducing one or more of the sensory symptoms associated with PHN. 49. The method of any one of embodiments 45-48, wherein preventing the neuropathic pain includes decreasing the incidence of one or more of the sensory symptoms associated with PHN. 50. The method of any one of embodiments 45-49, wherein the neuropathic pain is a sharp, burning, throbbing or stabbing . 51. The method of any one of embodiments 48-50, wherein the one or more sensory symptom is selected from itching or numbness. 52. The method of any one of embodiments 45-51, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain. 53. The method of any one of embodiments 45-52, wherein the modified NSAID reduces pain generated via peripheral sensitization. 54. The method of any one of embodiments 45-53, wherein the modified NSAID reduces pain generated via central sensitization. 55. The method of any one of embodiments 45-54, wherein the modified NSAID reduces pain signalling occurring centrally. 56. The method of any one of embodiments 45-55, wherein the neuropathic pain is allodynia. 57. The method of embodiment 56, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 58. The method of any one of embodiments 45-57, wherein the neuropathic pain is hyperalgesia. 59. A method of treating corneal neuropathic pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that corneal neuropathic pain is treated, wherein the modified NSAID is administered oreally. 60. The method of embodiment 59, wherein treating the corneal neuropathic pain comprises reducing the corneal neuropathic pain. 61. The method of embodiment 59 or 60, wherein treating the corneal neuropathic pain includes reducing one or more of the symptoms associated with corneal neuropathic pain. 62. The method of embodiment 61, wherein the one or more symptom is selected from paresthesia, photosensitivity, photoallodynia, anxiety, depression or apathy. 63. The method of embodiment 62, wherein the paresthesia includes one or more of numbness, tingling, pricking, or formication. 64. The method of any one of embodiments 59-63, wherein the modified NSAID reduces pain generated via central sensitization. 65. The method of any one of embodiments 59-64, wherein the modified NSAID reduces pain signalling occurring centrally. 66. The method of any one of embodiments 59-65, wherein the modified NSAID reduces pain signalling occurring in the higher order neurons and / or one or more of the areas of the brain involved in pain sensation, for example trigeminothalamic neurons. 67. The method of any one of embodiments 59-66, wherein the corneal neuropathic pain is allodynia. 68. The method of embodiment 67, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 69. The method of any one of embodiments 59-68, wherein the corneal neuropathic pain is hyperalgesia. 70. A method of treating and / or preventing neuropathic pain associated with chemotherapy induced peripheral neuropathy (CIPN) comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that neuropathic pain associated with CIPN is treated and / or prevented, wherein the modified NSAID is administered orally. 71. The method of embodiment 70, wherein treating the neuropathic pain comprises reducing the neuropathic pain. 72. The method of embodiment 70 or 71, wherein preventing the neuropathic pain comprises decreasing the incidence of the neuropathic pain. 73. The method of any one of embodiments 70-72, wherein treating the neuropathic pain includes reducing one or more of the sensory symptoms associated with CIPN. 74. The method of any one of embodiments 70-73, wherein preventing the neuropathic pain includes decreasing the incidence of one or more of the sensory symptoms associated with CIPN. 75. The method of embodiment 73 or 74, wherein the one or more sensory symptom is selected from paresthesia, burning sensations and shooting sensations. 76. The method of embodiment 75, wherein the paresthesia includes one or more of numbness, tingling, pricking, or formication. 77. The method of any one of embodiments 70-76, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain. 78. The method of any one of embodiments 70-77, wherein the modified NSAID reduces pain generated via central sensitization. 79. The method of any one of embodiments 70-78, wherein the modified NSAID reduces pain signalling occurring centrally. 80. The method of any one of embodiments 70-79, wherein the neuropathic pain is allodynia. 81. The method of embodiment 80, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 82. The method of any one of embodiments 70-81, wherein the neuropathic pain is hyperalgesia. 83. The method of any one of embodiments 70-82, wherein the subject has cancer and is receiving or has been previously treated with one or more chemotherapeutic compounds. 84. The method of embodiment 83, wherein the one or more chemotherapeutic compounds is selected from one or more of platinum-based drugs, taxanes, immunomodulatory drugs, epothilones, vinva alkaloids, and proteasome inhibitors. 85. The method of embodiment 384, wherein the one or more chemotherapeutic compound is selected from one or more of oxaliplatin, cisplatin, carboplatin, taxane, paclitaxel, docetaxel, cabazitaxel, thalidomide and its analogues, vincristine, vinblastine, vinorelbine, vindesine, and bortezomib. 86. The method of any one of embodiments 83-85, wherein the chemotherapeutic compound is a taxane, for example paclitaxel. 87. The method of any one of embodiments 83-85, wherein the chemotherapeutic compound is a vinca alkaloid, for example vincristine. 88. The method of any one of embodiments 83-85, wherein the chemotherapeutic compound is a platinum-based antineoplastic, for example oxaliplatin. 89. The method of any one of embodiments 83-88, wherein the subject has a solid tumor cancer. 90. The method of any one of embodiments 83-89, wherein the subject has ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, and / or pancreatic cancer. 91. A method of treating and / or preventing neuropathic pain associated with diabetic peripheral neuropathy (DPN) comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that neuropathic pain associated with DPN is treated and / or prevented, wherein the modified NSAID is administered orally. 92. The method of embodiment 91, wherein treating the neuropathic pain comprises reducing the neuropathic pain. 93. The method of embodiment 91 or 92, wherein preventing the neuropathic pain comprises decreasing the incidence of the neuropathic pain. 94. The method of any one of embodiments 91-93, wherein treating the neuropathic pain includes reducing one or more of the sensory symptoms associated with DPN. 95. The method of any one of embodiments 91-94, wherein preventing the neuropathic pain includes decreasing the incidence of one or more of the sensory symptoms associated with DPN. 96. The method of embodiment 94 or 95, wherein the one or more sensory symptom is selected from paresthesia, burning sensations and shooting sensations. 97. The method of embodiment 96, wherein the paresthesia includes one or more of numbness, tingling, pricking, or formication. 98. The method of any one of embodiments 91-97, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain. 99. The method of any one of embodiments 91-98, wherein the modified NSAID reduces pain generated via central sensitization. 100. The method of any one of embodiments 91-99, wherein the modified NSAID reduces pain signalling occurring centrally. 101. The method of any one of embodiments 91-100, wherein the neuropathic pain is allodynia. 102. The method of embodiment 101, wherein the allodynia is mechanical allodynia and / or thermal allodynia. 103. The method of any one of embodiments 91-102, wherein the neuropathic pain is hyperalgesia. 104. The method of any one of the preceding embodiments , wherein the modified NSAID is selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs, phosphoramide-modified NSAIDs, selenium-modified NSAIDs, metal complex-NSAIDs, H2S- releasing NSAIDs, NO-releasing NSAIDs and NO-, SH-releasing NSAIDs. 105. The method of any one of the preceding embodiments , wherein the modified NSAID is modified sulindac, modified ibuprofen, modified naproxen, modified flurbiprofen, modified aspirin, modified ketoprofen, modified tiaprofenic acid, modified diclofenac sodium, modified aceclofenac, modified etodolac, modified indometacin, modified mefenamic acid, modified meloxicam, modified nabumetone, modified phenylbutazone, modified piroxicam, modified tenoxicam, modified tolfenamic acid, modified ketorolac trometamol, modified parecoxib, modified etoricoxib, or modified celecoxib. 106. The method of any one of the preceding embodiments, wherein the modified NSAID is selected from one or more of the following: phosphosulindac, such as formula I or II; phosphonaproxen, such as formula VIII; NO-sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; phosphosulindac amide, such as formula X; phospho-ibuprofen, such as formula III; phospho- glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen amide, such as formula XI. 107. The method of any one of embodiments 1-105, wherein the modified NSAID is a phopsho- NSAID, for example phosphosulindac (PS), such as formula I or II; phosphonaproxen, such as formula VIII; phospho-ibuprofen, such as formula III; or phospho-glycerol ibuprofen, such as formula LXXI. 108. The method of any one of embodiments 1-105, wherein the modified NSAID is a phosphoramide NSAID, for example phosphosulindac amide, such as formula X; or phospho- ibuprofen amide, such as formula XI. 109. The method of any one of embodiments 1-105, wherein the modified NSAID is a modified sulindac, for example PS, such as formula I or II; phosphosulindac amide, such as formula X; NO- sulindac, such as formula XLIV; or HS-sulindac, such as formula XXXIV. 110. The method of any one of embodiments 1-105, wherein the modified NSAID is a modified ibuprofen, for example phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen-amide, such as formula XI, in particular phospho-ibuprofen- amide, such as formula XI 111. The method of any one of the preceding embodiments, wherein the therapeutically effective amount of the modified NSAID is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. 112. The method of any one of the preceding embodiments, wherein the modified NSAID is formulated as a liquid or solid dosage form. 113. The method of embodiment 112, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup or and elixir. 114. The method of embodiment 112, wherein the solid dosage form is a capsule, tablet, pill, powder, or granule. 115. The method of any one of the preceding embodiments, wherein the modified NSAID is administered orally at dosage levels of about 0.01 mg / kg to about 100 mg / kg, from about 0.05 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg of subject body weight, for example about 1 mg / kg to about 5 mg / kg, for example about 3 mg / kg of subject body weight. 116. The method of any one of the preceding embodiments, wherein the modified NSAID is administered orally at a dosage of about 1 mg to about 2000 mg, of about 100 mg to 1500 mg, of about 200 mg to about 100 mg, of about 50 mg to about 400 mg, for example about 100 mg to about 350 mg, for example about 150 mg to about 300 mg, for example about 150mg to about 250 mg. 117. The method of any one of the preceding embodiments, wherein the modified NSAID is administered orally at a dosage of about 250 mg to about 300 mg, preferably about 250 mg. 118. The method of any one of the preceding embodiments, wherein the modified NSAID is administered once a day. 119. The method of any one of the preceding embodiments, wherein the modified NSAID is administered at least twice a day, at least three times a day, or at least four times a day. 120. The method of any one of the preceding embodiments, wherein the modified NSAID is administered orally two or three times a day. 121. The method of any one of the preceding embodiments, wherein the modified NSAID is administered at a dosage of from about 150 mg to about 200 mg twice a day. 122. The method of any one of the preceding embodiments, wherein the modified NSAID is administered at a daily dosage of about 300 mg to about 400 mg. 123. The method of any one of the preceding embodiments, wherein the modified NSAID is administered orally at a daily dosage of about 250 mg to about 300 mg (for example, about 250 mg) two or three times a day. 124. The method of any one of the preceding embodiments, wherein the modified NSAID is administered orally at a daily dosage of about 500 mg to up to about 900 mg a day. 125. The method of any one of embodiments 112-124, wherein the modified NSAID is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. 126. The method of any one of embodiments 111-125, wherein the pharmaceutical composition is a gastro-retentive pharmaceutical composition. 127. The method of embodiment 126, wherein the gastro-retentive pharmaceutical composition comprises the modified NSAID and one or more gastro-retentive agents, for example one or more gastro-retentive excipients. 128. A method of treating and / or preventing pain comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID is administered orally. 129. The method of any one of the preceding embodiments, wherein the subject is a human. 130. A gastro-retentive pharmaceutical composition comprising a modified NSAID, for example PS. 131. A pharmaceutical composition comprising a modified NSAID, for example PS, and one or more gastro-retentive agents. 132. The pharmaceutical composition of embodiment 131, wherein the one or more gastro-retentive agents is a gastro-retentive excipient. 133. A method comprising administering a therapeutically effective amount of gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof. 134. A modified NSAID, for example PS, and one or more gastro-retentive agents as a combined preparation for simultaneous, separate or sequential use in therapy. 135. A gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, for use in therapy. 136. Use of a modified NSAID, for example PS, and one or more gastro-retentive agents in the manufacture of a medicament. EXAMPLES The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein. Example 1: The effect of orally administered PS and phospho-naproxen (PN) on treating neuropathic pain in a mouse model of CIPN The present Example demonstrates that oral administration of PS and phospho-naproxen (Formula VIII) surprisingly treats neuropathic pain associated with CIPN, as demonstrated in an established animal model. On the contrary, both of the parent compounds, sulindac and naproxen respectively, failed to treat neuropathic pain associated with CIPN, even administered in the same way and in equimolar amounts to the experimental compounds. The observations demonstrate an unprecedented activity of orally administered modified NSAIDs in the treatment of neuropathic pain associated with CIPN, confirming the utility of modified NSAIDs in treating challenging forms of neuropathic pain, even upon oral administration. Methods Adult male C57BL / 6J mice, 8 weeks of age at the beginning of the experiments and weighing 20–30 g, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were housed in an AAALAC-accredited facility in groups of four. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 am to 7:00 pm) and animals were euthanized with CO2 asphyxiation. The mice in each cage were randomly allocated to treatment groups. All studies were conducted by experimenters blinded to the identity of the treatment groups. Studies were approved by the Institutional Animal Care and Use Committee of Stony Brook University and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al, 2010). CIPN was induced in 8-weeks-old male C57BL / 6J mice (~25 g). CIPN was induced in mice with chemotherapeutic agents using established protocols (Carozzi et al, 2010; Currie et al, 2019; Eldridge et al, 2020). Briefly, four intraperitoneal injections of paclitaxel at 8 mg / kg were given every other day, resulting in a cumulative dose of 32 mg / kg. This dosing regimen of paclitaxel produces pain associated with CIPN with time courses that are similar to those of pain after paclitaxel administration in cancer patients. PS, phospho-naproxen (PN), sulindac and naproxen were given by oral gavage, three times a day for 7 days. Their doses were as follows: PS, 50 mg / kg; PN, 65 mg / kg; naproxen, 35 mg / kg (equimolar to PN); sulindac, 33 mg / kg (equimolar to PS). Mechanical allodynia was determined for all mice study groups below: 1. Group 1: naïve mice (i.e. no paclitaxel, n=8) 2. Group 2: paclitaxel only (n=8) 3. Group 3: paclitaxel plus vehicle (n=8) 4. Group 4: paclitaxel plus PS (n=8) 5. Group 5: paclitaxel plus sulindac (n=8) 6. Group 6: paclitaxel plus PN (n=8) 7. Group 7: paclitaxel plus naproxen (n=8) Mechanical allodynia thresholds (paw withdrawal thresholds) were determined using von Frey filaments according to an established method (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 min and then were put in a Plexiglas cage with mesh metal flooring and allowed to acclimatise for 30 min before testing. A series of calibrated von Frey filaments (Stoelting, Wood Dale, IL) with incremental stiffness were applied perpendicularly to the paw with sufficient force to cause slight bending and held 2–3 s. This process was repeated at each level of stiffness 5 times, a few seconds apart. Paw withdrawn, licking or shaking were considered positive responses. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Additionally, thermal allodynia was determined for all mice study groups below: 1. Group 1: paclitaxel plus vehicle (n=8) 2. Group 2: paclitaxel plus PS (n=8) 3. Group 3: paclitaxel pluse sulindac (n=8) Briefly, thermal allodynia tests use a radiant heat source (Hargreaves et al., 1988). The animal is placed into a plastic box with an elevated glass floor. The beam of the lamp probe is focused on the paw plantar surface, until the animal withdraws the paw, and sensors in the device shut off the lamp. The thermal allodynia threshold is defined as the latency time until paw withdrawal (PWL) and expressed in seconds (sec) or thermal allodynia threshold. The response of thermal allodynia to PS and sulindac was tested on day 16 of treatment. Results The administration of paclitaxel resulted in a significant decrease in PWT (p<0.001 vs. naïve mice), as expected. Therefore, the model established neuropathic pain associated with chemotherapy, manifested as allodynia. The additional administration of vehicle has no significant effect on the PWT compared to treatment with paclitaxel only, while administration of PS achieved a significant increase in PWT compared to vehicle (p<0.003 vs vehicle). By contrast, administration of sulindac failed to demonstrate a significant effect on PWT, its score being similar to that of vehicle (0.56 ± 0.05 g vs.0.54 ± 0.03 g; statistically not significant). Administration of PN achieved a significant increase in PWT compared to vehicle (p<0.01 vs vehicle). By contrast, administration of naproxen failed to demonstrate a significant effect on PWT, its score being similar to that of vehicle (0.53 ± 0.05 g vs.0.54 ± 0.03 g; statistically not significant). The values are provided in Table 1. Table 1 – PWT in the study groups. Groups PWT, g P values To co al latency (PWL) were assessed in thermal allodynia tests in CIPN model mice. PS significantly increased the PWL compared to vehicle control (p < 0.04). In contrast, the effect of sulindac was not significant compared to vehicle control. PWL values are provided in Table 2. Table 2 – PWL in the study groups. Groups PWL, sec P values Mean ± SEM Concl The or al administration of PS resulted in a significant increase in PWT and PWL, in contrast to its parent compound, sulindac. Additionally, the oral administration of phospho-naproxen resulted in a significant increase in PWT in mice with established neuropathic pain caused by paclitaxel (i.e., CIPN). This was in contrast to its parent compound, naproxen. These positive results are surprising not least in light of the ability of orally administered PS and phospho-naproxen to achieve significant analgesic effects on pain originating at peripheral sites distal from the site of absorption (i.e., the stomach) but persisting via activity of central neurons even in the absence of on-going peripheral triggers. These observations suggest that PS and phospho-naproxen act centrally and demonstrate the broad applicability of orally administered modified NSAIDs in treating neuropathic pain associated with CIPN. Indeed, further observations herein indicate that orally administered PS and PN reach central sites of pain generation, thus cementing the unprecedented activity of these modified NSAIDs as direct acting nerve analgesics effective at central sites of action, even upon oral administration. Example 2: The effect of orally administered phospho-ibuprofen (PI), phospho-glycerol- ibuprofen (PGI), phospho-ibuprofen-amide (PIA), and ibuprofen on CIPN Methods CIPN was induced in 8-weeks-old male C57BL / 6J mice (~25 g), with paclitaxel, as previously detailed herein. This dosing regimen of paclitaxel produces pain associated with CIPN with time courses that are similar to those of pain after paclitaxel administration in cancer patients. Phospho-ibuprofen (PI) (Formula III), phospho-glycerol-ibuprofen (PGI) (Formula LXXI), phospho- ibuprofen-amide (PIA) (Formula XI), and ibuprofen were given by oral gavage, three times a day for 6 days. Their doses were as follows: ibuprofen, 40 mg / kg; PI, 80 mg / kg; PIA, 80 mg / kg; all three were equimolar. The dose of PGI, selected based on its maximum tolerated dose in these mice, was 60 mg / kg. Mechanical allodynia was determined for all CIPN mice study groups below (8 mice per group): 1. Group 1: naïve mice (i.e. no paclitaxel) 2. Group 2: paclitaxel only 3. Group 3: paclitaxel plus vehicle 4. Group 4: paclitaxel plus ibuprofen 5. Group 5: paclitaxel plus phospho-ibuprofen 6. Group 6: paclitaxel plus phospho-ibuprofen-amide (PIA) 7. Group 7: paclitaxel plus phospho-glycerol-ibuprofen (PGI) Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The response of mechanical allodynia to these compounds was tested on day 6, using the PWT test. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results The administration of paclitaxel resulted in a significant decrease in PWT, as expected. Therefore, the model established pain associated with chemotherapy manifested as allodynia. The additional administration of vehicle has no significant effect on the PWT compared to treatment with paclitaxel only. Ibuprofen had no significant effect on PWT compared to vehicle treatment. In contrast, administration of PI, PIA and PGI all achieved a significant increase in PWT compared to vehicle. The values are provided in Table 3. Table 3 – PWT in the study groups. Groups PWT, g P value Conclusio The oral administration of these modified ibuprofen compounds resulted in a significant increase in PWT in mice with established neuropathic pain caused by paclitaxel (i.e., CIPN). This was in contrast to its parent compound, ibuprofen. Indeed, oral administration of the modified ibuprofen compounds achieved analgesic activity beyond that seen for oral administration of PS. Furthermore, the oral administration of phospho-ibuprofen in this model was significantly improved compared to the topical administration of the same compound in the same model (see the data in WO2024 / 112725 and WO2024 / 112727). In line with further observations herein, these observations demonstrate a striking activity of modified NSAIDs in a specific animal model of CIPN. The activity is contrary to the established activity of typical NSAIDs, as explained herein and demonstrated by the failure of the parent compound in the same experiment. Therefore, similar to the observations for PS and PN, the modification of these NSAIDs imparts an unexpected activity on these compounds such that they are able to treat established neuropathic pain associated with CIPN, even upon oral administration. Furthermore, the positive results are surprising not least in light of the ability of orally administered modified NSAIDs to achieve significant analgesic effects on pain originating at peripheral sites distal from the site of absorption (i.e., the stomach) but persisting via activity of central neurons even in the absence of on-going peripheral triggers. However, these observations are in line with observations that modified NSAIDs accumulate at central sites of action to impart a direct effect on neuronal signalling that explains the broad applicability of this modified NSAID (even upon oral administration). Therefore, the positive results in these previously untested dosage forms, in contrast to the inactivity of the parent compound, are surprising, and confirm observations suggesting that modified NSAIDs act centrally and demonstrate the broad applicability of modified NSAIDs in treating different forms of neuropathic pain, even upon oral adminstration. Example 3: The effect of orally administered NO-sulindac, HS-sulindac, platinum-sulindac, and NOSH-1 on treating neuropathic pain in a mouse model of CIPN Methods CIPN was induced in 8-weeks-old male C57BL / 6J mice (~25 g), with paclitaxel, as previously detailed in earlier Examples. This dosing regimen of paclitaxel produces pain associated with CIPN with time courses that are similar to those of pain after paclitaxel administration in cancer patients. NO-sulindac (Formula XLIV), HS-sulindac (Formula XXXIV), platinum-sulindac (Formula LXVII), and NOSH-1 (Formula LIX) were given by oral gavage, three times a day throughout the study period. Their doses were all 100 mg / kg. Mechanical allodynia was determined for all CIPN mice study groups below (8 mice per group): 1. Group 1: naïve mice (i.e. no paclitaxel) 2. Group 2: paclitaxel only 3. Group 3: paclitaxel plus vehicle 4. Group 4: paclitaxel plus NO-sulindac 5. Group 5: paclitaxel plus HS-sulindac 6. Group 6: paclitaxel plus platinum-sulindac 7. Group 7: paclitaxel plus NOSH-1 Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The response of mechanical allodynia to these compounds was tested on the days set out in the table below, via the PWT test. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results The administration of paclitaxel resulted in a significant decrease in PWT, as expected (p<0.0001). Therefore, the model established pain associated with chemotherapy manifested as allodynia. The additional administration of vehicle has no significant effect on the PWT compared to treatment with paclitaxel only. All the modified NSAIDs, NO-sulindac, HS-sulindac, platinum-sulindac, and NOSH-1 achieved a significant increase in PWT compared to vehicle. The values are provided in Table 4A. Table 4A – PWT in the study groups. Groups PWT, g P value P value As al l of neuropathic pain. Indeed, in a separate experiment recorded herein, sulindac, administered at 33 mg / kg had no significant effect on PWT compared to vehicle (see Table 4B). Table 4B – PWT in the study groups. Groups PWT, g P values Mean ± SEM Concl The or a a m n s ra on o ese mo e S compoun s resu e n a s gn can ncrease in PWT in mice with established neuropathic pain caused by paclitaxel (i.e., CIPN). The surprising activity of the modified sulindac compounds was in contrast to the failure of the parent compound, sulindac, to be effective upon oral administration in the same model of pain associated with CIPN disclosed herein. The efficacy of the orally administered modified NSAIDs is at least equivalent to orally administered PS in the same animal model, with NO-sulindac and NOSH1 appearing further improved. These results are in line with the observations herein with respect to the activity of orally administered PS in treating neuropathic pain associated with CIPN. The positive results upon oral administration of a variety of differently modified NSAIDs (in particular modified sulindac) is surprising, but further support observations herein that modified NSAIDs may act centrally and serves to emphasise the broad applicability of modified NSAIDs in treating neuropathic pain associated with CIPN, even upon oral administration. Additionally, it appears that the modified NSAIDs are not only reaching a central site of action (like PS), but equally achieve direct analgesic effects on nerve activity, a property not shared by the parent compound. Therefore, similar to the observations for PS, the modification of these NSAIDs imparts an unexpected activity on these compounds such that they are able to treat established neuropathic pain associated with CIPN, even upon oral administration. Example 4: The effect of an orally administered formulation of a compound having Formula LXIX in treating neuropathic pain in a mouse model of CIPN Methods CIPN was induced in 8-weeks-old male C57BL / 6J mice (~25 g), with paclitaxel, as previously detailed in earlier Examples. This dosing regimen of paclitaxel produces pain associated with CIPN with time courses that are similar to those of pain after paclitaxel administration in cancer patients. LXIX was given by oral gavage, once a day for 14 days at a dose of 100 mg / kg. Mechanical allodynia was determined for all CIPN mice study groups below (8 mice per group): 1. Group 1: naïve mice (i.e. no paclitaxel) 2. Group 2: paclitaxel only 3. Group 3: paclitaxel plus vehicle 4. Group 4: paclitaxel plus LXIX Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The response of mechanical allodynia to these compounds was tested on day 14, via the PWT test. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results The administration of paclitaxel markedly suppressed PWT values as expected (p<0.0001), indicating establishment of severe neuropathic pain associated with CIPN. The administration of the vehicle control did not result in a significant change in the PWT compared to treatment with paclitaxel only. However, LXIX showed a significant improvement of PWT compared to vehicle (p < 0.029), indicating an effect on mechanical allodynia. The values are provided in Table 5. Table 5 – PWT across the study groups Group PWT, g P value Con The oral administration of LXIX resulted in a significant increase in PWT in mice with established neuropathic pain caused by paclitaxel (i.e., CIPN). These results are in line with the observations herein with respect to the activity of topically administered LXIX in treating neuropathic pain associated with CIPN. The positive results upon oral administration of LXIX is surprising, but confirm earlier observations suggesting that modified NSAIDs may act centrally and serves to emphasise the broad applicability of modified NSAIDs in treating different forms of neuropathic pain even upon oral administration. The modified NSAID herein, for example LXIX display an unexpected activity compared to typical NSAIDs – an ability to treat established neuropathic pain associated with CIPN, even upon oral administration. Example 5: The effect of orally administered PS in treating neuropathic pain in a mouse model of PTPN Orally administered PS was investigated in a mouse model of PTPN, building on observations herein demonstrating the broad applicability of PS as a centrally acting analgesic upon oral administration. Methods Adult male C57BL / 6J mice, 8 weeks of age at the beginning of the experiments and weighing 20–30 g, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were housed in an AAALAC-accredited facility in groups of four. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 am to 7:00 pm) and animals were euthanized with CO2 asphyxiation. The mice in each cage were randomly allocated to treatment groups. All studies were conducted by experimenters blinded to the identity of the treatment groups. Studies were approved by the Institutional Animal Care and Use Committee of Stony Brook University and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al, 2010). Chronic constriction injury-induced peripheral neuropathy (a form of post-traumatic peripheral neuropathy) was induced in 8 weeks old male C57BL / 6J mice (~25 g) under anesthesia. The left sciatic nerve was exposed by a skin incision and cutting through the connective tissue between the gluteus superficialis and biceps femoris muscles. Two chronic gut ligatures with a 7-0 suture were tied loosely around the sciatic nerve 1 mm apart, to just occlude but not arrest epineurial blood flow. For the control sham mice, a similar skin incision was made on the left side but without ligating the sciatic nerve. In either case, the surgical wound was closed with sutures in the muscle and staples in the skin. Pain hypersensitivity testing was performed after 5-7 days of recovery from surgery. This model establishes neuropathic pain associated with PTPN (manifested as allodynia). PS was administered orally three times a day for 6 days, at 100 mg / kg. Mechanical allodynia was determined for all mice study groups below: 1. Group 1: ligation only (i.e, surgical control with no treatment, n=9) 2. Group 2: vehicle (n=9) 3. Group 3: PS (n=9) Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed on day 6. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results As expected, treating mice with the vehicle control did not results in a significant change from PWT values following ligation. In contrast, treatment with orally administered PS significantly increased PWT compared to vehicle control treatment. The values are provided in Table 6A.

[0006] Table 6A – PWT in the study groups Groups PWT, g P value Mean ± SEM In ano lindac, was s indac, administered orally at 33 mg / kg had no significant effect on PWT compared to vehicle (Table 6B). Table 6B – PWT in the study groups Groups PWT, g P value Concl Similar to the observations in neuropathic pain associated with CIPN, the oral administration of PS resulted in a significant increase in PWT in a mouse model of PTPN. This activity is in contrast to the parent compound, sulindac, which fails to achieve analgesia in this challenging pain model. Strikingly, the efficacy of orally administered PS in this model was beyond that observed for topically administered PS in the same model system (see the data in WO2024 / 112725 and WO2024 / 112727). These positive results affirm data herein demonstrating the efficacy of orally administered PS in the treatment of neuropathic pain associated with CIPN. Thus these observations confirm that PS is not acting as a local analgesic, but instead is able to reach central sites of action and achieve significant effects on pain known to be associated with central sensitization, manifested as allodynia. The ability of PS to act on centrally generated pain even upon oral administration, is particularly surprising, and supported by further observations herein that indicate that orally administered PS reaches central sites of pain generation. The results further confirm the broad applicability of PS, as an apparent direct acting nerve analgesic, in treating different forms of neuropathic pain. Example 6: The effect of orally administered PS and PSA, and the failure of sulindac, in treating neuropathic pain in a mouse model of PTPN To support the observations in previous Examples, lower doses of orally administered PS were tested for efficacy in treating neuropathic pain associated with PTPN, and also compared to the parent compound sulindac. Furthermore, the feasibility of orally administered phosphosulindac amide (PSA) (Formula X), another modified sulindac variant, was determined in the same model. Methods Chronic constriction injury was exploited in induce neuropathic pain associated with PTPN. The neuropathic pain was induced in 8 weeks old male C57BL / 6J mice (~25 g) under anesthesia, as previously described, by ligating the left sciatic nerve. This establishes neuropathic pain associated with PTPN (manifested as allodynia). PS, phosphosulindac amide (PSA), sulindac, or vehicle were administered orally once a day for 6 days or 14 days, as indicated in the Table below. The dose of both PS and PSA was 50 mg / kg; the dose of sulindac was 33 mg / kg (equimolar). Mechanical allodynia was determined for all mice study groups below: 1. Group 1: ligation only (i.e, surgical control with no treatment, n=9) 2. Group 2: vehicle (n=9) 3. Group 3: PS (n=9) 4. Group 4: PSA (n=9) 5. Group 4: sulindac (n=9) Mechanical allodynia was determined using von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed on day 6 or day 14, as indicated. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results As expected, treating mice with the vehicle control did not result in a significant change from PWT values comparted to ligation alone. This failure persisted until day 14. In contrast, treatment with orally administered PS significantly increased PWT compared to vehicle control treatment (day 6: 1.22 ± 0.14 g vs 0.51 ± 0.01 g, p <0.0002). This effect was increased over the longer, 14-day administration time (1.62 ± 0.13 g vs 0.56 ± 0.03 g, p <0.00001). Treatment with orally administered PSA also significantly increased PWT compared to vehicle control treatment at both measured time points (for example, day 6: 1.0 ± 0.11 g vs 0.51 ± 0.01 g, p <0.0005). In contrast, sulindac failed to achieve any significant change compared to vehicle control, at either time point. The values are provided in Table 7. Table 7– PWT in the study groups Groups PWT, g P value Conclusions These results confirm the striking effect of higher doses of PS in treating pain associated with PTPN observed herein. In particular, the oral administration of PS at both a lower dose and lower frequency of administration remarkably still resulted in a significant increase in PWT in a mouse model of PTPN. Such an effect is surprising and demonstrates that PS is a particularly effective compound in treating established neuropathic pain even upon oral administration at lower doses. This effect is strengthened over a longer treatment period, at which point the effect is comparable to the higher dose used in previous Examples. These positive results further point to the clinical applicability of orally administered PS in treating challenging pain indications, including those with established neuropathic pain and having central sites of action. Indeed, the observations point to the utility of lower doses of PS over extended dosing intervals. The oral administration of PSA also significantly increased the PWT in this established model of neuropathic pain. The observations are in line with successful treatment of PTPN upon topical administration of PSA, and the ability of this compound to treat CIPN upon topical administration (see the data in WO2024 / 112727). Therefore, PSA is able to treat established neuropathic pain associated with PTPN, even when administered orally, suggesting an ability of this compound to access key sites of pain generation upon oral administration, and to target pain signalling centrally even if the initial trigger of the pain is manifested at distal sites. As consistently observed herein, the anti-inflammatory activity of sulindac is simply insufficient for treatment of the complex neuropathic pain developed in this animal model, with the success of orally administered PS and PSA further pointing to a direct activity of these compounds on centrally located neurons involved in persistent pain signalling – an activity mechanistically distinct to the parent NSAID. As demonstrates herein, orally administered PS and PSA accumulate in central sites of action, for example key sites of pain signalling and sensation. Without wishing to be bound by theory, this supports the conclusion that orally administered modified NSAIDs have direct analgesic effects on neuronal pain signalling at central sites of action, in particular pain generating neuronal signalling in the brain. In combination with the observations here of distinct orally administered modified NSAIDs in a number of challenging neuropathic pain models, the observations in this example point to an unprecedented and surprising broad applicability of orally administered modified NSAIDs in treating and preventing pain having central mechanisms (i.e., generated in central sites or due to central sensitization). Example 7: The effect of orally administered phospho-ibuprofen (PI), phospho-ibuprofen- amide (PIA), and ibuprofen in treating pain in a mouse model of PTPN Further to the successful observations of oral administration of PS, the efficacy of oral administration of other modified NSAIDs was assessed in a mouse model of PTPN. Methods Adult male C57BL / 6J mice, 8 weeks of age at the beginning of the experiments and weighing 20–30 g, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were housed in an AAALAC-accredited facility in groups of four. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 am to 7:00 pm) and animals were euthanized with CO2 asphyxiation. The mice in each cage were randomly allocated to treatment groups. All studies were conducted by experimenters blinded to the identity of the treatment groups. Studies were approved by the Institutional Animal Care and Use Committee of Stony Brook University and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al, 2010). Chronic constriction injury-induced peripheral neuropathy (a form of post-traumatic peripheral neuropathy) was induced in 8 weeks old male C57BL / 6J mice (~25 g) under anesthesia, as previously described, by ligating the left sciatic nerve. This establishes neuropathic pain associated with PTPN (manifested as allodynia). Phospho-ibuprofen (PI) (Formula III), phospho-ibuprofen-amide (PIA) (Formula XI), ibuprofen and vehicle control were all administered orally, three times a day for 14 days. Their doses were as follows: PI 80mg / kg, PIA 80 mg / kg, ibuprofen 40 mg / kg (all three are equimolar). Mechanical allodynia was determined for all mice study groups below: 1. Group 1: vehicle (n=5-8) 2. Group 2: ibuprofen (n=5-8) 3. Group 3: phospho-ibuprofen (PI) (n=5-8) 4. Group 4: phospho-ibuprofen-amide (PIA) (n=5-8) Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed on day 14. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results Following ligation, the PWT value for sham operated mice (n=5-8) was 1.08±0.08 g, whilst the PWT value for ligated, but vehicle treated mice was 0.58 ±0.03. Therefore, the chronic constriction injury model ensures a significant reduction in PWT compared to sham operated animals, confirming establishment of central sensitization (manifested as allodynia). As expected, the vehicle control has no effect on PTW . However, administration of both modified NSAIDs achieved a significant increase in PWT compared to vehicle. The effect of phospho-ibuprofen-amide (PIA) was particularly remarkable, as significant improvements in PWT were seen as early as day 5 compared to vehicle control (1.43±0.19 g vs 0.58±0.06 g, p<0.0005). In contrast, the parent NSAID ibuprofen did not significantly change PWT compared to vehicle control. The values are provided in Table 8. Table 8 – PWT across the study groups Group PWT, g P value Conclusions The oral administration of these modified NSAID compounds significantly increased the PWT in mice with chronic constriction injury, an established model of PTPN. This was in contrast to the parent compound ibuprofen, which failed to show efficacy in this animal model of neuropathic pain despite being administered in equimolar amounts. The observations are in line with the ability of modified ibuprofen compounds to treat neuropathic pain associated with CIPN upon oral administration, as discussed herein. Therefore, these modified NSAIDs treat established pain associated with PTPN, even when administered orally. In light of further observations herein with distinct modified NSAIDs and distinct models of neuropathic pain, these observations further support the broad applicability of different modified NSAIDs in treating different forms of neuropathic pain. The results seen with phospho-ibuprofen-amide (PIA) were particularly striking and unexpected, with positive results being observed in as few as five days following treatment, and analgesic effect above and beyond the efficacy of orally administered PS in the same model. These observations serve to further demonstrate the potential of orally administered modified NSAIDs in treating different forms of neuropathic pain. The activity is contrary to the established activity of typical NSAIDs, as demonstrated by the absence of PWT change observed with the parent NSAID, ibuprofen. These results, in combination with the observations herein of the accumulation of PS, and other NSAIDs, at central sites of action, point to an unprecedented and surprising broad applicability of modified NSAIDs in treating and preventing pain having central mechanisms (i.e., generated in central sites or due to central sensitization). Example 8: The effect of orally administered modified NSAIDs in treating pain in a mouse model of migraine Oral administration of PS and another modified NSAID was investigated in a mouse model of migraine pain, building on the observations herein demonstrating the broad applicability of PS, and other modified NSAIDs as a centrally acting analgesics for the treatment of challenging pain indications. Methods Adult male C57BL / 6J mice, 8 weeks of age at the beginning of the experiments and weighing 20–30 g, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were housed in an AAALAC-accredited facility in groups of four. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 am to 7:00 pm) and animals were euthanized with CO2asphyxiation. The mice in each cage were randomly allocated to treatment groups. All studies were conducted by experimenters blinded to the identity of the treatment groups. Studies were approved by the Institutional Animal Care and Use Committee of Stony Brook University and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al, 2010). An NTG-induced migraine mouse model similar to that described in Bates et al, 2010 was used. Specifically, instead of the intraperitoneal injection of NTG, a finely crushed 0.4 mg NTG tablet (Greenstone Brand) was administered sublingually. As a control, a Practi-Nitroglycerin Sublingual 0.4 mg Simulated Medication tablet was used. The mechanical nociceptive threshold was reduced as early as 30 minutes post NTG administration and persisted for about 24 hours. The ability of NTG to trigger central sensitization, manifested as allodynia, renders this model applicable for both migraine and other pain disorders associated with central sensitization more generally. PS, its parent compound, sulindac, and phosphonaproxen (Formula VIII), and its parent compound, naproxen, were administered orally to each mouse group. All compounds were admininstered at equimolar doses. In particular, PS was administered at 50 mg / kg, sulindac was administered at 33 mg / kg, phosphonaproxen was administered at 65 mg / kg, and naproxen was administered at 35 mg / kg, 30 minutes after NTG administration. The response of mechanical allodynia was tested 30 minutes after administration. Mechanical allodynia was determined for all mice study groups below: 1. Group 1: baseline (i.e, no NTG treatment, n=6) 2. Group 2: vehicle (n=6) 3. Group 3: PS (n=6) 4. Group 4: sulindac (n=6) 5. Group 5: phosphonaproxen (n=6) 6. Group 6: naproxen (n=6) Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed 30 minutes after compound administration. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results Initially, we confirmed the NTG model of migraine followed by an assessment of the effect of modified NSAIDs, and their parent compounds, in treating migraine pain. In the first study, we used 6 separate groups of mice, 3 for the 30 min time point and 3 for the 60 minute time point, as determination of mechanical allodynia on the same animals within 30 minutes may affect the results. As shown in the table below, the administration of NTG generates allodynia within 30 minutes of NTG administration, in line with the understanding that this compound rapidly triggers neuronal activity corresponding to central sensitization. For completeness, the oral NTG placebo control had no effect on PWT compared to baseline (i.e., did not generate allodynia) (see Table 9A). Table 9A – Confirmation of NTG model Group PWT, g PWT, g P value 30 min 60 min e to baseline values measured prior to the induction of migraine (i.e., sublingual administration of NTG establishes allodynia that is not reversed by administration of vehicle). These results are consistent with the induction of migraine in line with the observations above regarding NTG and its corresponding placebo. Oral administration of PS achieved a significant increase in PWT compared to vehicle (p < 0.002). Oral administration of sulindac did not significantly increase PWT compared to vehicle. The values are provided in Table 9B. Table 9B – PWT in the study groups. Group PWT, g P value n=6 / group Mean ± SEM Conclu Similar to observat ons n c a eng ng neuropat c pa n mode s ere n, t e ora adm n stration of PS, and another modified NSAID, resulted in a significant increase in PWT in a mouse model of migraine compared to vehicle control. In contrast, the oral administration of the parent compounds, sulindac or naproxen, had no significant effect. Critically, the pain generated in this model, exploiting the activity of NTG, corresponds to that occurring during central sensitization, implicating a central site of action of these compounds, potentially acting directly on neuronal signalling. Therefore, these results demonstrate a distinct mechanism of action of PS (and likely other modified NSAIDs) compared to its parent compound rendering it suitable for treatment of migraine pain, and indeed other complex pain indications having central pain mechanisms. These positive results affirm data herein that indicate that modified NSAIDs, for example PS, are not acting as local analgesics, but instead reach central sites of action and achieve significant effects on pain known to be generated at central sites (e.g., via central sensitization). The ability of PS and other modified NSAIDs to act on centrally generated pain even upon oral administration, is particularly surprising, and supported by observations herein that indicate that orally administered PS and other modified NSAIDs reach central sites of pain generation (including the brain). The failure of orally administered sulindac and naproxen to treat pain in this pain model, which generates pain associated with central sensitization, are in line with the understanding that sulindac and naproxen are ineffective in models of centrally generated pain, demonstrating that the mere anti- inflammatory activity of typical NSAIDs is insufficient to resolve the pain signalling in this model. Sulindac and naproxen certainly fail to act as an analgesic against neuronal pain signalling, certainly not on pain signalling generated at central sites of action. On the contrary, and without wishing to be bound by theory, these results, in combination with other results herein, confirm the broad applicability of orally administered PS and other modified NSAIDs, for example phosphonaproxen, as apparent direct acting nerve analgesics, in treating different forms of neuropathic pain and pain having a central site of generation. Indeed, the allodynia associated with NTG administration is due to activation of nerve signalling through the trigeminal nucleus caudalis, confirming the observations herein that the analgesic activity of PS and other modified NSAIDs is distinct from any anti- inflammatory activity, and is more like the direct nerve acting activity of centrally acting agents. Example 9: The effect of topiramate, sumatriptan, propranolol and gabapentin in a mouse model of migraine pain To confirm the clinical applicability of our mouse model of migraine pain, the ability of four compounds – topiramate, sumatriptan, propranolol and gabapentin – to reduce allodynia was tested. These compounds are widely used in the treatment or prophylaxis of pain associated with migraine, and their administration was confirmed to reduce allodynia in this mouse model of migraine pain. Methods In line with the earlier Examples, migraine was induced using 0.4 mg of NTG administered sublingually in the form of a finely crushed 0.4 mg NTG tablet (Greenstone Brand). Mechanical allodynia in response to NTG lasts less than 24 hours. A single intraperitoneal dose of topiramate (30 mg / kg), sumatriptan (600 µg / kg), propranolol (10 mg / kg), gabapentin (30 mg / kg) or vehicle was administered 30 min after the induction of migraine, at the indicated doses. Mechanical allodynia was determined for all mice study groups below (with 5 mice per group): 1. Group 1: baseline (i.e, no NTG treatment) 2. Group 2: vehicle 3. Group 3: topimarate 4. Group 4: sumatriptan 5. Group 5: propanolol 6. Group 6: gabapentin Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed 30 minutes after compound or vehicle control administration. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results As expected, following migraine induction, vehicle-treated mice had lower PWT values compared to baseline values measured prior to the induction of migraine (i.e., sublingual administration of NTG establishes allodynia that is not reverse by administration of vehicle). These results are consistent with the induction of migraine pain. The administration of all four compounds achieved a significant increase in PWT compared to vehicle. The values are provided in Table 10. Table 10 – PWT across the study groups Group PWT, g P value Sumatriptan 1.34 ± 0.12 p<0.0001 vs vehicle Pr n l l 137±014 <00003 v v hi l Con The , , sulted in significant increased in PWT in a mouse model of migraine, compared to vehicle control. These data confirm the clinical applicability of the mouse model for migraine pain. This further supports the conclusions in previous Examples that modified NSAIDs, including PS, are suitable for treating migraine pain, as well as different forms of neuropathic pain and pain having a central site of generation. Notably, these clinical compounds are known to work directly on central neurons through mechanisms that include reducing action potential firing, thereby attenuating pain signalling. As previously noted, a persistently high state of action potential firing is associated with central sensitisation, which is manifested upon NTG administration in this model. Accordingly, the use of modified NSAIDs, including PS, as disclosed in the previous Examples herein achieve analgesic activity similar to that observed for direct nerve acting clinical treatments for migraine pain. These observations further support the hypothesis that modified NSAIDs achieve treatment of pain, for example migraine pain, by direct action on neurons, in particular those involved in generating pain associated with central sensitization. Example 10: The effect of orally administered PS, and failure of sulindac, in treating pain in a mouse model of chronic migraine Building on the observations herein in the mouse model of migraine pain, the analgesic efficacy of orally administered PS was investigated in mice with manifestations of chronic (i.e., on-going) migraine pain. In contrast to the earlier experiments, the pain established in this model is chronic, creating further manifestations of central sensitization, thus generating a more challenging pain model. Methods An NTG-induced chronic migraine model was used (Pradhan et al, 2014) (Moye & Pradhan, 2017). In particular, mice receive sublingual NTG 0.4 mg in the form of a finely crushed 0.4 mg NTG tablet (Greenstone Brand) every two days, receiving a total of five doses. For control mice, an NTG placebo (Practi-Nitroglycerin Sublingual 0.4 mg Simulated Medication tablet) was administered in the same way. The long-term dosing of NTG ensures the effects of central sensitization are generated over a longer period, enabling a consideration of the efficacy of PS in the treatment of pain associated with on-going sensitization from centrally located neurons. As for the migraine pain model considered elsewhere herein, the ability of NTG to trigger central sensitization, manifested as allodynia, renders this model applicable for both migraine and other pain disorders associated with central sensitization more generally. PS and sulindac were administered orally to each mouse. PS was administered at 50 mg / kg and sulindac was administered at 33 mg / kg (equimolar to the PS dose), once a day for 11 days, concurrent with NTG administration. Mechanical allodynia was determined for all mice study groups below: 1. Group 1: placebo NTG (i.e, no NTG treatment, n=8) 2. Group 2: NTG (n=8) 3. Group 3: NTG + vehicle (n=8) 4. Group 4: NTG + PS (n=8) 5. Group 5: NTG + sulindac (n=8) Mechanical allodynia was determined using von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed prior to NTG (or placebo NTG) administration to determine baseline values, as indicated. The PWT test was then subsequently performed 30 minutes after PS, sulindac or vehicle control administration. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results As expected, following administration of NTG, mice had lower PWT values compared to baseline values measured prior to administration (0.66 ± 0.11 g vs 1.95±0.18 g, p<0.0003). These results are consistent with the induction of pain associated with chronic migraine. The placebo NTG did not significantly alter the baseline value. There was no significant different in PWT values for vehicle- treated mice after 11 days compared to NTG-treated mice (i.e., sublingual administration of NTG establishes allodynia that is not reversed by administration of vehicle). Oral administration of PS, however, achieved a significant increase in PWT compared to vehicle (1.18 ± 0.10 g vs 0.58 ± 0.02 g, p<0.0001). In contrast, in line with observations elsewhere herein, oral administration of sulindac did not significantly increase PWT compared to vehicle. The values are provided in Table 11. Table 11 – PWT in the study groups Group PWT, g NTG0.66 ± 0.11 p<0.0003 vs baseline NTG p<0.0001 vs placebo day 11 e Conclu Similar , administration of PS resulted in a significant increase in PWT in a mouse model of chronic migraine compared to vehicle control, in contrast to the oral administration of sulindac which had no significant effect. These striking results confirm the data herein that orally administered PS can treat pain associated with central sensitization manifested in this model of migraine pain. Furthermore, the data demonstrate that orally administered PS can continue to treat pain associated with central sensitization over a long period of sustained pain generation and sensation (i.e., corresponding to pain manifestations in chronic migraine). These observations are particularly striking as continued administration of NTG causes consistent activation of centrally located neurons corresponding to the decoupled neuronal signalling experienced during central sensitization, further supporting a role of PS in acting directly on neuronal signalling generated at central sites, in line with further observations herein. Example 11: The effect of topiramate and sumatriptan in a mouse model of chronic migraine Similar to the short-term migraine pain experiments, to confirm the clinical applicability of the chronic migraine pain model, the ability of topiramate and sumatriptan to reduce allodynia was tested. Methods The NTG-induced chronic migraine model was used as described previously. 12 days following the first dose of NTG, a single intraperitoneal dose of topiramate (30 mg / kg), sumatriptan (600 µg / kg), or vehicle was administered. Mechanical allodynia was determined for all mice study groups below: 1. Group 1: NTG + vehicle (n=8) 2. Group 2: NTG + topiramate (n=8) 3. Group 3: NTG + sumatriptan (n=8) Mechanical allodynia was determined using von Frey filaments in line with that performed in the earlier Examples. The PWT test was performed prior to NTG administration to determine baseline values and also at day 12, prior to compound administration, as indicated. The PWT test was then subsequently performed 30 minutes after topiramate or sumatriptan administration. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results As expected, following administration of NTG, vehicle-treated mice had lower PWT values compared to baseline values measured prior to NTG administration. These results are consistent with the induction of migraine pain. The administration of both topiramate and sumatriptan achieved a significant increase in PWT compared to vehicle. The values are provided in Table 12. Table 12 – PWT in the study groups Group PWT, g Mean ± SEM P value e n Conclu Similar to the observations in the model of short-term migraine pain, the administration of topiramate and sumatriptan, compounds known to be effective in treating migraine pain likely via direct action of neuronal signalling, resulted in significant increase in PWT, compared to vehicle control, in this chronic migraine pain model. These data therefore confirm the clinical applicability of the long-term NTG administration model for determining the therapeutic potential of compounds in treating chronic migraine pain. Example 12: Pharmacokinetics and biodistribution of modified NSAIDs upon oral administration The Examples herein demonstrate a broad applicability of PS and other modified NSAIDs as analgesic compounds with direct nerve acting activity, even at central sites of action, even upon oral administration. The surprising observations of the analgesic activity of orally administered modified NSAIDs, in particular PS, in a range of particularly challenging animal models of pain associated with central neuronal activity, led to a consideration of the potential site of action of the orally administered modified NSAIDs. To the inventor’s surprise, orally administered modified NSAIDs (e.g., PS, phosphonaproxen (PN, formula VIII) and phosphosulindac amide (PSA, formula X)) are seen to accumulate in therapeutically relevant amounts in the pain sensing centres of the brain, further pointing to a direct analgesic activity of these modified NSAIDs on centrally located pain generating neurons. Methods Dosing and tissue harvesting A single dose of PS, PN or PSA was given by oral gavage to groups of three Sprague-Dawley rats, each weighing 200-300 g (Charles River Labs, Wilmington, MA), which were euthanized at the following time points via CO2 inhalation: for PS: at 0.5, 1, 3 and 6 h post-dose; for PN at 0.5, 1, 3, 6 and 24 h post-dose; and for PSA at 3 h post-dose. PS was dissolved in 10% ethanol and then suspended in corn oil. The oral gavage solution of phosphonaproxen was prepared by dissolving in 10% DMSO and then suspending it in corn oil. Phosphosulindac amide was dissolved in 10% ethanol and then suspended in corn oil. Approximately 800 µL of blood were collected through cardiac puncture and immediately centrifuged. Tissue samples were harvested using separate dissection instruments for each tissue sample to avoid cross contamination, and snap frozen. The levels of the test drug were determined by HPLC. To determine the levels of PS, PN or PSA in the wall of the stomach and duodenum, we harvested these two organs in toto last and after washing away their contents with PBS, three times and with 10% DMSO in PBS twice to remove gastric contents and residual PS that might be adsorbed onto the gastroduodenal mucosa. Control experiments revealed that a 10% solution of DMSO did not damage the mucosa and removed quantitatively any adherent PS following its oral administration. As previously described (Wen et al, 2019), each plasma sample was mixed with double volume of acetonitrile and centrifuged at 13,200 rpm for 15 min. Tissue samples were weighed, ddH2O (100- 300 µL, depending on tissue weight) was added, and they were homogenized. Following addition of acetonitrile (twice the volume of the homogenate), the mixture was sonicated for 10 min, centrifuged at 13,200 rpm for 15 min, and analyzed by HPLC, as reported (Wen et al, 2019). The lower limit of quantitation is 0.1 μM for PS and 0.05 μM for sulindac, sulindac sulfone, sulindac sulfide and their glucuronidated derivatives. HPLC analysis It was performed following a previously reported method (Xie et al, 2012). Briefly, the HPLC system consisted of a Waters Alliance 2695 Separations Module (Milford, MA, USA) equipped with a Waters 2998 photodiode array detector (328 nm) and a Thermo Hypersil BDS C18 column (150 × 4.6 mm, particle size 3 µm). The mobile phase consisted of a gradient between solvent A (formic acid, CH3CN, H2O (0.1:4.9:95 v / v / v)) and solvent B (CH3CN) at a flow rate of 1 mL·min−1 at 30°C. We applied gradient elution from 30 to 100% solvent B from 0–6 min, and it was maintained at 100% solvent B until 8 min. Results As foreshadowed above, the possibility that PS may reach the brain following oral administration was assessed. PS was administered to rats once orally and levels were determined in the stomach wall, the vagus nerve (the anterior and posterior trunks that innervate the stomach), the medulla (medulla oblongata, where the vagus originates), and the cerebellum. The medulla includes multiple nuclei and tracts that play a critical role in transmitting signals between the spinal cord and the higher parts of the brain, for example those involved in the sensation of pain. The vagus nerve has four nuclei in the medulla. The cerebellum lies posterior and partially superior to the medulla. All these tissues therefore represent an uninterrupted anatomical continuum. As shown in Table 13, after the oral administration of PS (250 mg / kg), PS was detected in the gastric wall, the vagus nerve, the medulla and the cerebellum. No PS was detected in the systemic circulation, as expected (Xie et al, 2012). The concentration of PS progressively decreased from the stomach to the cerebellum, evidenced by the respective values of Cmax(from 661.0 ± 6.5 µM to 0.3 ± 0.07 µM). The Tmaxof PS was the same in all tissues (0.5 h), suggesting the transportation of PS to the CNS, via the vagus nerve, is rapid, as predicted from further observations herein. These data establish that that orally administered PS reaches the CNS from the stomach, and that its transportation to the CNS occurs via the vagus nerve and not through the circulation. This notion is supported by the progressive decrease of the Cmaxand AUC0-24hvalues of PS from the gastric wall to the cerebellum, and the absence of detectable levels of PS in the blood. Table 13 – PK parameters of PS in rat tissues and peripheral blood Tissue Cmax,µMTmax, h T1 / 2, hAUC0-24h, µM⋅h Following the surprising PK observations with PS, the pharmacokinetics of orally administered phosphonaproxen were assessed. PN is hydrolyzed by carboxylesterases about 5 times slower than PS and thus can reach the circulation. As shown in Table 14, after a single oral dose of PN (95 mg / kg), it was detected in the stomach wall, the vagus nerve, medulla, cerebellum, and blood. The concentration of PN progressively decreased from the stomach to the cerebellum, evidenced by the respective values of Cmax. The Tmax of PN in different tissues suggests its accumulation in the CNS is rapid, as predicted from further observations herein. These data establish that that orally administered PN likely reaches the CNS from the stomach, and that its transportation to the CNS occurs via the vagus nerve and not through the circulation. This notion is supported by the progressive decrease of the Cmax and AUC0-24h values of PN from the gastric wall to the cerebellum. Table 14 – PK parameters of PN in rat tissues and peripheral blood Tissue Cmax, µM Tmax, h T1 / 2, h AUC0-24h, Mean ± SEM µM⋅h The pharmacokinetics of orally administered phosphosulindac amide were also assessed. We evaluated the levels of phosphosulindac amide at a single time point, 3 hours after its oral administration (100 mg / kg). At 3 hours, PSA was present in the stomach wall, the vagus nerve, medulla, cerebellum, but not blood. The values are provided in Table 15. The concentration of PSA progressively decreased from the stomach to the cerebellum, evidenced by the respective concentrations. These data establish that that orally administered PSA likely reaches the CNS from the stomach, and that its transportation to the CNS occurs via the vagus nerve and not through the circulation.

[0007] Table 15 – Concentration of PSA in rat tissues and peripheral blood Tissue PSA, µM St h 158 Conclusions In line with obser va ons o e ana ges c ac v y o ora y a m n s ere , an indeed other modified NSAIDs, the present Example confirms that modified NSAIDs are able to accumulate in central sites of action, where they may be exerting direct analgesic activity on pain generating nerves, even upon oral administration. PS is seen preferentially binding to the stomach lining, where it is taken up by neurons connecting to the vagus nerve. The PS then traverses along the vagus nerve towards the brain, where it is found in therapeutically relevant amounts in the medulla and cerebellum. The data herein, as well as the absence of PS in detectable levels in the blood, confirms that PS must be reaching distal sites of action via translocation along neurons. This unprecedented mechanism of action further explains how PS and other modified NSAIDs achieve striking analgesic effects in multiple challenging animal models of neuropathic pain and pain associated with central sensitization, even when orally administered. Without wishing to be bound by theory, the experiments confirm that PS and other modified NSAIDs represent broadly applicable pain therapies with direct analgesic effects on neuronal pain signalling, even at sites of pain generation and sensation in the brain. As outlined elsewhere herein, the analgesic effects of PS and other modified NSAIDs are distinct to any anti-inflammatory activity linked to the parent compounds; indeed, the centrally generated pain signalling, for example in the NTG migraine model, is a consequence of pathological nerve activity (e.g., due to central sensitization), rather than inflammation. Example 13: Comments on observations of orally administered modified NSAIDs The data herein demonstrate the striking efficacy of orally administered modified NSAIDs in the treatment of a range of challenging pain indications, in particular neuropathic pain and pain associated with central sensitization. Phosphosulindac is remarkably effective, upon oral administration, in treating neuropathic pain associated with CIPN, neuropathic pain associated with PTPN, and migraine pain. Further surprisingly, but in line with these observations, other modified sulindac compounds are effective in treating neuropathic pain associated with CIPN upon oral administration. Furthermore, other modified NSAIDs are effective in the treatment of these indications upon oral administration in animal models where central sensitization (manifested as allodynia) has been established. These observations are surprising, as explained further below, but are consistent with data in WO2022 / 251805 and WO2022 / 251806 (both hereby incorporated by reference in their entirety), where topically administered PS is shown to have a direct analgesic effect on two distinct types of neuropathic pain (i.e., associated with CIPN and DPN), and with the data in WO2024 / 112725 and WO2024 / 112727, where topically administered PS and other modified NSAIDs are effective in the treatment of a variety of neuropathic pain indications (pain associated with PTPN, pain associated with PHN, as well as migraine pain and corneal neuropathic pain) and on pain associated with central sensitization. The observations herein demonstrate an analgesic activity of modified NSAIDs that distinguishes them from their parent compounds, typical NSAIDs having anti-inflammatory activity. Indeed, the parent compounds studied in the Examples herein failed to achieve analgesic effects in the challenging pain indications studied. This corresponds to the established view that typical NSAIDs are known not to be effective in the treatment of neuropathic pain (Moore et al. Cochrane Database of Systematic Reviews (2015); 10: 1–25). Without wishing to be bound by theory, the reason for the absence of any response to typical NSAIDs in the prior art is likely that the pain is caused by neuropathic nerve damage or activity of central neurons, rather than by inflammation (i.e., any anti- inflammatory activity of typical NSAIDs, e.g., via COX-1 and COX-2 inhibition, is not sufficient to prevent or treat the neuropathic pain). Any alleged analgesic activity of NSAIDs observed in the prior art is a reflection of their anti-inflammatory activity (i.e., stopping potential triggers causing the pain) rather than an actual analgesic activity directed towards nerve signalling (i.e., that would result in a reduction in pain caused by nerve damage and sensitization). Accordingly, the analgesic activity of PS upon oral administration observed herein is a reflection of a property imparted by its modification (enabling direct analgesic activity on pain signalling neurons at central sites of action), and the observations herein suggest the same is true of other modified NSAIDs (i.e., the modifications impart properties that are unique and not shared by their typical NSAID parent compounds). Indeed, for example PS unlike its parent compound, the NSAID sulindac, does not inhibit COX-1 and COX-2 expression or prostaglandin synthesis, and so is not a typical NSAID. The observations of the activity of PS in the treatment of neuropathic pain associated with CIPN and DPN do not suggest an activity of other modified NSAIDs in treating these indications, or an activity of PS or other modified NSAIDs in treating other challenging neuropathic pain indications, not least given the failure of typical NSAIDs to treat such indications. As noted above, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, generally associated with central sensitization, and ketorolac has been shown to have limited analgesic activity in models of such pain. Accordingly, the anti-inflammatory activity alone of typical NSAIDs is considered not sufficient for challenging pain indications. For example, certain typical NSAIDs (e.g., naproxen) have been shown to be not clinically useful as analgesics for migraine, while others (e.g., ketorolac), are ineffective analgesics in treating neuropathic pain associated with PTPN. Furthermore, loxoprofen sodium is ineffective in reducing pain signalling in paclitaxel induced CIPN. Accordingly, specific animal models are important during the development of therapies for treating neuropathic pain and pain associated with central sensitization. Indeed, given the pathogenesis of such pain, involving alterations in the sensitivity of centrally located neurons, observations of efficacy of a particular compound, for example, in an acute pain model, for example of inflammatory pain, cannot indicate the utility of that compound in treating pain associated with central sites of action, for example pain associated with central sensitization or neuropathic pain. Therefore, the efficacy of modified NSAIDs, certainly an orally administered modified NSAID, in treating pain associated with central sites of action, for example central sensitization, is demonstrated only by observations indicating the ability of the compound to reverse manifestations of central sensitization (e.g., allodynia) in a model system in which chronic pain has been established. Indeed, a demonstration of efficacy of the specific compound in a model of the specific neuropathic pain indication is typically required. Accordingly, the animal models used in early testing before further clinical development are crucial. Therefore, any observations in the art of typical NSAIDs or other modified NSAIDs in corresponding pain indications fail to suggest a role of the modified NSAIDs herein in treating that pain indication. Furthermore, observations in the art of the modified NSAIDs herein in distinct neuropathic pain indications fail to suggest a role of the modified NSAIDs herein in treating the challenging neuropathic pain indications associated with central sites of generation (i.e., distinct to peripheral inflammatory responses), for example pain associated with central sensitization or neuropathic pain and migraine pain disclosed herein, certainly not upon oral administration. On the contrary, the observations herein demonstrate an unprecedented activity of PS and other modified NSAIDs in reducing pain generated at central sites of action, for example that involved in neuropathic pain and pain associated with central sensitization, similar to the activity of established centrally acting or direct nerve acting analgesics. Based on the specific animal models of pain generated via sensitization of central neurons (e.g., allodynia), the observations herein demonstrate an unprecedented efficacy of orally administered modified NSAIDs in the treatment and / or prevention of pain with a central site of generation, for example pain associated with central sensitization and the pain indications disclosed herein. Indeed, the migraine model exploited herein (i.e., NTG administration) is known to establish central sensitization, a clinical feature of migraine – activity in this model demonstrates an activity on the mechanisms involved in central sensitization. The efficacy in treating pain with a central site of action in the animal models herein, even upon oral administration, is in part explained by the surprising ability of modified NSAIDs to accumulate in the CNS, in particular in regions of the brain implicated in pain signalling. These are unprecedented observations with respect to the ability of orally administered modified NSAIDs to directly impact neuronal pain signalling at central sites of action. Given the limited stability of PS and other modified NSAIDs in the blood, and the observations herein, the inventor has demonstrated, for the first time, that these compounds traverse along the vagus nerve from the stomach to the brain. The ability of modified NSAIDs, for example PS, to access central regions of the CNS, in particular regions of the brain implicated in pain signalling, explains the activity of these compounds in a broad range of distinct challenging pain indications, each associated with neuropathic pain and / or central sensitization – that is, the PS or other modified NSAIDs can reach key sites of action in sufficient concentrations such that they can impart their previously unappreciated analgesic activity directly on neuronal signalling involved in pain sensation, even when administered orally. Therefore, given the wealth of data generated by the inventor (see the observations in WO2024 / 112725 and WO2024 / 112727), with multiple different NSAIDs and multiple different animal models of neuropathic pain, along with observations that orally administered modifed NSAIDs accumulate in regions of the brain implicated in pain signalling, the inventor appreciates, for the first time, the broad applicability of these compounds in treating neuropathic pain and pain associated with central sensitization. That is, in light of the observations of a direct activity on neuronal signalling in multiple distinct pain models, as provided by the inventor herein, the need for data in specific animal models for each indication is less critical – the analgesic activity of orally administered modified NSAIDs at central sites of action represents a unifying mechanism enabling the treatment of pain indications having a central site of action. Previous observations of topically administered PS in the treatment of neuropathic pain associated with CIPN and DPN fail to demonstrate the efficacy of orally administered PS in treating these indications, let alone the further challenging pain indications disclosed herein. With topical administration, PS is administered to areas with a high concentration of sensory neurons in the periphery, permitting its uptake and movement to central sites of action in high enough quantities to achieve an analgesic effect. Upon oral administration, PS is exposed to gut endothelial surfaces distinct to those of the skin epithelium exposed to PS upon topical administration, in terms of environment, structure and neuronal physiology and concentration. PS, like other modified NSAIDs, is unstable in the blood (as shown herein). Therefore, oral administration would typically not be appropriate given the potential for the active compound to be destroyed either in the gut environment or in the bloodstream after absorption, and administering the concentrations of modified NSAID required to overcome these issues would have been considered to be inappropriate. Accordingly, it could not have been predicted that oral administration of PS would also achieve an analgesic effect for indications known to have a central site of pain generation, as shown herein. Indeed, as noted above, typical NSAIDs have been shown to be ineffective in the treatment of neuropathic pain, irrespective of route of administration. Contrary to these considerations, the observations herein demonstrate that upon oral administration, PS is found in therapeutically relevant amounts in regions of the brain implicated in pain signalling (e.g., the medulla and cerebellum). Evidence herein demonstrates that PS is preferentially taken up by the neurons innervating the stomach lining and traverses along the vagus nerve to reach central sites in the brain in therapeutically relevant concentrations. These observations are supported by observations that the amount of PS is shown to incrementally decrease as the tissues investigated approach the brain, and the absence of therapeutic levels of PS in the blood. Therefore, without wishing to be bound by theory, orally administered PS can impart its direct analgesic effects on the neurons within the centrally located regions of the brain implicated in pain signalling by traversing from the stomach to the brain along the vagus nerve. This provides an unprecedented and elegant mechanism by which centrally generated pain can be resolved by orally administered PS irrespective of its original aetiology. Indeed, orally administered PS demonstrated improved analgesic activity in the PTPN model herein compared to topically administered PS in the same model system. Similarly, orally administered phospho-ibuprofen showed improved analgesic activity in the CIPN model herein compared to topically administered phospho-ibuprofen in the same model. The same rationale applies for other orally administered modified NSAIDs. Indeed, the data herein demonstrate the efficacy of modified NSAIDs in a range of pain models associated with central sites of action, and modified NSAIDs beyond PS are shown to accumulate in regions of the brain implicated in pain signalling upon oral administration. Therefore, the observations herein indicate that the modification of NSAIDs imparts in them not only an analgesic activity directly on pain sensing neurons (distinct to the anti-inflammatory activity of typical NSAIDs), but also an ability to effectively traverse neurons and accumulate in therapeutically relevant amounts in central sites of action, for example the pain sensing regions of the brain. Accordingly, without wishing to be bound by theory, the observations herein suggest it may be possible to overcome evident failings of NSAIDs in the treatment of challenging pain indications by modifying the NSAIDs such that they may act directly on neuronal signalling and more readily access key sites of action, even upon oral administration, enabling the modified version to impart its analgesic activity on nerve signalling even more effectively. Therefore, these observations indicate a likely broad applicability of orally administered modified NSAIDs in the treatment of challenging neuropathic pain disorders and pain associated with central sensitization. Beyond the data herein, this broad applicability is supported by the striking activity of topically administered modified NSAIDs in a range of challenging animal models of pain – an activity not shared by typical NSAIDs (see the observations disclosed in WO2024 / 112725 and WO2024 / 112727). Example 14: Increased gastric retention enhances the efficacy of PS in a mouse model of neuropathic pain associated with CIPN As explained above, PS preferentially binds the stomach lining and traverses through the vagus nerve towards the brain, where it is found in therapeutically relevant amounts, for example in the pain sensing regions of the brain, such as the medulla and cerebellum. In this Example, the inventor investigated whether increasing the residence time of PS in the stomach might improve its bioavailability at the key therapeutic sites of action in the brain. Strikingly, increasing retention of PS in the stomach results in significantly improved analgesia in a mouse model of neuropathic pain associated with CIPN. Similar observations are seen with PI. Methods CIPN was induced in adult male C57BL / 6J mice, with paclitaxel, as previously detailed in earlier Examples. The dosing regimen of paclitaxel generates neuropathic pain associated with CIPN with time courses that are similar to those of neuropathic pain after paclitaxel administration in cancer patients. PS was given by oral galvage, three times a day for 10 days at a dose of 50 mg / kg. Sulindac and phospho-ibuprofen (PI) were given by oral gavage, three times a day for 7 days at a dose of 33 mg / kg, and 80 mg / kg, respectively, with sulindac equimolar to PS. EnsurePlus® was used in this study as a means of delaying gastric emptying, thus acting as a gastro-retentive agent (Solnes et al., (2019) Clin Nucl Med; 44(6):459-461). 200 µL of EnsurePlus® high-protein shake was given by gastric lavage five minutes before the administration of approximately 100 µL of the respective drug, with minor adjustments in volume depending on animal weight. Mechanical allodynia was determined for all CIPN mice study groups: 1. Group 1: vehicle (8 mice) 2. Group 2: PS (8 mice) 3. Group 3: PS plus EnsurePlus® (8 mice) 4. Group 4: sulindac (7 mice) 5. Group 5: sulindac plus EnsurePlus® (7 mice) 6. Group 6: PI (7 mice) 7. Group 7: PI plus EnsurePlus® (7 mice) Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The response of mechanical allodynia to these compounds was tested on days 0 (before the first treatment), 7, and 10, via the PWT test. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results The PWT values for each treatment group are reported in Table 16 and Figures 1-4. As supported by the observations in Examples 1 and 2, the oral administration of PS and PI results in a significant increase of PWT values (p<0.005 and p<0.001 vs vehicle, respectively), whereas the oral administration of sulindac has no significant effect on PWT values and thus fails to treat neuropathic pain associated with CIPN. The efficacy of oral administration of PS and PI in treating neuropathic pain associated with CIPN was significantly increased when the mice were pre-treated with EnsurePlus®, which induces gastric retention, as opposed to when the mice did not receive any pre-treatment (p<0.024 and p<0.030 vs no pre-treatment, and Figures 1 and 2, respectively; see also Figure 4). In contrast, sulindac had no effect in alleviating mechanical allodynia, regardless of whether the mice were pre-treated with EnsurePlus® or not (Figure 3). Table 16 – PWT in the study groups Group PWT, g P value Sulindac plus EnsurePlus® 0.60 ± 0.15 p<0.852 vs Vehicle plus EnsurePlus® p<0.659 vs Sulindac e o se a o s e e e o s a e a e a g e s o ac o o ge pe o s esu s a significant increase in the efficacy of PS in treating neuropathic pain associated with CIPN. These results are surprising, but are consistent with the inventor’s observations herein that orally administered PS accumulates at central sites of action, for example the pain sensing regions of the brain, by traversing along the vagus nerve from the stomach to the brain. Without wishing to be bound by theory, in retaining orally administered PS in the stomach for longer periods, the inventor was able to increase the concentration of PS at key sites of action in the brain, by exploiting the ability of PS to traverse along the vagus nerve from the stomach to the brain. Therefore, the inventor has demonstrated further therapeutic utility of PS, in combination with a gastro-retentive agent, in treating pain with a central site of action, for example neuropathic pain or pain associated with central sensitization. Furthermore, the inventor has demonstrated similar observations with a further modified NSAID, PI, establishing gastric retention as a therapeutic strategy for improving the surprising analgesic activity of modified NSAIDs in the treatment of challenging pain indications, in particular those having a central site of action, for example neuropathic pain and pain associated with central sensitization. As expected, sulindac failed treat neuropathic pain associated with CIPN, even upon retention in the stomach. Example 15: Increased gastric retention enhances the efficacy of PS in a mouse model of neuropathic pain associated with CIPN Further to the data in Example 14, the effect of gastric retention on the efficacy of PS in a mouse model of neuropathic pain associated with CIPN was assessed using extra virgin olive oil (EVOO) as a gastro-retentive agent (see Example 16). Methods CIPN was induced in adult male C57BL / 6J mice, with paclitaxel, as previously detailed in earlier Examples. After the establishment of neuropathic pain associated with CIPN (indicated by a reduction in paw withdrawal threshold occurring after the full course of 4 doses of paclitaxel over 7 days), mice were treated three times a day for 4 days with PS (50 mg / kg), administered by oral gavage, 5 minutes after the administration of 0.2 ml of EVOO, EnsurePlus® (as positive control), or water (i.e., as a volume control). EVOO consists of a saponifiable fraction (98%–99%; mainly triglycerides and polyunsaturated fats), and an unsaponifiable fraction (1%–2%; mainly tocopherols and polyphenols). EVOO delays gastric emptying (Bozzetto, L. et al. (2019) Clin Nutr; 38:2645-51). EnsurePlus® (237 mL or 8 oz) has 350 calories, 20 g of protein, 13 g of fat, and 40 g of carbohydrate, and delays gastric emptying as described herein. Mechanical allodynia was determined for all CIPN mice study groups (n = 7-8 / group): 1. Group 1: PS plus water 2. Group 2: PS plus EnsurePlus® 3. Group 3: PS plus EVOO Mechanical allodynia was determined using the method of von Frey filaments in line with that performed in the earlier Examples. The response of mechanical allodynia to these compounds was tested on days 0 (before the first treatment, to determine the CIPN baseline), and day 4 via the PWT test. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal reacted. Results The PWT values for each treatment group are reported in Table 17. Table 17 – PWT in the study groups Groups PWT, g P value The observations herein further confirm that retaining PS in the stomach for longer periods results in a significant increase in the efficacy of PS in treating neuropathic pain associated with CIPN (as demonstrated by an increase in paw withdrawal threshold, indicative of a reduction in mechanical allodynia). Furthermore, the results demonstrate that the use of EVOO as a gastro-retentive agent provides significantly enhanced therapeutic effects compared to EnsurePlus®. This corresponds with the improved ability of EVOO to delay gastric emptying compared to EnsurePlus® as demonstrated in Example 16. Therefore, a range of gastro-retentive agents can be used to retain PS in the stomach and ultimately achieve its therapeutic effect (due to its increased accumulation at key sites of action in the pain sensing regions of the brain). This confirms the broad applicability of PS within gastro- retentive compositions or combinations for oral administration for the treatment of pain with a central site of action, for example neuropathic pain or pain associated with central sensitization. Example 16: Determination of gastric volume in mice after administration of EnsurePlus® or EVOO using MRI The following example confirms the gastro-retentive activity of EnsurePlus® and EVOO using magnetic resonance imaging (MRI) (as described in Chavero-Pieres, M. et al., (2023) Neurogastroenterol Motil; 35:e14490). Methods Adult male C57BL / 6J mice, housed in cages without bedding, were fasted overnight but with free access to water. Mice were single housed in fresh cages 2 hours before MRI scanning. Any fecal pellets deposited prior to the scanning period were removed. Mice were given 0.2 ml of EVOO or EnsurePlus® or water (as a volume control). Five minutes later, they were fed a standardized meal containing 0.20±0.01 g of scrambled high fat diet; all diet leftovers were removed 5 minutes later. MRI scans were obtained 2 hours after meal digestion under isoflurane anesthesia. MRI images were acquired using a Bruker 7.0T Biospec small animal scanner (Bruker BioSpin) with a horizontal bore of 20 cm and equipped with actively shielded gradients (600 mT / m). All images were processed using the Paravision 6.0 software (Bruker BioSpin) and were converted to DICOM for further analysis in a freely available Mango software. Results The gastric volume of mice after administration of water, EnsurePlus® and EVOO is shown in Table 18. Table 18 – Gastric volume measured by MRI Groups Gastric volume, mm3P value S The results confirm that EnsurePlus® and EVOO significantly increase gastric volume compared to mice that received no additional intake or those that received only water. In line with the observations above regarding the improved treatment of neuropathic pain associated with CIPN, EVOO showed the greatest increase in gastric volume. These results confirm that the improved efficacy of PS observed with these agents is a consequence of these agents retaining PS in the stomach for longer periods, enabling an increased uptake of PS to the stomach lining and ultimately to the pain sensing regions of the brain via the vagus nerve. Example 17: Increased gastric retention enhances the efficacy of PS in a mouse model of migraine pain The following example demonstrates the broad applicability of gastric retention of orally administered PS in treating pain generated at central sites of action in a mouse model of migraine pain. Methods An NTG-induced migraine mouse model was used as reported in Example 8 herein. Briefly, a crushed 0.4 mg NTG tablet (Greenstone Brand) was administered sublingually. The resulting mechanical allodynia lasts less than 24 hours. After establishment of allodynia, mice were treated orally once with PS (50 mg / kg dissolved in 10% ethanol and suspended in corn oil) or vehicle (a solution of 10% ethanol with corn oil), with or without a gastric retention agent (e.g., EnsurePlus® as described in Example 15). The gastric retention agent was administered 5 minutes before PS or vehicle. As a control for the NTG administration (NTG placebo), a Practi-Nitroglycerin Sublingual 0.4 mg Simulated Medication tablet was used. Mechanical allodynia was evaluated after 30 minutes of treatment for all mice study groups below (n = 5-6 / group): 1. Group 1: NTG alone 2. Group 2: NTG plus vehicle 3. Group 3: NTG plus PS (50 mg / kg) 4. Group 4: NTG plus vehicle plus EnsurePlus® 5. Group 5: NTG plus PS (50 mg / kg) plus EnsurePlus® Results The effect of EnsurePlus on the efficacy of PS against migraine pain was examined. Studies reported herein demonstrate that orally administered PS treats migraine pain (manifested as mechanical allodynia). The results are summarized in Table 19 and Figure 5. As can be seen, the paw withdrawal threshold was assessed before and after NTG administration. For completeness, the baseline paw withdrawal threshold of untreated animals remained consistent (not significantly different) across the timeframe of the experiment between “before NTG” and “after NTG” (1.78±0.16 and 1.82±0.12, respectively). Similarly, as expected, the paw withdrawal threshold did not significantly change before and after administration of the NTG placebo (1.96±0.21 and 1.82±0.12, respectively) and was not significantly different compared to the baseline. However, as shown in the table, and corresponding figure, administration of NTG led to a significant reduction in paw withdrawal threshold that was not resolved by treatment with the PS vehicle control. In line with the observations herein, oral administration of PS lead to a significant increase in paw withdrawal threshold compared to the vehicle control. Furthermore, retaining orally administered PS in the stomach for longer periods, using EnsurePlus® (see Example 16) achieved a further significant increase in paw withdrawal threshold compared to administration of PS alone, an observation which was not a consequence of administration of EnsurePlus® (see vehicle plus EnsurePlus® group in the NTG background, which failed to increase paw withdrawal threshold compared to vehicle alone). These results are also presented in Figure 5, with the astericks corresponding to the significance values provided in Table 19 below. Table 19 – The effect of EnsurePlus® on the efficacy of PS in migraine pain Groups PWT, g P value n=5-6 / rou Mean ± SEM 1 r Further to the results herein demonstrating the efficacy of orally administered PS in the treatment of migraine pain, these observations confirm that retaining PS in the stomach for longer periods results in a significant increase in the efficacy of PS in treating pain with a central site of action in migraine (as demonstrated by an increase in paw withdrawal threshold, indicative of a reduction in mechanical allodynia). These observations confirm the finding that PS is able to treat pain generated at central sites of action (including that associated with central sensitization) even after oral administration. The results further support the view that PS is effective in the treatment of pain generated at central sites (e.g., migraine pain or pain associated with central sensitization) given its ability to accumulate at key central sites of action, for example in the pain sensing regions of the brain, via translocation along the vagus nerve. Indeed, retaining PS in the stomach for longer periods provides improved analgesic effects likely due to an increase in therapeutically relevant concentrations of PS at central sites of action, for example within the pain sensing regions of the brain, as more PS is available to be taken up by the vagus nerve. Example 18: Increased gastric retention enhances the efficacy of PS in a mouse model of migraine pain The following example further demonstrates the broad applicability of gastric retention of orally administered PS in treating pain generated at central sites of action in a mouse model of migraine pain. Methods Migraine pain was induced using the NTG model described in earlier Examples. After establishment of allodynia, mice were treated orally once with PS (50 mg / kg dissolved in 10% ethanol and suspended in corn oil) or vehicle (a solution of 10% ethanol with corn oil), administered 5 minutes after administration of 0.2 ml of EVOO (as described in Example 15), EnsurePlus® (as a positive control described in Example 15) or water (i.e., as a volume control). Mechanical allodynia was evaluated after 30 minutes of treatment for all mice study groups below (n = 6 / group): 1. Group 1: baseline 2. Group 2: NTG alone 3. Group 3: NTG plus vehicle 4. Group 4: NTG plus PS (50 mg / kg) 5. Group 5: NTG plus PS (50 mg / kg) plus EnsurePlus® 6. Group 6: NTG plus PS (50 mg / kg) plus EVOO Results The effect of a further gastric retention composition (EVOO) on the efficacy of PS against migraine pain was examined and compared with results observed for EnsurePlus®. Studies reported herein demonstrate that EVOO improves gastric retention in mice and enhances the therapeutic efficacy of PS in models of neuropathic pain associated with PTPN, indicating the broad applicability of PS in combination with gastro-retentive agents. The results in a further model of pain associated with a central site of action are summarized in Table 20. As shown in the table, the use of NTG significantly reduces paw withdrawal threshold compared to baseline. This reduction is not resolved by administration of vehicle, but is significantly increased upon oral administration of PS. This value remains similar when PS administration follows administration of water (which is not a gastro-retentive agent) but is further improved when PS administration follows administration of EnsurePlus® and EVOO (both gastro-retentive agents). Although not significantly different, pre-adminsitration of EVOO showed a further increase in paw withdrawal threshold compared to EnsurePlus®, corresponding with observations herein that EVOO is an improved gastro-retentive agent compared to EnsurePlus® (see Example 16). Table 20 – The effect of EnsurePlus® and EVOO on the efficacy of PS in migraine pain Groups PWT, g P l vs. EnsurePlus, NS Conclusions gastro-retentive agents) results in a significant increase in the efficacy of PS in treating pain with a central site of action, for example migraine pain. Therefore, as noted in earlier Examples, a range of gastro-retentive agents can be used to retain PS in the stomach and ultimately improve its therapeutic efficacy (due to its increased accumulation at central sites of pain generation and sensing, for example the pain sensing regions of the brain). Furthermore, in light of observations of the improved efficacy of PS upon its retention in the stomach in a range of animal models of pain associated with a central site of action (e.g., neuropathic pain associated with PTPN and migraine pain), the orally administered gastro-retentive compositions or combinations comprising PS described herein are broadly applicable for treatment of pain generated at central sites of action, for example the pain sensing regions of the brain. (e.g., neuropathic pain associated with the indications described herein, migraine pain, and pain associated with central sensitization). It will be understood that the inventor’s work has been described above by way of example only and modifications may be made while remaining within the scope and spirit of the invention.

Claims

CLAIMS 1. A method of administering a therapeutically effective amount of a modified NSAID, for example PS, to the central nervous system of a subject in need thereof, wherein the modified NSAID is administered orally.

2. A method of treating and / or preventing pain comprising administering a therapeutically effective amount of a modified NSAID to the central nervous system of a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID is administered orally 3. The method of claim 1 or 2, wherein the modified NSAID is administered to the brain, for example one or more of the areas of the brain involved in pain signalling and / or sensation.

4. The method of claim 1 or 3, wherein the administration of the modified NSAID leads to the treatment and / or prevention of pain.

5. A method of treating and / or preventing pain generated by neurons located in one or more areas of the brain involved in pain signalling and / or sensation, comprising administering a therapeutically effective amount of a modified NSAID to a subject in need thereof such that the pain is treated and / or prevented, wherein the modified NSAID is administered orally.

6. The method of any one of claims 2-5, wherein the modified NSAID reduces pain signalling occurring centrally, for example in one or more of the areas of the brain involved in pain signalling and / or sensation.

7. The method of any one of claims 1-6, wherein the modified NSAID acts directly on centrally located neurons, for example neurons in the one or more areas of the brain involved in pain signalling and / or sensation.

8. The method of any one of the preceding claims, wherein the modified NSAID translocates along the vagus nerve to accumulate in the central nervous system, for example in one or more areas of the brain involved in pain signalling and / or sensation.

9. The method of any one of claims 3-8, wherein the one or more of the areas of the brain involved in pain signalling and / or sensation is the brainstem, for example the midbrain, medulla oblongata and the pons; or the cortical regions, for example the cerebral cortext.

10. The method of any one of claims 3-9, wherein the one or more of the areas of the brain involved in pain signalling and / or sensation is selected from the following: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter (PAG).

11. The method of any one of claims 3-10, wherein the one or more areas of the brain involved in pain signalling and / or sensation is the medulla oblongata or cerebellum.

12. The method of any one of claims 2-11, wherein the pain is neuropathic pain or pain associated with central sensitization.

13. The method of claim 12, wherein the neuropathic pain is neuropathic pain associated with CIPN; neuropathic pain associated with DPN; neuropathic pain associated with PTPN; neuropathic pain associated with PHN; or corneal neuropathic pain.

14. The method of claim 13, wherein the pain associated with central sensitization is pain associated with CIPN; pain associated with DPN; pain associated with PTPN; pain associated with PHN; corneal neuropathic pain; or migraine pain.

15. The method of any one of claims 2-11, wherein the pain is migraine pain.

16. The method of any one of claims 2-15, wherein the pain is caused by central sensitization.

17. The method of any one of claims 2-16, wherein the 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 claims 2-18, wherein the pain is hyperalgesia.

20. The method of any one of claims 2-19, wherein the pain may be centrally generated pain, for example central pain or chronic pain.

21. A method of treating and / or preventing pain associated with central sensitization comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that the pain associated with central sensitization is treated and / or prevented, wherein the modified NSAID is administered orally.

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

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

24. A method of treating and / or preventing neuropathic pain associated with PTPN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PTPN is treated and / or prevented, wherein the modified NSAID is administered orally.

25. A method of treating and / or preventing neuropathic pain associated with PHN comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that neuropathic pain associated with PHN is treated and / or prevented, wherein the modified NSAID is administered orally.

26. A method of treating and / or preventing migraine pain comprising administering a therapeutically effective amount of a modified NSAID, for example PS, to a subject in need thereof such that migraine pain is treated and / or prevented, wherein the modified NSAID is administered orally.

27. The method of any one of claims 21-26, wherein the modified NSAID reduces pain signalling occurring centrally, for example in one or more of the areas of the brain involved in pain signalling and / or sensation.

28. The method of any one of claims 21-27, wherein the modified NSAID acts directly on centrally located neurons, for example neurons in the one or more areas of the brain involved in pain signalling and / or sensation.

29. The method of any one of claims 21-28, wherein the modified NSAID translocates along the vagus nerve to accumulate in the central nervous system, for example in one or more areas of the brain involved in pain signalling and / or sensation.

30. The method of any one of claims 27-29, wherein the one or more of the areas of the brain involved in pain signalling and / or sensation is the brainstem, for example the midbrain, medulla oblongata and the pons; or the cortical regions, for example the cerebral cortext.

31. The method of any one of claims 27-30, wherein the one or more of the areas of the brain involved in pain signalling and / or sensation is selected from the following: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter (PAG).

32. The method of any one of claims 27-31, wherein the one or more areas of the brain involved in pain signalling and / or sensation is the medulla oblongata or cerebellum.

33. The method of any one of the preceding claims, wherein the modified NSAID is selected from one or more of the following classes of modified NSAIDs: phospho-modified NSAIDs (phospho-NSAIDs), phosphoramide-modified NSAIDs (phosphoramide-NSAIDs), selenium- modified NSAIDs (Se-NSAIDs), metal complex-NSAIDs, H2S-releasing NSAIDs (HS- NSAIDs), NO-releasing NSAIDs (NO-NSAIDs) and NO-, SH-releasing NSAIDs (NOSH- NSAIDs).

34. The method of claim 33, wherein the modified NSAID is a phospho-modified NSAID (phospho- NSAID), or a phosphoramide-modified NSAID (phosphoramide-NSAID).

35. The method of claim 34, wherein the phospho-NSAID is selected from: a. phosphosulindac (PS), such as formula I:or (II) ; I); (LXXI); ord. phosphonaproxen, such as formula VIII: (VIII).

36. Thea. phosphosulindac amide, such as formula X: or b..

37. The method of anyis a modified sulindac, ibuprofen or naproxen.

38. The meothd of claim 37, wherein the modified sulindac is: a. a phospho-sulindac, for example phosphosulindac (PS), such as formula I or II; b. an NO-releasing sulindac, for example NO-sulindac, such as formula XLIV:or c. a H2S-releasing sulindac, for example HS-sulindac, such as formula XXXIV: ; d. aLXVII: (LXVII); ore. a amide, such as formula X.

39. The method of claim 37, wherein the modified ibuprofen is phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; or phospho-ibuprofen-amide, such as formula XI.

40. The method of claim 37, wherein the modified naproxen is phosphonaproxen, such as formula VIII.

41. The method of any one of the preceding claims, wherein the modified NSAID is selected from one or more of the following: PS, such as formula I or II; phospho-ibuprofen, such as formula III; phospho-glycerol-ibuprofen, such as formula LXXI; NO-sulindac, such as formula XLIV; HS-sulindac, such as formula XXXIV; platinum-sulindac, such as formula LXVII; phosphosulindac amide, such as formula X; phospho-ibuprofen amide, such as formula XI; phosphonaproxen, such as formula VIII; or NOSH1, such as formula LIX: , 42. The method of any one of NSAID is selected fromphosphosulindac amide, as or amide, such as formula XI.

43. The method of claim 42, wherein the modifed NSAID is phosphosulindac amide, such as formula X.

44. The method of claim 42, wherein the modified NSAID is phospho-ibuprofen amide, such as formula XI.

45. The method of any one of the preceding claims, wherein the modified NSAID is phosphosulindac (PS), optionally wherein PS has the formula I (PS-I) for formula II (PS-II).

46. The method of any one of claims 2-45, wherein treating the pain comprises reducing the pain.

47. The method of any one of claims 2-46, wherein preventing the pain comprises decreasing the incidence of the pain.

48. The method of any one of claims 22-47, wherein treating the pain includes reducing one or more of the sensory symptoms associated with the pain.

49. The method of any one of claims 22-47, wherein preventing the pain includes decreasing the incidence of one or more of the sensory symptoms associated with the pain.

50. The method of any one of claims 2-49, wherein the modified NSAID reduces the neuronal signalling involved in the sensation of pain in the central nervous system.

51. The method of any one of claims 2-50, wherein the modified NSAID reduces pain generated via central sensitization.

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

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

54. A modified NSAID for use in treating and / or preventing pain via administration of the modified NSAID to the central nervous system, wherein the modified NSAID is administered orally.

55. Use of modified NSAID for the manufacture of a medicament for treating and / or preventing pain via administration of the modified NSAID to the central nervous system, wherein the modified NSAID is administered orally.

56. The method of any one of claims 1-53, the modified NSAID for use of claim 54, or the use of claim 55, wherein the modified NSAID is formulated as a liquid or solid dosage form.

57. The method of claim 56, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup or and elixir.

58. The method of claim 56, wherein the solid dosage form is a capsule, tablet, pill, powder, or granule.

59. The method of any one of the preceding claims, wherein the modified NSAID is administered orally at dosage levels of about 0.01 mg / kg to about 100 mg / kg, from about 0.05 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg of subject body weight, for example about 1 mg / kg to about 5 mg / kg, for example about 3 mg / kg of subject body weight.

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

61. The method of any one of the preceding claims, wherein the modified NSAID is administered orally at a dosage of about 250 mg to about 300 mg, preferably about 250 mg.

62. The method of any one of the preceding claims, wherein the modified NSAID is administered orally once a day.

63. The method of any one of the preceding claims, 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.

64. The method of claim 63, wherein the modified NSAID is administered two or three times a day.

65. The method of any one of the preceding claims, wherein the modified NSAID is administered orally at a dosage of from about 150 mg to about 200 mg twice a day.

66. The method of any one of the preceding claims, wherein the modified NSAID is administered orally at a daily dosage of about 300 mg to about 400 mg.

67. The method of any one of the preceding claims, wherein the modified NSAID is administered orally at a daily dosage of about 250 mg to about 300 mg (for example, about 250 mg) two or three times a day.

68. The method of any one of the preceding claims, wherein the modified NSAID is administered orally at a daily dosage of about 500 mg to up to about 900 mg a day.

69. The method of any one of the preceding claims, wherein the modified NSAID is administered in a pharmaceutical composition.

70. The method of any one of claims 53 and 56-69, wherein the pharmaceutical composition is a gastro-retentive pharmaceutical composition.

71. The method of claim 70, wherein the gastro-retentive pharmaceutical composition comprises the modified NSAID and one or more gastro-retentive agents, for example one or more gastro- retentive excipients.

72. A gastro-retentive pharmaceutical composition comprising a modified NSAID, for example PS.

73. A pharmaceutical composition comprising a modified NSAID, for example PS, and one or more gastro-retentive agents.

74. The pharmaceutical composition of claim 73, wherein the gastro-retentive agent is a gastro- retentive excipient.

75. A method comprising administering a therapeutically effective amount of gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, to a subject in need thereof.

76. A gastro-retentive pharmaceutical composition of a modified NSAID, for example PS, for use in therapy.

77. Use of a modified NSAID, for example PS, in the manufacture of a gastro-retentive medicament.

78. A modified NSAID, for example PS, and one or more gastro-retentive agents as a combined preparation for simultaneous, separate or sequential use in therapy.

79. A method comprising administering a therapeutically effective amount of a modified NSAID, for example PS, and one or more gastro-retentive agents, to a subject in need thereof, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally.

80. A modified NSAID, for example PS, and one or more gastro-retentive agents for use in therapy, wherein the modified NSAID, for example PS, and the one or more gastro-retentive agents are administered orally.

81. Use of a modified NSAID, for example PS, and one or more gastro-retentive agents for the manufacture of a medicament.

82. The method of claim 79, the modified NSAID and one or more gastro-retentive agents for use of claim 80, and the use of claim 81, wherein the one or more gastro-retentive agents is administered prior to administration of the modified NSAID.

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