Treating pain associated with central sensitization

Abstract

The present invention features methods of treating pain, eg, pain associated with central sensitization, using phosphosulindac and compositions thereof.

Description

Related Applications

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

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

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

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

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

[0006] Central sensitization can be a component of neuropathic pain associated with neuropathy.Neuropathy is a disease or disorder of the nervous system, which affects more than 20 million people in the United States alone.In fact, according to recent research, about 1 in 10 adults suffer from neuropathic pain, and the economic burden of treating this pain is increasing.

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

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

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

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

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

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

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

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

[0015] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound (NSAID sulindac), PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, as well as activity in the treatment of rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED) and suggests that PS reduces corneal sensitivity in the acute model. The observation of decreased sensitivity to acute stimuli that do not produce persistent pain does not demonstrate efficacy in treating pain associated with central sensitization (i.e., originating at a central site of action). Furthermore, in this acute model, the effects of PS were observed immediately, suggesting that the local activity of this atypical NSAID is similar to that observed with typical NSAIDs (e.g., ketorolac) in the same model. Again, such peripheral activity does not demonstrate efficacy of PS in treating pain originating at a central site of action. Indeed, clinical guidance in the field generally recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain associated with central sensitization, and ketorolac has been shown to have limited analgesic activity in such models of pain. Furthermore, in a DED model, PS was found to restore suppressed ocular sensitivity, suggesting a role for PS in increasing, rather than reducing, nociception. Thus, while these observations fall short of suggesting a role for PS in treating pain associated with central sensitization, the observations herein demonstrate the unprecedented activity of PS in reducing pain generated at a central site of action.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0029] [Figure 1] Schematic of a therapeutic study of pain associated with central sensitization. [Figure 2] Effect of PS on the treatment of pain associated with central sensitization. [Figure 3] Effect of PS on the treatment of pain associated with central sensitization induced by paclitaxel. The effect of PS compared to vehicle control was significant from day 5 and increased thereafter (†, p<0.002; ‡, p=4.9×10-5; &, p=1.7×10-7; *, p=2.2×10-7). [Figure 4] Effect of PS on the treatment of pain associated with central sensitization caused by vincristine. The effect of PS compared to vehicle control was significant at day 16 (*p=8.6×10-6). [Figure 5] Effect of PS on the treatment of pain associated with central sensitization caused by oxaliplatin. The effect of PS compared to vehicle control was significant at day 22 (*p=0.004). [Figure 6]Effect of PS compared with sulindac, lidocaine, and pregabalin on the treatment of pain associated with central sensitization. A. Mechanical allodynia (*, statistically significant difference; NS, statistically not significant). B. Cold allodynia (values: mean ± SEM; *, p<0.0001). [Figure 7] Schematic of therapeutic studies on pain associated with central sensitization. STZ is streptozotocin. PWT is the paw withdrawal threshold test. [Figure 8] Effect of PS on pain associated with central sensitization caused by STZ compared with vehicle. [Figure 9] Effects of sulindac, lidocaine, and pregabalin on pain associated with central sensitization. [Figure 10] A) Confirmation of the validity of the model system. B) Effect of PS compared to sulindac and pregabalin on treating pain associated with PTPN. The effect of PS compared to vehicle control was significant at day 14 (p<0.005). [Figure 11] Schematic diagram of PS metabolism. [Figure 12] Biodistribution of PS in various tissues after local administration. SN = sciatic nerve. DRG = dorsal root ganglion. [Figure 13-1] Distribution of PS metabolites in various tissues after local administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion. [Figure 13-2] Distribution of PS metabolites in various tissues after local administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion. [Figure 14] A) Biodistribution of PS in ocular tissues upon topical administration of PS to the outer surface of the eyelid; B) Levels of sulindac detected in ocular tissues as a result of hydrolysis of PS upon administration to the outer surface of the eyelid. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition The following definitions of pain types follow those of the International Association for the Study of Pain (IASP). "Pain" is an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage. "Central sensitization" refers to increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. "Peripheral sensitization" refers to increased responsiveness and lowered threshold of nociceptive neurons in the periphery to stimulation of their receptive fields. "Allodynia" is pain resulting from stimuli that normally do not elicit pain. "Hyperalgesia" is increased pain from stimuli that normally elicit pain. Pain associated with central sensitization can be either systemic or at multiple locations within the body. Given the involvement of the relevant nervous systems, pain associated with central sensitization exhibits symptoms corresponding to those observed in neuropathic pain. Therefore, patients with pain associated with central sensitization may experience one or more sensations described as hot, burning, throbbing, electric shock, stabbing, sharp pain, cramping, tingling, numbness, or tingling.Pain associated with central sensitization is also associated with mood swings, fatigue, cognitive impairment, sleep changes, and pain-catastrophizing.In addition, patients with pain associated with central sensitization may have multifocal pain, memory complaints, and comorbid conditions, including major depressive disorder or generalized anxiety disorder.

[0031] "Neuropathic pain" is caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain is a clinical description (and not a diagnosis) that requires a demonstrable lesion or disease that meets established neurological diagnostic criteria. Patients with neuropathic pain may experience one or more sensations described as heating, burning, throbbing, electric shocks, stabbing, sharp pain, cramping, aching, tingling, numbness, or tingling. The term "lesion of the somatosensory nervous system" is generally used when diagnostic testing (e.g., imaging, neurophysiological testing, biopsy, clinical examination) reveals an abnormality or there has been obvious trauma. The term "disease of the somatosensory nervous system" is generally used when the underlying cause of the lesion (e.g., stroke, vasculitis, diabetes, genetic abnormality) is known. "Peripheral neuropathic pain" is pain caused by a lesion or disease of the peripheral somatosensory nervous system. "Central neuropathic pain" is pain caused by a lesion or disease of the central somatosensory nervous system.

[0032] The following definitions of headache types follow the International Classification of Headache Disorders (ICHD), Third Edition (ICHD-3). There are two major types of migraine: "migraine without aura," a clinical syndrome characterized by headache with specific characteristics and associated symptoms, and "migraine with aura," characterized primarily by transient focal neurological symptoms that usually precede or sometimes accompany the headache. "Migraine without aura" (i.e., common migraine; simple hemicrania) is a recurrent headache disorder that begins episodically and lasts 4 to 72 hours. The headache typically has a unilateral location, a pulsatile quality, moderate or severe intensity, worsens with everyday physical activity, and is associated with nausea and / or photophobia and phonophobia. "Migraine with aura" (i.e., typical or classic migraine) usually develops gradually and involves recurrent attacks of unilateral, fully reversible visual, sensory, or other CNS symptoms lasting several minutes, usually followed by headache and associated migraine symptoms. "Episodic migraine" generally involves approximately 1-2 migraines / headaches per month. "Chronic migraine" is headaches occurring 15 or more days per month for more than 3 months, with at least 8 of those days per month having migraine characteristics.

[0033] Generally, the term "disease" refers to a physical condition or state of health of a patient or subject that can be treated using the methods provided herein.

[0034] The term "therapeutically effective amount" refers to an amount of a compound or a combination of compounds described herein that is sufficient to produce the effect of the intended application. Thus, if the intended application is to treat a disease, the "therapeutically effective amount" refers to an amount of a compound or a combination of compounds described herein that is sufficient to treat the disease. If the intended application is to treat and / or prevent a disease, the "therapeutically effective amount" refers to an amount of a compound or a combination of compounds described herein that is sufficient to treat and / or prevent the disease.

[0035] "Pharmaceutically acceptable excipients" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inactive ingredients contained in pharmaceutical compositions. The use of such pharmaceutically acceptable excipients to formulate active pharmaceutical ingredients is well known in the art. To the extent that any conventional pharmaceutically acceptable excipient is incompatible with PS, its use in the therapeutic compositions of the present invention is contemplated.

[0036] Use of the term "about" when referring to a numerical value is optional and means that the number referred to is an approximation within typical experimental variation (or within statistical experimental error), and therefore the number may vary accordingly.

[0037] The term "comprising" encompasses both "including" and "consisting," e.g., a composition "comprising" X may consist exclusively of X, or may include something additional (e.g., X+Y).

[0038] Pain related to central sensitization As outlined above, pain associated with central sensitization occurs when centrally located neurons exhibit reduced sensitivity to firing action potentials (i.e., neurons are sensitized). This occurs in the context of persistent nociceptive signaling from the periphery, resulting in peripheral sensitization, which ultimately leads to hyperexcitability of central neurons, which ultimately manifests as pain sensations even in the absence of ongoing peripheral input. In fact, central sensitization is associated with spontaneous pain, but typically manifests as allodynia (pain induced by non-painful stimuli) or hyperalgesia (enhanced pain sensation in response to noxious stimuli). Central sensitization is associated with chronic pain states in which pain is generated or amplified by hyperexcitability of higher-order neurons. Pain can manifest as widespread pain or radiating pain, sometimes localized near the original site of nociception. In some embodiments, the present invention provides a method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that pain associated with central sensitization is treated. Subjects experiencing pain associated with central sensitization would benefit from an analgesic that can reduce the pain caused by central sensitization and prevent further pain associated with central sensitization. Thus, in some embodiments, PS can be used to treat and prevent pain associated with central sensitization. In accordance with the above, the present invention provides PS for use in treating pain associated with central sensitization. Furthermore, the present invention provides use of PS for the manufacture of a medicament for treating pain associated with central sensitization.

[0039] Pain associated with central sensitization is not acute nociceptive pain (i.e., pain that subsides when the noxious stimulus is removed). Thus, in some embodiments, pain associated with central sensitization is chronic pain (i.e., pain that persists or recurs for more than three months). In certain embodiments, pain is perceived in the absence of peripheral nociceptor input, for example, to noxious or innocuous stimuli. The pathogenesis of central sensitization can vary depending on the initial pathology that triggers peripheral input and contributes to central sensitization. For example, central sensitization can be the result of an inflammatory pain mechanism, i.e., the initial trigger was an inflammatory response, but the resulting central sensitization causes pain even in the absence of ongoing inflammation. In certain cases, central sensitization is the result of a neuropathic pain mechanism. Central sensitization is a characteristic of some chronic pain conditions. Pain associated with central sensitization can be pain associated with one or more of the following: inflammatory pain, neuropathic pain, fibromyalgia, chronic pain, chronic regional pain syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, spondyloarthritis, lupus, temporomandibular disorders, and / or idiopathic low back pain. Pain associated with central sensitization resulting from inflammatory pain is not due to an ongoing peripheral inflammatory response. In certain embodiments, pain associated with central sensitization can be pain associated with one or more of the following: neuropathic pain, fibromyalgia, chronic pain, chronic regional pain syndrome, osteoarthritis, temporomandibular disorders, and / or idiopathic low back pain. In some embodiments, pain associated with central sensitization occurs after a stroke or spinal cord injury or in subjects with multiple sclerosis. In some embodiments, pain associated with central sensitization can be pain associated with post-traumatic peripheral neuropathy. In some embodiments, pain associated with central sensitization can be pain associated with postherpetic neuralgia. In some embodiments, the pain associated with central sensitization can be pain from a migraine. In some embodiments, the pain associated with central sensitization can be pain from other headache disorders. In some embodiments, the pain associated with central sensitization can be pain associated with corneal neuropathic pain.

[0040] Based on the observations herein, PS has a direct analgesic effect on pain associated with central sensitization. In treating pain associated with central sensitization, PS can reduce pain. In some cases, the reduction is complete, such that the pain disappears. In treating pain associated with central sensitization, PS can also reduce one or more symptoms associated with central sensitization. In treating and preventing pain associated with central sensitization, PS can reduce the incidence of pain. In treating and preventing pain associated with central sensitization, PS can also reduce the incidence of one or more symptoms associated with central sensitization.

[0041] Pain associated with central sensitization may be radiating pain. The pain may be widespread. In some embodiments, the pain may be radiating around the area of ​​the initial injury. In some embodiments, pain associated with central sensitization may have characteristics of neuropathic pain and thus may result in one or more sensations described as heating, burning, throbbing, electric shocks, stabbing, sharp pain, cramping, aching, tingling, numbness, or tingling. Patients suffering from pain associated with central sensitization may experience a variety of symptoms. Symptoms include mood swings, fatigue, cognitive impairment, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia, and / or phonophobia. Even if the symptoms experienced by a subject experiencing pain associated with central sensitization are not considered painful (or do not reach the threshold required to be considered painful per se), PS may reduce any one or more of the symptoms experienced by the subject. In some cases, the reduction is complete, such that one or more of the symptoms experienced by the subject disappears. Indeed, elimination of the underlying pain associated with central sensitization will result in amelioration of many of the associated symptoms.

[0042] As described above, pain associated with central sensitization can be allodynia and / or hyperalgesia. In certain embodiments, pain associated with central sensitization is allodynia (e.g., mechanical or thermal allodynia). PS can reduce neuronal signaling involved in pain sensation generated through central sensitization. In some cases, the reduction can be complete, such that pain generation is eliminated. Thus, PS can reduce pain signaling generated centrally. PS can reduce pain signaling generated in the dorsal root ganglion. PS can reduce pain signaling generated in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce pain signaling generated in the CNS. In some cases, the reduction can be complete, such that pain signaling is eliminated. Pain associated with central sensitization in a subject can be neuropathic pain. In some embodiments, pain associated with central sensitization, such as neuropathic pain, is not pain associated with central sensitization caused by CIPN or DPN. In some embodiments, PS does not prevent the development of central sensitization.

[0043] Pain associated with central sensitization in a patient can be measured using a visual analog pain scale or other suitable method in the art.

[0044] Pain associated with post-traumatic peripheral neuropathy Posttraumatic peripheral neuropathy (PTPN) can result from a variety of traumatic peripheral nerve injuries and is associated with neuropathic pain that can cause anything from mild discomfort to lifelong disability. Traumatic nerve injuries can be classified into categories (Seddon and Sunderland Grades I to VI) based on the presence of demyelination and the degree of damage to the nerve's axons and connective tissue (see Menorca et al., Hand Clin. (2013); 29(3):317-330). The main classifications, in order of severity, are transient nerve conduction disturbances (Grade I), axonotmesis (including Grades II to IV), and neurectomy (Grade V). Grade VI (later added to the Seddon and Sunderland classification) involves damage at different levels along the nerve (Grades III to V).

[0045] Naturally, such peripheral nerve trauma can be associated with chronic neuropathic pain. Trauma can result in tangles of nerve fibers and connective tissue (traumatic neuroma) that develop after nerve injury, and this area is associated with paresthesia. The damaged nerve and any surrounding nerves can show changes in gene expression, which makes them hypersensitive due to the occurrence of spontaneous discharges. Thus, trauma results in painful hypersensitivity to innocuous stimuli (allodynia) or exaggerated pain response to noxious stimuli (hyperalgesia), which reflects central sensitization. Traumatic neuropathic pain can cause patients to experience burning, stabbing, burning, pins and needles, or nauseous sensations, as well as numbness, tingling, and pricking.

[0046] Neuropathic pain associated with PTPN is particularly difficult to treat. It is currently managed with secondary amine tricyclic antidepressants (e.g., nortriptyline, desipramine), calcium channel α-2-δ ligand anticonvulsants (e.g., pregabalin, gabapentin), opioids, ketamine, and topical lidocaine. Additionally, techniques including nerve blocks, ablation, and nerve stimulation designed to disrupt, block, or modulate pain pathways are available. Unfortunately, pain management is not very satisfactory, and many systemic treatments induce significant side effects that lead to poor treatment adherence.

[0047] Therefore, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly PTPN.

[0048] The present inventors have surprisingly found that PS is effective in treating and preventing pain associated with PTPN.

[0049] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and to be active in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore the ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as mentioned above, it exhibited similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in the treatment of PTPN-associated neuropathic pain. Furthermore, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and therefore, anti-inflammatory activity alone is considered insufficient for therapeutic benefit.

[0050] Nevertheless, preliminary in vivo evidence indicates the efficacy of PS in treating neuropathic pain associated with PTPN. Further experiments in specific animal models of PTPN-associated neuropathic pain will confirm these preliminary observations.

[0051] Thus, the present invention provides a method for treating and / or preventing neuropathic pain associated with PTPN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PTPN is treated and / or prevented.

[0052] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0053] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0054] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0055] Neuropathic pain associated with PTPN can result from traumatic nerve injury that meets any one or more of the Seddon and Sunderland classifications (i.e., grades I to VI). For example, traumatic nerve injury can be a transient nerve conduction disorder (grade I, defined by focal demyelination (causing asynchronous conduction or even conduction block) without damage to the axon or connective tissue). Transient nerve conduction disorders can be caused by mild compression or traction of the nerve. Compression injuries can occur where the nerve passes through narrow anatomical gaps, such as in the upper extremity, including the carpal tunnel and cubital tunnel. Nerves can also be compressed by displaced fracture fragments, joint dislocations, or expanding hematomas.

[0056] Traumatic nerve injury can be axonotmesis (Grades II-IV, in increasing order of severity: with intact endoneurium and axonal damage (Grade II); with intact perineurium and axonal and endoneurial damage (Grade III); and with intact epineurium and axonal, endoneurial, and perineurial damage (Grade IV)). Axonotmesis can be caused by a crush injury that does not result in complete severance of the nerve. Such crush injuries, with varying degrees of nerve damage, can result from acute traumatic compression of the nerve with a blunt body such as a bat, surgical clamp, or other crushable object.

[0057] In some cases, traumatic nerve injury can be a nerve transection (Grade V, where complete transection of the nerve is observed, defined by complete severance of the axon and connective tissue layer). Injuries involving complete transection of the nerve can occur due to a knife, gunshot, laceration with glass, or as a result of a car accident or surgical complications.

[0058] Finally, traumatic nerve injury can be a combination of any one of these classes (Grade VI).

[0059] In some embodiments, the traumatic nerve injury is a compression injury. In certain embodiments, the traumatic nerve injury is a crush injury. In certain embodiments, the neuropathic pain associated with PTPN is pain caused by nerve compression injury and / or nerve crush injury. Nerve compression injuries can be caused by accidents and trauma, joint sprains (e.g., ankle, knee, or wrist), arthritis, fractures, bone spurs, joint dislocations (e.g., elbow or shoulder), herniated discs, hypothyroidism, surgical complications, tumors, and / or cysts.

[0060] Traumatic nerve injury can affect one or more of the following nerves: median nerve, radial nerve, suprascapular nerve, ulnar nerve, lateral femoral cutaneous nerve, peroneal nerve, pudendal nerve, sciatic nerve, tibial nerve, and / or spinal nerve. Spinal nerves can be one or more of the following: cervical nerve, thoracic nerve, lumbar nerve, sacral nerve, and / or coccygeal nerve. Thus, neuropathic pain associated with PTPN can be pain caused by one or more of the following: carpal tunnel syndrome, pronator teres syndrome, radial tunnel syndrome, suprascapular nerve entrapment, thoracic outlet syndrome, ulnar nerve entrapment (cubital tunnel syndrome or Guyon tunnel syndrome), dysesthesias of femoral neuralgia, peroneal nerve compression, pudendal nerve entrapment syndrome, sciatica, tarsal tunnel syndrome, cervical disc herniation, thoracic disc herniation, and / or lumbar disc herniation. In certain embodiments, the neuropathic pain associated with PTPN can be pain caused by a herniated disc.

[0061] Neuropathic pain associated with PTPN can be caused by a herniated disc in the vertebrae of the spine. A herniated disc (disc prolapse or disc slippage) occurs when the fibrous outer portion of the disc ruptures or tears, causing the disc to bulge out of the vertebrae of the spine. Such a herniated disc can cause compression of the nerves located between the adjacent vertebrae, or even the spinal cord itself. This can cause pain, numbness, tingling, or weakness in the arms or legs. Long-term compression of the disc can result in symptoms associated with neuropathic pain (e.g., allodynia and hyperalgesia). Although disc bulging is less severe than a herniated disc, it is also a cause of neuropathic pain associated with PTPN. A herniated (or bulging) disc can be a cervical disc, causing pain in the neck, shoulder, or arm, for example. The herniated (or bulging) disc can be, for example, a herniated (or bulging) thoracic disc, causing pain in the mid-back around the level of the herniated (or bulging) disc. The herniated (or bulging) disc can be, for example, a lumbar herniated (or bulging) disc, causing intermittent or continuous back pain and / or sciatica.

[0062] Neuropathic pain associated with post-traumatic peripheral neuropathy, for example, due to traumatic injury to peripheral neurons, can occur immediately after injury and can manifest as, for example, a poorly localized, sometimes diffuse burning, stinging, tingling, pins and needles, or nausea, and is associated with other sensory symptoms. Thus, in some embodiments, the present invention provides a method for treating neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that neuropathic pain associated with PTPN is treated. Pain can also occur delayed after injury. Thus, the present invention provides a method for preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that neuropathic pain associated with PTPN is prevented. Considering that pain can be experienced both immediately and delayed, a subject may experience pain immediately upon injury, which may develop into a different pain sensation that occurs later. Thus, in some embodiments, PS can be used for the treatment and prevention of neuropathic pain associated with PTPN. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of neuropathic pain associated with PTPN. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PTPN.

[0063] Based on the observations herein, PS has a direct analgesic effect on PTPN-associated neuropathic pain. PTPN-associated neuropathic pain can be stabbing or burning pain. In treating PTPN-associated neuropathic pain, PS can reduce neuropathic pain. In some cases, the reduction can be complete, such that PTPN-associated neuropathic pain disappears. In treating PTPN-associated neuropathic pain, PS can also reduce one or more of the sensory symptoms associated with PTPN. In preventing PTPN-associated neuropathic pain, PS can reduce the incidence of neuropathic pain. In preventing PTPN-associated neuropathic pain, PS can also reduce the incidence of one or more of the sensory symptoms associated with PTPN.

[0064] Patients with PTPN describe a variety of sensory symptoms. Sensory symptoms include paresthesia (e.g., numbness, tingling, prickling, and / or crawling), burning, or pricking sensations. Even if the sensory symptoms experienced by a subject with traumatic nerve injury are not considered painful (or do not reach the threshold required to be considered pain in themselves), PS can reduce any one or more of the sensory symptoms experienced by the subject, including those listed above. In some cases, the reduction can be complete, such that one or more of the sensory symptoms associated with PTPN disappear.

[0065] As described above, nerve injury associated with PTPN can result in overactivation of pain signaling pathways, leading to sensitization of peripheral and / or central neurons, which exhibit a decreased stimulation threshold. Therefore, subjects with PTPN may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Thus, neuropathic pain associated with PTPN may be the result of central sensitization leading to allodynia and / or hyperalgesia. PS may reduce neuronal signaling involved in pain sensation in subjects with traumatic peripheral nerve injury. PS may reduce pain generated via peripheral sensitization or central sensitization. In particular, given the ability of PS to traverse toward the primary pain-generating site, PS may reduce pain generated via central sensitization. In some cases, the reduction can be complete, such that pain generation is eliminated. Thus, PS can reduce pain signaling originating centrally. PS can reduce pain signaling originating in peripheral nerves. PS can reduce pain signaling originating in the dorsal root ganglion. PS can reduce pain signaling originating in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce pain signaling originating in the CNS. In some cases, the reduction can be complete, such that pain signaling is eliminated. Neuropathic pain in a subject with PTPN can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, neuropathic pain in a subject with PTPN can be hyperalgesia.

[0066] Neuropathic pain in patients can be measured using a visual analog pain scale or other suitable methods in the art.

[0067] PS can be formulated into pharmaceutical compositions for use in the present invention.In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients.PS can be formulated for local administration, particularly for local administration near or to the area of ​​trauma on the subject's body.

[0068] In certain embodiments for treating and / or preventing pain associated with PTPN, PS may be administered orally.

[0069] Pain associated with postherpetic neuralgia PHN is a common complication of shingles caused by reactivation of the varicella-zoster virus (VZV). VZV is a highly virulent neurotropic virus that can cause chickenpox (varicella) as a primary infection in susceptible individuals. The virus can be retrogradely transported from the skin along the axons of sensory neurons to establish latent infections within sensory ganglia of the peripheral nervous system. If a previously infected subject becomes immunosuppressed, the virus can reactivate and manifest as acute herpes zoster (AHZ, "shingles"). Recovery from AHZ is often accompanied by the development of postherpetic neuralgia, a neuropathic pain syndrome characterized by persistent pain in the area affected by shingles. PHN is typically defined as pain that persists for more than 90 days after the initial appearance of the rash or at least 3 months after healing of the skin lesions. AHZ is diagnosed more than 1 million times annually in the United States alone. Approximately 20% of patients with AHZ will experience PHN and continue to suffer from intermittent neuropathic symptoms, including itching and pain. The pain is characterized by sharp, stabbing, throbbing, or burning sensations, often localized to the original rash site. Long-lasting pain is associated with painful hypersensitivity to innocuous stimuli (allodynia) or exaggerated pain responses to noxious stimuli (hyperalgesia), reflecting central sensitization. Without treatment, the incidence of pain persisting 3 months after rash onset is reported to be approximately 8–15%, with this figure increasing rapidly in the elderly.

[0070] Pain associated with PHN is associated with peripheral and particularly central sensitization (Hadley et al., Curr Pain Headache Rep. (2016); 20:17). During VZV reactivation, the virus replicates and spreads from the dorsal root ganglia to the periphery. Viral spread causes nerve damage (e.g., due to an immune response against neurons), which leads to more frequent depolarization of nociceptors. A decrease in the threshold for nociceptor signaling leads to peripheral sensitization. Ongoing peripheral signaling leads to central sensitization, characterized by a state of heightened activation of centrally located neurons (e.g., in the dorsal root horn and higher-order neurons). Additional pathogenesis mechanisms resulting in altered gene expression in centrally located neurons, loss of co-inhibitory signaling, or alterations in neuronal signaling networks (e.g., deafferentation) all contribute to the hypersensitivity experienced in subjects with PHN-associated pain. Persistent pain associated with central sensitization manifests as hyperalgesia (increased response to noxious stimuli) and / or allodynia (pain induced by non-painful stimuli).

[0071] Neuropathic pain associated with PHN is particularly difficult to treat. Current treatments for PHN-associated neuropathic pain include systemic tricyclic antidepressants, anticonvulsants, and opioids, as well as topical lidocaine and capsaicin. Additionally, interventional therapies exist, including subcutaneous botulinum toxin injections, nerve blocks, and nerve stimulation. However, these therapies are not always effective. In fact, even with the most effective medications, only 30–50% of patients achieve greater than 50% pain relief, often with significant side effects. PHN-associated neuropathic pain causes significant suffering and economic burden, manifested in both medical costs and lost quality-adjusted life years. Given the lack of effectiveness of current treatments, PHN-associated pain represents an area of ​​largely unmet medical need.

[0072] Thus, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly PHN.

[0073] The present inventors have surprisingly found that PS is effective in treating and preventing pain associated with PHN.

[0074] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and to be active in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as mentioned above, it exhibited similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in the treatment of neuropathic pain associated with PHN. Furthermore, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and therefore, anti-inflammatory activity alone is considered insufficient for therapeutic benefit. Indeed, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1-25) concluded that NSAIDs did not achieve pain reduction in PHN.

[0075] Nevertheless, preliminary in vivo evidence indicates the effectiveness of PS in treating neuropathic pain associated with PHN.

[0076] Accordingly, the present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is treated and / or prevented.

[0077] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0078] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0079] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0080] As outlined above, reactivation of the varicella-zoster virus can cause acute shingles, which manifests as a rash, followed by neuropathic pain associated with postherpetic neuralgia (PHN). As described above, neuropathic pain associated with PHN persists for 90 days or more after the initial appearance of the rash or for at least 3 months after the resolution of skin lesions. The pain can manifest as, for example, sharp, burning, throbbing, or stabbing pain. Because neuropathic pain associated with PHN typically occurs after the reactivation of shingles and the resolution of the rash, subjects can take preventative measures to avoid the development of neuropathic pain after the resolution of the rash and skin lesions. Thus, in some embodiments, the present invention provides a method for preventing neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is prevented. In another embodiment, the present invention provides a method for treating neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the neuropathic pain associated with PHN is treated. Because pain associated with PHN develops during the rash episode and persists after the rash has resolved, the subject would benefit from an analgesic that can both treat existing neuropathic pain and prevent the development of further neuropathic pain associated with PHN. Thus, in some embodiments, PS can be used for the treatment and prevention of neuropathic pain associated with PHN. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of neuropathic pain associated with PHN. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with PHN.

[0081] As described herein, pain associated with PHN is typically localized to the rash site. The rash (e.g., a maculopapular rash) may develop in one or more adjacent dermatomes (areas of the skin primarily innervated by a single spinal nerve). The spinal nerve may be a cervical nerve, a thoracic nerve, a lumbar nerve, and / or a sacral nerve. Thus, neuropathic pain associated with PHN may be experienced in one or more adjacent dermatomes. Neuropathic pain associated with PHN may be experienced in one or more dermatomes, where each dermatome is innervated by a cervical nerve, a thoracic nerve, a lumbar nerve, or a sacral nerve. Typically, neuropathic pain associated with PHN develops along the thoracic dermatome on the subject's trunk. In certain cases, for example, in immunocompromised individuals, the rash, and therefore the associated neuropathic pain, may be more widespread, affecting three or more dermatomes (i.e., due to disseminated herpes zoster).

[0082] Based on the observations herein, PS has a direct analgesic effect on the neuropathic pain associated with PHN. The neuropathic pain associated with PHN can be sharp, throbbing, stabbing, or burning pain. In the treatment of neuropathic pain associated with PHN, PS can reduce neuropathic pain. In some cases, the reduction is so complete that neuropathic pain disappears. In the treatment of neuropathic pain associated with PHN, PS can also reduce one or more of the sensory symptoms associated with PHN. In the prevention of neuropathic pain associated with PHN, PS can reduce the incidence of neuropathic pain. In the prevention of neuropathic pain associated with PHN, PS can also reduce the incidence of one or more of the sensory symptoms associated with PHN.

[0083] Patients with PHN describe a variety of sensory symptoms. These include itching and numbness. Even if the sensory symptoms experienced by a subject with PHN are not considered painful (or do not reach the threshold required to be considered painful in themselves), PS can reduce any one or more of the sensory symptoms experienced by the subject. In some cases, the reduction is so complete that one or more of the sensory symptoms experienced by the subject disappear.

[0084] As described above, nerve damage associated with PHN can result in overactivation of pain signaling pathways, leading to sensitization of peripheral and / or central neurons, and these neurons exhibit a decreased stimulation threshold. Therefore, subjects with PHN may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS can have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Therefore, neuropathic pain associated with PHN can be the result of central sensitization leading to allodynia and / or hyperalgesia. PS can reduce neuronal signaling involved in pain sensation in subjects with PHN. In some cases, the reduction can be complete, such that pain disappears. PS can reduce pain that occurs through peripheral sensitization or central sensitization. In some cases, the reduction can be complete, such that pain disappears. In particular, given PS's ability to travel longitudinally toward central pain-generating sites, PS can reduce pain generated through central sensitization. Therefore, PS can reduce centrally generated pain signaling. PS can reduce pain signaling in peripheral nerves, such as nerves innervating one or more dermatomes. PS can reduce pain signaling in one or more spinal nerves, such as one or more cervical nerves, one or more thoracic nerves, one or more lumbar nerves, and / or one or more sacral nerves. In particular, PS can reduce pain signaling in one or more thoracic nerves. PS can reduce pain signaling in the dorsal root ganglia. PS can reduce pain signaling in the dorsal horn of the spinal cord. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce pain signaling in the CNS. In some cases, the reduction can be so complete that pain signaling is eliminated. Neuropathic pain in subjects with PHN can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in a subject with PHN can be hyperalgesia.

[0085] Neuropathic pain in patients can be measured using a visual analog pain scale or other suitable methods in the art.

[0086] In another embodiment, PS may also be useful for treating other herpes zoster-related pain, such as prodromal pain (preceding the onset of rash symptoms) or acute herpes zoster pain (occurring simultaneously with the onset of rash symptoms). Damage to peripheral neurons caused by viral translocation leads to increased signaling from centrally located neurons. This may drive neuronal sensitization prior to the onset of persistent pain characteristic of PHN-associated neuropathic pain. Therefore, PS may be useful for treating pain during these stages of the pathology of infectious diseases. Therefore, the present invention also provides a method for treating pain experienced by a subject as a result of herpes zoster, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the pain is treated. The present invention also provides a method for treating acute herpes zoster pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the acute herpes zoster pain is treated. The present invention also provides a method for treating prodromal pain of shingles, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the prodromal pain of shingles is treated.

[0087] The PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises the PS and one or more pharmaceutically acceptable excipients. The PS can be formulated for topical administration, particularly to the area of ​​the skin (e.g., a dermatome) affected by the rash, for example, to the trunk of a subject.

[0088] In certain embodiments for treating and / or preventing pain associated with PHN, PS may be administered orally.

[0089] Migraine pain Migraine is a disabling neurological disorder that affects over 1 billion people worldwide, with a 1-year prevalence of 15%. Its prevalence peaks in people aged 35-39 years and is the leading cause of disability in people under 50 years of age, thus representing a significant socioeconomic burden. Migraine is typically characterized by recurrent, unilateral, throbbing headaches of moderate to severe intensity, accompanied by symptoms of nausea, vomiting, and hyperesthesia.

[0090] The pathophysiology of migraine continues to be debated and is now classified as a neuronal disorder (Goadsby et al., Physiol Rev (2017); 97:553-622). The previous theory of pain generation via dilation of cranial arteries lost ground following the failure of effective therapies (e.g., sumatriptan) to reverse the slight dilation of these arteries observed during migraine attacks. Furthermore, the suggestion that migraine is triggered by so-called neurogenic inflammation (local release of endogenous inflammatory mediators in the dura) has also been deemed impractical, especially in light of the clinical failure of compounds designed to inhibit this process. Indeed, evidence of an inflammatory pathology in migraine patients is lacking. Therefore, migraine is considered a purely neuronal disorder resulting from alterations or dysfunction in the brainstem and hypothalamic regions, which contribute to altered cellular and vascular function in many areas of the brain. These changes result in neurons being unable to normally modulate or gate sensory input. Dysfunction in these areas may lead to the perception of headache due to normal vascular pulsation, and continued dysfunction may lead to central sensitization of trigeminovascular neurons, exacerbation of pain with normal physical activity, and cutaneous allodynia. Indeed, peripheral and central sensitization of trigeminal neurons, as observed clinically in migraine patients, is considered a fundamental component of this pathophysiology. This neuronal mechanism may explain the prolonged duration of migraine attacks and the transition to chronic migraine and certain associated symptoms (e.g., cutaneous allodynia).

[0091] Central sensitization occurs when the function of neural circuits in sensory pathways is enhanced or inappropriately regulated, resulting in abnormal sensitivity, manifested, for example, as the presence of persistent spontaneous pain often associated with hyperalgesia (increased response to noxious stimuli) and allodynia (pain induced by non-painful stimuli). Central sensitization results from changes in the properties of neurons in the CNS, such that the perception of pain is no longer associated with the presence, intensity, or duration of a specific peripheral stimulus (noxious or not). Thus, central sensitization is associated with the generation and maintenance of pain when pain signaling occurs centrally even in the absence of peripheral stimuli (i.e., due to hypersensitivity of central pain-signaling neurons).

[0092] As alluded to above, sensitization in migraine develops as a result of the failure of sensory signaling integration and filtering, ultimately resulting in the perception of activation of the sensory system under normal conditions, such as the cutaneous allodynia experienced by migraine sufferers. Such symptoms are experienced in both episodic and chronic migraines, although pain amplification is thought to be more involved in chronic migraines.

[0093] There is currently a global need for additional pain therapies for the treatment of migraine and other headache disorders.

[0094] Reflecting the diverse nature of this disorder, various pharmacological interventions for treating migraine have been proposed. Indeed, relatively nonselective drugs such as ergot alkaloids have been used for decades. Other treatments include opiates (e.g., oxycodone), beta-blockers (e.g., propranolol), anticonvulsants (e.g., topiramate), or serotonin receptor agonists (e.g., sumatriptan). Patients with milder symptoms may be able to manage their symptoms with nonsteroidal anti-inflammatory drugs (NSAIDs), but as noted above, the inflammatory response is considered of limited relevance when considering the pathophysiology of migraine. Indeed, studies have demonstrated that certain NSAIDs, such as naproxen, are not clinically useful for treating migraine (see, e.g., Law et al., Cochrane Database of Systematic Reviews (2013);10:1-45).

[0095] Thus, there is a great need for compounds that treat and / or prevent migraine pain and pain from other headache disorders, particularly pain associated with central sensitization.

[0096] The present inventors have surprisingly found that PS is effective in treating and preventing pain caused by migraine headaches.

[0097] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit COX-1 and COX-2 or prostaglandin synthesis. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and to be active in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than reducing, nociception. Although PS is not a typical NSAID, as noted above, it exhibited similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations do not suggest a role for PS in treating migraine pain, which develops as a result of dysfunctional sensory neuron signaling rather than an inflammatory response. Indeed, certain typical NSAIDs (e.g., naproxen) have been shown to be clinically ineffective as analgesics for migraine headaches, suggesting that anti-inflammatory activity alone is insufficient to treat migraine pain.

[0098] Nevertheless, preliminary in vivo evidence indicates the efficacy of PS in the treatment of migraine pain. Further experiments in specific animal models of migraine pain will confirm these preliminary observations.

[0099] Accordingly, the present invention provides a method for treating and / or preventing migraine pain, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is treated and / or prevented.

[0100] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0101] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0102] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0103] As outlined above, migraine is characterized by moderate to severe attacks of unilateral, throbbing headache associated with photophobia, phonophobia, nausea, and / or vomiting. Accordingly, in some embodiments, the present invention provides a method for treating migraine pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is treated. Typically, a migraine attack consists of three phases: the prodromal phase, the migraine itself, and the postaural phase. The prodromal phase occurs approximately 24-48 hours before the headache phase and is typically characterized by symptoms such as mood changes, fatigue, and neck discomfort. Some individuals also experience aura, a transient, focal neurological symptom of visual, sensory, or motor disturbances. Subjects in the prodromal phase, prior to the onset of the headache phase, may be administered a therapeutic agent to prevent the onset of the headache phase. Accordingly, in other embodiments, the present invention provides a method for preventing migraine pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain is prevented. A subject may experience recurrent migraine attacks, particularly if there are short interictal periods between attacks, and thus administration of a therapeutic agent may treat the pain of ongoing attacks and prevent the pain of subsequent attacks. Thus, in some embodiments, PS can be used to treat and prevent migraine pain. In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of migraine pain. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment and / or prevention of migraine pain.

[0104] In some embodiments, when treating and / or preventing migraine pain, PS can be administered during the aura phase, headache phase, and / or aura phase. In particular, to prevent migraine pain, PS can be administered during the aura phase. To treat migraine pain, PS can be administered during the headache phase.

[0105] The migraine may be an episodic migraine. In certain cases, the migraine may be a chronic migraine. The migraine may be a migraine without aura or a migraine with aura.

[0106] Based on the observations herein, PS has a direct analgesic effect on migraine pain. Migraine pain can be a pulsating headache. Subjects with migraine, especially chronic migraine, may experience persistent migraine and / or aura-like periods with limited neurological recovery and baseline return between attacks. Subjects suffering from migraine may experience several associated symptoms, including aura, nausea, vomiting, photophobia, and / or phonophobia. Sensory disturbances associated with aura may include visual symptoms, tingling, and / or numbness. In addition, subjects may experience cranial autonomic symptoms, such as bloodshot or tearing eyes. In addition, subjects may experience cutaneous allodynia.

[0107] Migraine with aura can be typical migraine with aura or migraine with brainstem aura. Migraine can be hemiplegic migraine (e.g., familial hemiplegic migraine or sporadic hemiplegic migraine), retinal migraine, chronic migraine, or suspected migraine (with or without aura).

[0108] In treating migraine pain, PS can reduce pain. In some cases, the reduction can be complete, such that the migraine pain disappears. In treating migraine pain, PS can also reduce one or more of the symptoms associated with migraine. In preventing migraine pain, PS can reduce the incidence of pain. In preventing migraine pain, PS can also reduce the incidence of one or more of the symptoms associated with migraine. PS can reduce cutaneous allodynia. In certain embodiments, PS can reduce chronic migraine pain. As described above, the reduction can be complete, such that the pain disappears.

[0109] In treating and / or preventing pain from migraine, PS may reduce any one or more of the symptoms experienced by a subject with migraine, even if the symptoms experienced by the subject with migraine, such as aura or cranial autonomic symptoms, are not considered painful (or do not reach the threshold required to be considered painful in themselves). In some cases, the reduction may be complete, such that one or more of the symptoms experienced by a subject with migraine disappear.

[0110] Peripheral and central sensitization are characteristic of migraine pain. Migraine pain can be the result of central sensitization, which leads to allodynia, e.g., cutaneous allodynia, and / or hyperalgesia. Thus, a subject with migraine may experience pain as a result of this sensitization, for example, experiencing pain induced by non-painful stimuli (allodynia) or experiencing increased pain in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Thus, PS may reduce neuronal signaling involved in pain sensation in a subject with migraine. In some cases, the reduction may be complete, such that pain disappears. Furthermore, PS may reduce pain generated via peripheral sensitization or, particularly, via central sensitization. In particular, given the ability of PS to traverse to the central pain-generating site, PS may reduce pain generated via central sensitization. The reduction may be complete, such that pain generation disappears. Thus, PS can reduce pain signaling originating centrally. PS can reduce pain signaling originating in the trigeminal nerve. PS can reduce pain signaling originating in the trigeminal ganglion. PS can reduce pain signaling originating in the trigeminal nucleus caudalis within the trigeminocervical complex (TCC). Given that PS has been shown herein to ascend through peripheral neurons toward the CNS, preliminary observations of the analgesic activity of PS in migraine indicate that PS can reduce pain signaling originating in higher neurons and / or pain-sensing areas of the brain (e.g., trigeminothalamic neurons). The reduction can be complete, such that pain signaling is abolished. In some embodiments, the pain is allodynia, e.g., cutaneous allodynia. The allodynia can be in response to mechanical and / or thermal stimuli. Furthermore, in some embodiments, the pain is hyperalgesia. The pain due to migraine can be neuropathic pain.

[0111] Patients with migraine headaches can be diagnosed using the well-known ICHD-3 guidelines. Migraine pain can be measured using a visual analog pain scale or other suitable methods in the art.

[0112] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS is preferred as a formulation for topical administration. PS can be administered near the sensory branches of the trigeminal nerve (i.e., the ophthalmic nerve, maxillary nerve, and / or mandibular nerve). PS can be administered locally to the face and / or neck of a subject. PS can be administered locally to one or both temples of a subject. In certain cases, PS can be administered locally behind one or both ears of a subject.

[0113] In certain embodiments, PS may be administered orally to treat and / or prevent migraine pain.

[0114] Pain from other headache disorders In light of the observations herein regarding the effectiveness of PS in treating migraine pain, PS may also treat and / or prevent pain in other headache disorders, particularly headache disorders whose pathophysiology manifests as trigeminal dysfunction.

[0115] For example, PS may treat and / or prevent chronic headache, tension-type headache, and / or trigeminal-autonomic headache. Trigeminal-autonomic headache may be cluster headache, hemicrania continua, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms. In some embodiments, PS may treat and / or prevent trigeminal neuralgia, e.g., head-facial pain.

[0116] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS is preferred as a formulation for topical administration. PS can be administered near the sensory branches of the trigeminal nerve (i.e., the ophthalmic nerve, maxillary nerve, and / or mandibular nerve). PS can be administered locally to the face and / or neck of a subject. PS can be administered locally to one or both temples of a subject. In certain cases, PS can be administered locally behind one or both ears of a subject.

[0117] In certain embodiments, PS may be administered orally to treat and / or prevent pain from other headache disorders.

[0118] Corneal neuropathic pain Corneal discomfort affects 5-30% of the population over the age of 50. Corneal neuropathic pain is a condition in which corneal pain is experienced in response to normally non-painful stimuli (e.g., wind or drafts). It reflects the sensitization of centrally acting neurons after prolonged and repeated nociceptive signaling from peripheral neurons in response to direct injury to the corneal nerve. Any mechanical or chemical injury to corneal nerve endings can result in ectopic sprouting and neuroma formation, which exhibit spontaneous activity. Central sensitization, manifested as painful hypersensitivity to innocuous stimuli (allodynia) or exaggerated pain responses to noxious stimuli (hyperalgesia), or even spontaneous signaling, leads to chronic corneal pain that persists even in the absence of peripheral stimuli or clinical signs. Thus, corneal neuropathic pain has a distinctly different pain-generating mechanism compared to, for example, inflammatory eye disorders, which induce acute peripheral pain signaling from the cornea in response to ongoing inflammation.

[0119] Patients with corneal neuropathic pain experience severe corneal pain, as well as irritation such as burning, photophobia, and gritty sensations, even in the absence of peripheral symptoms. Therefore, this indication inevitably negatively impacts the patient's quality of life. Chronic pain accompanied by photosensitivity and irritation leads to functional impairment and an inability to perform normal daily activities.

[0120] Corneal neuropathic pain is particularly difficult to treat. For patients with corneal neuropathic pain who experience corneal pain in the absence of any ongoing corneal pathology, anti-inflammatory medications are ineffective. Instead, centrally acting neuromodulators are often recommended. For example, anticonvulsants (e.g., gabapentin and pregabalin) may be considered first-line treatments, serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine) second-line treatments, and tricyclic antidepressants (e.g., nortriptyline, amitriptyline) third-line treatments. Combination therapy or weak opioids (tramadol) may also be used in a wide range of neuropathic pain settings when treatment is resistant.

[0121] Unfortunately, pain management is not very satisfactory and many systemic treatments induce significant side effects that lead to poor treatment adherence.

[0122] Therefore, there is a great need for compounds that treat and / or prevent corneal neuropathic pain.

[0123] The present inventors have surprisingly found that phosphosulindac (PS) is effective in treating corneal neuropathic pain.

[0124] As mentioned herein, PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS is not a typical NSAID because it does not inhibit the synthesis of COX-1 and COX-2 prostaglandins. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, as well as activity in the treatment of rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests the anti-inflammatory activity of PS in an acute model of dry eye disease (DED) and suggests that PS reduces corneal sensitivity in an acute model of pain development in normal eyes. The observation of decreased sensitivity in healthy eyes to acute stimuli that do not produce persistent pain does not demonstrate efficacy in treating corneal neuropathic pain, which may be related to central sensitization and therefore originate at a central site of action. Furthermore, in this acute model, the effects of PS were observed immediately, suggesting a local action of PS, an atypical NSAID, similar to the activity observed with typical NSAIDs (e.g., ketorolac) in the same model. Again, such peripheral activity does not demonstrate the efficacy of PS in treating pain originating at a central site of action. Indeed, clinical guidance in the field recommends avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and ketorolac has been shown to have limited analgesic activity in this model. Therefore, observations in acute pain models cannot be extrapolated to the treatment of corneal neuropathic pain. Furthermore, in a DED model, PS was observed to restore suppressed corneal sensitivity, suggesting a role for PS in increasing, rather than reducing, nociception.Therefore, while these observations fall short of suggesting a role for PS in the treatment of corneal neuropathic pain, the observations herein demonstrate unprecedented activity of PS in reducing pain generated at a central site of action.

[0125] Indeed, preliminary in vivo evidence indicates the effectiveness of PS in treating corneal neuropathic pain.

[0126] Thus, the present invention provides a method for treating corneal neuropathic pain, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the corneal neuropathic pain is treated.

[0127] In some embodiments, PS is the sulfoxide form of PS. Thus, PS has the formula I (PS-I): [ka] may have:

[0128] In other embodiments, the PS is the sulfide form of PS. Thus, the PS has the formula II (PS-II): [ka] may have:

[0129] As used herein, reference to "phosphosulindac" or "PS" encompasses both PS-I and PS-II. The sulfoxide forms of the compounds are preferred. Compounds of formula I and II are described in U.S. Pat. No. 8,236,820, which is incorporated herein by reference in its entirety.

[0130] Corneal neuropathic pain is also known as ophthalmic neuropathic pain. Therefore, in this specification, the terms "corneal neuropathic pain" and "ophthalmic neuropathic pain" can be used interchangeably. As explained above, corneal neuropathic pain is persistent chronic pain that occurs in light of neuroplastic changes in centrally located neurons due to persistent nociceptive signaling from the periphery. Such changes lead to hyperexcitability of nociceptors in the CNS, so-called central sensitization, which manifests as, for example, allodynia. Pain persists even in the absence of ongoing peripheral triggers, and like other neuropathic pain, the resolution of peripheral pathology does not affect pain sensation, making corneal neuropathic pain particularly difficult to treat. Thus, corneal neuropathic pain can be chronic corneal pain.

[0131] Corneal neuropathic pain can develop as a result of several peripheral drivers of nociception. Typically, corneal neuropathic pain develops in the context of consistent pain signaling originating from the cornea (one of the most densely innervated tissues). As mentioned above, persistent peripheral signaling via the corneal nerves ultimately leads to central sensitization, a key feature of corneal neuropathic pain, which can result in pain sensation even in the absence of peripheral triggers. Therefore, corneal neuropathic pain can be caused by any peripheral stimulus that causes chronic stimulation of the corneal nerves. For example, corneal neuropathic pain can be caused by chronic corneal surface diseases or conditions, such as recurrent corneal erosions, corneal surface neoplasms, and / or inflammatory ocular conditions. Corneal neuropathic pain can be caused by surgical interventions, such as corneal refractive surgery (e.g., photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), and corneal inlay procedures), cataract surgery (e.g., laser cataract surgery), corneal transplant surgery, and / or laser retinopexy. Corneal neuropathic pain can also be caused by laser surgery for the treatment of retinal conditions (e.g., diabetic macular edema; proliferative diabetic retinopathy; macular edema due to retinal vein occlusion; neovascularization secondary to retinal vein occlusion; peripheral retinal degeneration, holes, and / or tears; Eales' disease and other retinal vasculitides; central serous retinopathy; retinopathy of prematurity; and extrafoveal polyps of polypoidal choroidal vasculopathy (PCV)). Corneal neuropathic pain can be caused by infectious diseases, such as herpes simplex keratitis and / or herpes zoster keratitis.Corneal neuropathic pain can be caused by toxic keratopathy, such as caused by topical or systemic drugs (e.g., antiseptics containing benzalkonium chloride or isotretinoin, respectively).Corneal neuropathic pain can be caused by radiation or ultraviolet light exposure.Corneal neuropathic pain can be the result of systemic neuropathy, such as small fiber neuropathy or multiple sclerosis.In addition, corneal neuropathic pain can be caused by trauma, such as chemical burns, which cause damage to corneal nerves.The initial trigger for pain may be air pollution or dry weather, which induces persistent corneal inflammation and ultimately corneal neuropathic pain. Therefore, corneal neuropathic pain can be caused by allergens, such as allergic conjunctivitis. Corneal neuropathic pain can be caused by one or more chalazions, resulting from persistent corneal irritation caused by chalazions during blinking. Persistent peripheral nociceptor signaling in response to these peripheral triggers leads to increased sensitivity of centrally located neurons, resulting in the development of pain even after the initial clinical symptoms have resolved. In fact, even local anesthesia cannot alleviate pain, given the dysregulation of central neuronal signaling.

[0132] Furthermore, in some embodiments, corneal neuropathic pain is caused by direct damage to centrally located neurons, for example, due to ischemia, hemorrhage, mechanical compression, infection, and / or degenerative processes. Additionally, corneal neuropathic pain can be the result of damage to adjacent tissues or nerves, such as the conjunctiva, ocular muscles, the eye, the optic nerve, and / or autonomic or sympathetic nerves.

[0133] Corneal neuropathic pain occurs as a result of persistent peripheral nociceptive signaling, resulting in neuronal sensitization, which manifests as hypersensitivity to innocuous peripheral triggers and associated long-lasting pain. Thus, central sensitization is a hallmark of corneal neuropathic pain. Pain can manifest, for example, as shooting, burning, or stabbing pain associated with other sensory symptoms. Thus, in some embodiments, the present invention provides a method for treating corneal neuropathic pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal neuropathic pain is treated. Subjects experiencing corneal neuropathic pain would benefit from an analgesic that can treat existing corneal neuropathic pain and prevent the development of further corneal neuropathic pain (i.e., prevent further central sensitization). Thus, in some embodiments, PS can be used for the treatment and prevention of corneal neuropathic pain. In accordance with the above, the present invention provides a PS for use in treating corneal neuropathic pain. Furthermore, the present invention provides use of PS for the manufacture of a medicament for the treatment of corneal neuropathic pain.

[0134] Based on the observations herein, PS has a direct analgesic effect on corneal neuropathic pain.Corneal neuropathic pain can be stabbing pain or burning pain.In treating corneal neuropathic pain, PS can reduce corneal neuropathic pain.In some cases, the reduction can be complete, such that corneal neuropathic pain disappears.In treating corneal neuropathic pain, PS can also reduce one or more of the associated sensory symptoms.

[0135] Patients suffering from corneal neuropathic pain describe a variety of sensory symptoms. These include paresthesia (e.g., numbness, tingling, prickling, and / or crawling), photosensitivity, or photoallodynia. Even if the sensory symptoms experienced by the subject are not considered painful (or do not reach the threshold required to be considered painful in themselves), PS can reduce any one or more of the sensory symptoms experienced by the subject, including those listed above. In some cases, the reduction can be complete, such that one or more of the associated sensory symptoms disappear. Furthermore, in treating corneal neuropathic pain, PS can improve other associated symptoms in the subject, such as anxiety, depression, and / or apathy.

[0136] As described above, corneal neuropathic pain occurs as a result of the overactivity of centrally located neurons, which exhibit a decreased stimulus threshold and can depolarize even in the absence of peripheral stimuli. Indeed, the perception of pain is no longer linked to the presence, intensity, or duration of a specific peripheral stimulus (noxious or not). Therefore, corneal neuropathic pain may be the result of central sensitization. Accordingly, subjects with corneal neuropathic pain may experience pain induced by non-painful stimuli (allodynia) and / or increased pain in response to noxious stimuli (hyperalgesia). Based on preliminary observations, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Therefore, PS may reduce neuronal signaling involved in pain sensation in subjects with corneal neuropathic pain. Given the ability of PS to traverse to the central pain-generating site, PS may reduce pain generated through central sensitization. Therefore, PS may reduce centrally generated pain signaling. Corneal nociceptors constitute the first branch of the trigeminal nerve and transmit to the trigeminal ganglion and trigeminal nucleus caudalis. PS can reduce pain signaling originating in the trigeminal ganglion. PS can reduce pain signaling originating in the trigeminal nucleus caudalis within the trigeminocervical complex (TCC). Given that PS is shown herein to ascend peripheral neurons toward the CNS, PS can reduce pain signaling originating in higher neurons and / or pain-sensing areas of the brain (e.g., trigeminothalamic neurons). In some cases, the reduction can be complete, such that pain signaling is eliminated. In some embodiments, the corneal neuropathic pain is allodynia. The allodynia can be in response to mechanical and / or thermal stimuli. Additionally or alternatively, the corneal neuropathic pain in a subject can be hyperalgesia. In some embodiments, the corneal neuropathic pain is chronic corneal neuropathic pain. In some embodiments, the corneal neuropathic pain is not acute corneal pain.

[0137] Corneal neuropathic pain in patients can be measured using a visual analog pain scale or other suitable methods in the art.

[0138] Considering the observations herein, PS exhibits direct activity on neurons involved in the generation of pain caused by central sensitization. Therefore, PS may also be useful for treating certain forms of corneal pain. Corneal pain is also known as ocular pain, and therefore these terms may be used interchangeably herein. For example, PS can treat corneal pain caused by central sensitization. Therefore, the present invention also provides a method for treating corneal pain caused by central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the corneal pain caused by central sensitization is treated. In fact, PS can treat corneal pain manifested as allodynia. PS can treat corneal pain manifested as hyperalgesia. Because pain is caused by central sensitization, it is experienced in the absence of ongoing harmful peripheral triggers (e.g., corneal inflammation). Corneal pain can be chronic pain (i.e., pain lasting for more than 3 months). In certain embodiments, the corneal pain is not acute pain, such as acute pain associated with DED (ie, pain experienced as a result of ongoing corneal inflammation).

[0139] PS can be useful for treating corneal pain that occurs at the central site of action (i.e., the site responsible for central pain signaling in the absence of ongoing peripheral triggers). Therefore, the present invention provides a method for treating corneal pain that occurs at the central site of action, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal pain that occurs at the central site of action is treated. Indeed, given the observations herein, PS may treat corneal pain in light of its ability to traverse to the central site of action. For example, PS may reduce corneal pain by accumulating in the trigeminal nucleus caudalis or higher-order neurons in the CNS. Therefore, PS may act directly on the pain-generating center in the trigeminal nucleus caudalis or higher-order neurons in the CNS. Therefore, the present invention provides a method for treating corneal pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal pain is treated, wherein PS reduces pain signaling that occurs in the trigeminal nucleus caudalis or higher-order neurons in the CNS. In some cases, the reduction can be complete, such that pain signaling is eliminated.

[0140] The observations herein demonstrate the ability of PS, when topically administered to the outer surface of the eyelid, to penetrate the eyelid tissue and reach the cornea in therapeutically significant amounts. Administration to the outer surface of the eyelid avoids the need for eye drops, which can cause a stinging sensation, thereby reducing patient compliance and, therefore, therapeutic success. Furthermore, administration to the outer surface of the eyelid is preferable for patients with reduced motor function or lost fine motor skills, who may have difficulty administering eye drops. Naturally, such administration to the outer surface of the eyelid requires that the therapeutic agent effectively penetrate the eyelid to reach the ocular surface in therapeutically significant amounts. Thus, the observations herein confirm the efficacy of administration of PS to the outer surface of the eyelid as a suitable topical administration route for treating various ocular diseases and conditions, particularly in cases where the therapeutic agent must reach the ocular surface in therapeutically significant amounts to achieve therapeutic efficacy. Without wishing to be bound by theory, the ability of PS to reach corneal nerves in therapeutically significant amounts may enable PS to traverse along peripheral corneal neurons toward its central site of action, thus providing a pathway by which PS can reach the pain-generating centers associated with corneal pain, even when administered topically to the outer surface of the eyelid.

[0141] Therefore, in a further aspect, the present invention provides PS for use in therapy, wherein PS is topically administered to the outer surface of one or more eyelids.The present invention also provides a method for treating and / or preventing an eye disease or eye condition, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the eye disease or eye condition is treated and / or prevented, wherein PS is topically administered to the outer surface of one or more eyelids.The eye disease or eye condition can be corneal pain, such as corneal pain described herein, for example, corneal neuropathic pain.Therefore, the present invention also provides a method for treating and / or preventing corneal pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof so that the corneal pain is treated and / or prevented, wherein PS is topically administered to the outer surface of one or more eyelids.The one or more eyelids can be one or both upper eyelids and / or one or both lower eyelids.

[0142] Corneal pain can be caused by central sensitization. Corneal pain can occur at a central site of action. As shown herein, corneal pain can be caused by one or more surgical interventions, such as corneal refractive surgery (including PRK, LASIK, SMILE, and / or corneal inlay procedures), laser retinopexy, cataract surgery (e.g., laser cataract surgery), and / or corneal transplant surgery. Also, as discussed herein, corneal pain can be caused by laser surgery for the treatment of retinal pathologies (e.g., diabetic macular edema; proliferative diabetic retinopathy; macular edema due to retinal vein occlusion; neovascularization secondary to retinal vein occlusion; peripheral retinal degeneration, holes, and / or tears; Eales' disease and other retinal vasculitis; central serous retinopathy; retinopathy of prematurity; extrafoveal polyps of polypoidal choroidal vasculopathy (PCV)). Corneal pain can be caused by intravitreal injection (e.g., for the treatment of wet age-related macular degeneration (AMD)). Corneal pain can be experienced during or after a surgical intervention or procedure. Thus, PS can be administered before, during, or after a surgical intervention or procedure. In certain cases, corneal pain is experienced during a surgical intervention or procedure. Thus, PS can be administered before or during a surgical intervention or procedure. As described herein, corneal pain can be caused by an inflammatory eye disease or ocular condition. The inflammatory eye disease or ocular condition can be dry eye disease (DED). The inflammatory eye disease or ocular condition can be allergic conjunctivitis. Corneal pain can be caused by one or more chalazions, for example, due to persistent irritation of the cornea caused by the chalazions during blinking. Corneal pain can be pain caused by one or more of the following: chronic corneal surface disease or condition (e.g., recurrent corneal erosions, corneal surface neoplasms, and / or inflammatory ocular conditions, such as dry eye disease (DED), or inflammatory ocular conditions caused by allergens, such as allergic conjunctivitis); infection (e.g., herpes simplex keratitis and / or herpes zoster keratitis); toxic keratopathy (e.g., to topical or systemic agents); radiation or ultraviolet light exposure; trauma (e.g., chemical burns).

[0143] The eye disease or eye condition can be an inflammatory eye disease or eye condition.The inflammatory eye disease or eye condition can be dry eye disease (DED), conjunctivitis (e.g., allergic conjunctivitis), keratitis, scleritis, or uveitis.In certain embodiments, the eye disease or eye condition is dry eye disease (DED).

[0144] In accordance with the above, the present invention provides PS for use in the treatment and / or prevention of an ocular disease or condition, wherein the PS is topically administered to the outer surface of one or more eyelids. Further, the present invention provides use of PS for the manufacture of a medicament for treating and / or preventing an ocular disease or condition, wherein the PS is topically administered to the outer surface of one or more eyelids.

[0145] PS can be formulated into a pharmaceutical composition for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS can be formulated for topical administration.

[0146] The preparation disclosed herein for topical administration of PS to the outer surface of eyelid can be used in the method disclosed herein.Eyelid can be upper eyelid or lower eyelid.When topical administration to the outer surface of eyelid, PS is applied substantially entirely to the outer surface of eyelid.

[0147] Pharmaceutical Composition The PS for use in the methods of the present invention can be formulated into a pharmaceutical composition suitable for administration to a subject in need thereof, such as a subject suffering from pain associated with central sensitization, a subject suffering from PTPN, a subject suffering from PHN, a subject suffering from migraine pain (or pain from other headache disorders), or a subject suffering from corneal neuropathic pain.The pharmaceutical composition is typically formulated to provide a therapeutically effective amount of PS and may further comprise a pharmaceutically acceptable excipient.In certain embodiments, the pharmaceutical composition comprising PS can be formulated for topical use in the present invention.

[0148] Pain associated with central sensitization can be systemic or occur in various parts of the body. Pain can be diffuse and widespread, or localized to the area where the initial pain signaling occurs. Pain typically manifests in peripheral areas. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral area where pain is experienced. Therefore, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration.

[0149] Neuropathic pain associated with PTPN is sensed within the injured tissue, but pain can also radiate proximal to the injury site. In either case, pain is sensed from peripheral regions. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral area where neuropathic pain is experienced. Furthermore, pharmaceutical compositions containing PS can be applied to the area where one or more sensory symptoms of PTPN are experienced. Therefore, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration. A single application to the affected area may require less than about 5 ml of pharmaceutical composition, for example, about 3 ml of pharmaceutical composition.

[0150] Neuropathic pain associated with PHN most commonly manifests on the subject's torso. As outlined above, PHN tends to affect one or two adjacent dermatomes and generally does not cross the midline of the body. Less frequently, PHN can affect three or more dermatomes, resulting in a more widespread condition. Typically, neuropathic pain associated with PHN manifests in one or more thoracic dermatomes (i.e., the subject's torso). Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to peripheral locations experiencing neuropathic pain, such as thoracic dermatomes on the subject's torso. Furthermore, pharmaceutical compositions containing PS can be applied to locations experiencing one or more sensory symptoms of PHN. Therefore, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration, particularly to the skin of a subject's thoracic dermatomes. A single application to one or more thoracic dermatomes may require up to about 15 ml of pharmaceutical composition. A single application to both areas (i.e., three or more dermatomes) affected by neuropathic pain associated with disseminated shingles may require up to about 30 ml of pharmaceutical composition.

[0151] Migraine pain (and the pain of other headache disorders) is perceived as headache and facial pain. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied directly to the peripheral location where pain is experienced, such as the head and / or neck of a subject. Thus, pharmaceutical compositions containing PS can be formulated for topical administration. In particular, pharmaceutical compositions containing PS can be formulated for transdermal administration, particularly to the skin near the sensory branches of the trigeminal nerve. PS can be administered to the skin of a subject's head and / or neck. PS can be administered locally where the neck meets the base of the skull. PS can be administered locally to one or both of a subject's temples. PS can be administered locally behind one or both of a subject's ears. For example, a single application to a temple or behind an ear may require less than about 2 ml of pharmaceutical composition, for example, about 1 ml of pharmaceutical composition (i.e., about 0.5 ml of pharmaceutical composition per temple or behind each ear).

[0152] Corneal neuropathic pain, such as corneal pain, is sensed by the eye. Therefore, particularly useful pharmaceutical compositions containing PS are those that can be applied so that they reach the eyeball of a subject experiencing corneal neuropathic pain in a therapeutically significant amount. Thus, a pharmaceutical composition containing PS can be directly applied to one or both eyes of a subject experiencing corneal neuropathic pain. Thus, a pharmaceutical composition containing PS can be formulated for topical administration to the ocular surface (i.e., to the eyeball), for example, onto the cornea or the canthus. In a preferred embodiment, a pharmaceutical composition containing PS can be topically applied to the outer surface of one or more eyelids of a subject. Thus, a pharmaceutical composition containing PS can be formulated for transdermal administration, particularly to the skin of one or more eyelids of a subject (i.e., the outer surface of one or more eyelids of a subject). The one or more eyelids can be one or both upper eyelids. The one or more eyelids can be one or both lower eyelids. In the case of topical administration to the outer surface of the eyelid, substantially all of the PS is applied to the outer surface of the eyelid. In certain cases, the lower eyelid may be preferred because the outer surface of the lower eyelid is less damaged by the blinking process than the outer surface of the upper eyelid (i.e., when the eye is open, the outer surface of the upper eyelid is parallel to the skin of the orbit).In certain cases, the upper eyelid may be preferred because the surface area of ​​the outer surface for topical administration is typically larger.A single application to one eyelid may require less than about 1 ml of pharmaceutical composition, for example, about 0.5 ml of pharmaceutical composition.

[0153] In some embodiments, pharmaceutical compositions containing PS can be formulated as semisolids or liquids. Thus, pharmaceutical compositions containing PS can be formulated as creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. These compositions vary in the relative concentrations of oil and water, resulting in different densities. Altering the density of the formulation is a means by which the exposure of the affected area to the pharmaceutical composition can be controlled. For example, a less dense formulation that requires rubbing until absorbed may result in a shorter exposure time. Alternatively, a denser formulation that is not easily absorbed may allow for prolonged exposure of the affected area to the pharmaceutical ingredient. Those skilled in the art will recognize the formulation of topical pharmaceutical compositions to alter the relative exposure of the affected area to the active pharmaceutical ingredient.

[0154] For the treatment of corneal neuropathic pain, pharmaceutical compositions containing PS for topical administration to the ocular surface and / or the outer surface of the eyelid can be formulated as a gel (e.g., hydrogel) or ointment. For topical administration to the ocular surface, pharmaceutical compositions containing PS can be formulated as a gel (e.g., hydrogel), ointment, and / or eye drops. For topical administration to the outer surface of the eyelid, pharmaceutical compositions containing PS can be formulated as a cream, gel (e.g., hydrogel), lotion, ointment, foam, and / or spray.

[0155] In other embodiments, pharmaceutical compositions containing PS can be formulated as patches that can be applied to the skin, which can be manufactured in a manner that ensures controlled release of PS to the affected area.

[0156] In some embodiments for treating corneal neuropathic pain, a pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin of one or more eyelids (e.g., one or both lower eyelids) of a subject. The patch can be manufactured in a manner that ensures controlled release of PS through the outer surface of the eyelid so that a therapeutically appropriate amount of PS reaches the ocular surface.

[0157] In certain embodiments for treating corneal neuropathic pain, a pharmaceutical composition comprising PS can be formulated as an eye drop. Such eye drop formulations can include liquid or semisolid pharmaceutical compositions adapted for administration to the eye. A typical example of an eye drop composition is an eye drop solution administered dropwise to the eye. In some embodiments, the eye drop composition is an eye drop emulsion administered dropwise to the eye. In some embodiments, the drop volume is about 10 to about 100 μL. The drop volume can be greater than about 10 μL, greater than about 20 μL, greater than about 30 μL, greater than about 40 μL, greater than about 50 μL, greater than about 60 μL, greater than about 70 μL, greater than about 80 μL, greater than about 90 μL, or greater than about 100 μL. The drop volume can be less than about 10 μL, less than about 20 μL, less than about 30 μL, less than about 40 μL, less than about 50 μL, less than about 60 μL, less than about 70 μL, less than about 80 μL, less than about 90 μL, or less than about 100 μL.

[0158] Formulations suitable for topical administration and suitable pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO2019 / 067919, which is incorporated herein by reference in its entirety.

[0159] In some embodiments, formulations of PS suitable for topical administration may contain PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, PS may be present in concentrations of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, PS can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0160] In some embodiments for treating corneal neuropathic pain, formulations of PS suitable for topical administration to the ocular surface and / or the outer surface of the eyelid may contain PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, PS may be present in concentrations of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, PS can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0161] Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating pain associated with central sensitization. Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating and / or preventing neuropathic pain associated with PTPN. Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating and / or preventing migraine pain (or pain from other headache disorders). Pharmaceutical compositions comprising PS may alternatively be formulated for any other dosage form suitable for treating and / or preventing neuropathic pain associated with PHN. For example, the composition may be formulated for transdermal administration or injection, for example, subcutaneous injection.

[0162] In certain embodiments for treating corneal neuropathic pain, the composition may be formulated for intravitreal injection.

[0163] The formulations disclosed herein are also suitable for treating corneal pain, such as corneal pain caused by central sensitization and / or corneal pain that occurs at a central site of action.

[0164] As previously disclosed herein, in a further aspect, the present invention provides PS for use in therapy, wherein the PS is topically administered to one or more outer surfaces of the eyelid. The present invention also provides a method for treating and / or preventing an ocular disease or condition, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the ocular disease or condition is treated and / or prevented, wherein the PS is topically administered to one or more outer surfaces of the eyelid.

[0165] In some embodiments of topical administration of PS to the outer surface of one or more eyelids, the pharmaceutical composition comprising PS can be formulated as a gel (e.g., a hydrogel) or an ointment. For topical administration to the outer surface of the eyelid, the pharmaceutical composition comprising PS can be formulated as a cream, gel (e.g., a hydrogel), lotion, ointment, foam, and / or spray.

[0166] In some embodiments of topical administration of PS to the outer surface of one or more eyelids, a pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin of one or more eyelids (e.g., one or both lower eyelids) of a subject. The patch can be manufactured in a manner that ensures controlled release of PS through the outer surface of the eyelid so that a therapeutically appropriate amount of PS reaches the ocular surface.

[0167] In some embodiments of topical administration of PS to the outer surface of one or more eyelids, the PS formulation may contain PS at a concentration of about 0.5% (w / w) to about 15% (w / w) of the pharmaceutical composition. Thus, PS may be present in concentrations of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% (w / w) of the pharmaceutical composition, particularly about 3% (w / w) of the pharmaceutical composition.As a further illustrative example, when formulated as a gel, PS can be at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, 5% (w / w) or less of the pharmaceutical composition, particularly 3% (w / w) or less of the pharmaceutical composition, for example, about 2% or about 1% (w / w) of the pharmaceutical composition.In certain formulations, for example, when formulated as a hydrogel or ointment, PS can be at a concentration of 5% (w / w) of the pharmaceutical composition.

[0168] A single application to one eyelid may require less than about 1 ml of the pharmaceutical composition, for example, about 0.5 ml of the pharmaceutical composition.

[0169] The observations herein surprisingly demonstrate that PS, even when administered orally, has a direct effect on neuronal pain signaling that originates centrally (e.g., via central sensitization). Previous observations have shown that when administered locally, PS traverses peripheral neurons toward central sites, thus enabling PS to act directly on neurons involved in pain generation. Local administration of PS is administered to areas of high peripheral sensory neuron concentration, allowing for its uptake and transport to the central site of action in amounts high enough to achieve analgesic effects. It was unexpected that oral administration of PS would also achieve analgesic effects for indications known to have central pain generation sites, such as pain associated with central sensitization, pain associated with PTPN, pain associated with postherpetic neuralgia (PHN), and pain due to migraine. Indeed, typical NSAIDs have been shown to be ineffective in treating neuropathic pain, regardless of the route of administration (Moore et al., Cochrane Database of Systematic Reviews (2015); 10:1-25). The Cochrane Library concluded that NSAIDs should not be recommended for the treatment of neuropathic pain.

[0170] The observations herein demonstrate that upon oral administration, PS is found in therapeutically significant amounts in pain-sensing regions of the brain (e.g., the medulla oblongata and cerebellum). The evidence herein demonstrates that PS is taken up by neurons innervating the stomach wall and traverses along the vagus nerve to reach central sites in the brain. These observations are supported by observations demonstrating the translocation of PS along the sciatic nerve and the absence of therapeutic levels of PS in the blood. Thus, without wishing to be bound by theory, PS may exert its direct analgesic effect on neurons in centrally located pain-sensing regions of the brain, providing an elegant mechanism by which centrally generated pain may be relieved regardless of its original etiology.

[0171] Thus, PS can be administered orally. In some embodiments, pharmaceutical compositions comprising PS for use in the present invention can be formulated for oral administration.

[0172] Thus, the present invention provides a method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that pain associated with central sensitization is treated, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with CIPN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with PTPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PTPN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing neuropathic pain associated with PHN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with PHN is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing migraine pain (or pain associated with other headache disorders), comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that migraine pain (or pain associated with other headache disorders) is treated and / or prevented, wherein the PS is administered orally. The present invention provides a method for treating and / or preventing corneal neuropathic pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that corneal neuropathic pain is treated and / or prevented, wherein the PS is administered orally.

[0173] PS for oral administration can be formulated as a liquid or solid dosage form.

[0174] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.

[0175] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, or granules. Tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation field. Capsules, tablets, and pills can be designed to release PS only or preferentially in a specific part of the intestinal tract, such as the stomach, optionally in a delayed manner.

[0176] In some embodiments, formulations for oral administration include one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-static agents.

[0177] Formulations suitable for oral administration may contain PS at a concentration of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0178] Even when administered orally, PS reduces pain signaling occurring in the CNS, particularly pain-sensing regions of the brain. In some embodiments, oral administration of PS reduces pain signaling occurring in the brain. Upon oral administration, PS can accumulate (via the vagus nerve) at therapeutically significant levels in the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray (PAG). In certain embodiments, upon oral administration, PS accumulates at therapeutically significant levels in the medulla oblongata and / or cerebellum. PS, for example, upon oral administration, can reduce pain signaling in the somatosensory cortex, for example, the primary somatosensory cortex. Orally administered PS can reduce pain signaling in one or more of the following brain regions: the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray. In certain embodiments, orally administered PS can reduce pain signaling in the medulla oblongata and / or cerebellum.

[0179] Dosing regimen An appropriate dosing regimen for PS for treating an indication described herein (e.g., pain associated with central sensitization, neuropathic pain associated with PTPN, neuropathic pain associated with PHN, migraine pain (and pain of other headache disorders), or corneal neuropathic pain) will depend on variables such as the type and progression of pain (e.g., as determined by the World Health Organization "pain ladder" guidelines), the severity of the pain (e.g., acute, subacute, or chronic), the age, weight, and general condition of the particular patient, the formulation of excipients, the route of administration, and the judgment of the attending clinician.

[0180] For local administration, PS can be administered to cover one or more affected areas (i.e., peripheral areas experiencing pain) of the subject. In some embodiments, about 0.01 to about 5 g of PS can be administered to the affected area. In terms of the size of the affected area, PS can be administered in a volume of about 0.005 to 0.25 g / 10 cm. 2 Therefore, PS can be administered at a dose of about 0.005 g / 10 cm2 , 0.01g / 10cm 2 , 0.05g / 10cm 2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 It can be administered locally.

[0181] In the case of local administration to treat and / or prevent neuropathic pain associated with PHN, PS can be administered to cover one or more affected areas of a subject, for example, one or more thoracic dermatomes. PS can be administered, for example, topically, to the site of the rash or to the area experiencing sensory symptoms preceding the onset of the rash. Thus, PS can be administered locally (e.g., to one or more thoracic dermatomes) during the prodromal phase or rash phase. Thus, PS can be administered prophylactically to prevent the development of neuropathic pain associated with PHN after the rash has resolved. In certain embodiments, PS is administered, for example, topically, to the original rash site after the rash and / or skin lesions have resolved. Thus, PS can be administered locally (e.g., to one or more thoracic dermatomes) after the rash and / or skin lesions have resolved. In these cases, PS can prevent PHN-associated neuropathic pain from occurring or treat PHN-associated neuropathic pain already established at the original rash site.

[0182] For local administration to treat and / or prevent migraine pain (or pain associated with other headache disorders), PS can be administered to cover one or more affected areas, for example, the subject's temples or behind each ear.

[0183] For topical administration to the ocular surface, PS can be administered to cover the affected area (i.e., the ocular surface). For topical administration to the outer surface of the eyelid, PS can be administered to ensure that a therapeutically appropriate amount of PS reaches the ocular surface upon topical administration to the outer surface of the eyelid. As described above, for topical administration to the outer surface of the eyelid, PS is applied substantially entirely to the outer surface of the eyelid.

[0184] In embodiments of topical administration to the ocular surface, about 0.001 to about 1 mg of PS may be administered to the ocular surface. In terms of ocular surface size, PS may be administered in the range of about 0.005 to 0.25 mg / cm. 2 It can be administered on the ocular surface. Thus, PS can be administered at a concentration of about 0.005 mg / cm 2 , 0.01 mg / cm 2 , 0.05 mg / cm 2 , 0.1 mg / cm 2 , 0.15 mg / cm 2 , 0.2 mg / cm 2 or 0.25 mg / cm 2 The PS may be administered superficially to the eye. The PS may be administered at about 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, or 0.25 mg per drop.

[0185] In embodiments of topical administration to the outer surface of the eyelid, about 0.1 to about 250 mg of PS may be administered to the outer surface of the eyelid. With respect to the size of the outer surface of the eyelid, PS may be administered in a range of about 0.5 to 100 mg / cm. 2 It can be administered on the outer surface of the eyelid. Thus, PS can be administered at a dose of about 0.5 mg / cm 2 , 5 mg / cm 2 , 10 mg / cm 2 , 25 mg / cm 2 , 50 mg / cm 2 , 75 mg / cm 2 or 100 mg / cm 2 It may be administered on the outer surface of the eyelid.

[0186] In some cases, PS for use in topical administration for the methods of the present invention may be applied to the affected area and then removed from the affected area (e.g., by washing off) before reapplication. In some cases, the PS is washed off after a certain period of time. Alternatively, because the analgesic effect may decrease over time, making reapplication necessary, in some cases the PS is not washed off; instead, the PS is simply reapplied to the affected area after an appropriate administration period has elapsed. For example, the PS may be applied to the affected area and left on the affected area for about 0.5 to about 5 hours (before removal or reapplication). Thus, the PS may be applied topically to the affected area and left on for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours (before removal or reapplication).

[0187] Because the analgesic effect may decrease over time, PS for topical administration to the ocular surface and / or outer eyelid surface may, in some cases, be reapplied to the ocular surface and / or outer eyelid surface after an appropriate administration period has elapsed. For embodiments involving topical administration to the outer eyelid surface, PS may be removed from the outer eyelid surface (e.g., by rinsing) before reapplication. In some cases, PS is washed off after a period of time. In some cases, PS is not washed off; instead, PS is simply reapplied. For example, PS may be applied to the ocular surface and / or outer eyelid surface and left on the ocular surface and / or outer eyelid surface for about 0.5 to about 5 hours (before removal or reapplication). Thus, PS may be topically applied to the ocular surface and / or outer eyelid surface and left on the ocular surface and / or outer eyelid surface for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours (before removal or reapplication).

[0188] Pain associated with the indications described herein (e.g., pain associated with central sensitization, neuropathic pain associated with PTPN, and neuropathic pain associated with PHN) is chronic, necessitating repeated topical administration of PS. Similarly, pain from migraine (and other headache disorders) can be prolonged, e.g., up to 72 hours, and even longer in the case of chronic migraine, necessitating repeated topical administration of PS. Therefore, PS can be applied topically one to four times daily. Thus, PS can be applied once daily, twice daily, three times daily, or four times daily. In certain formulations of PS, such as hydrogels or ointments with a PS concentration of approximately 5% (w / w) of the pharmaceutical composition, the formulation can be applied topically three times daily. In more severe cases, additional applications of PS can be applied approximately 0.5 hours after each application.

[0189] Because corneal neuropathic pain is chronic, repeated topical administration of PS is necessary. Therefore, PS can be applied topically to the ocular surface and / or outer surface of the eyelid one to four times daily. Therefore, PS can be applied once daily, twice daily, three times daily, or four times daily. In certain formulations of PS, such as hydrogels or ointments with a PS concentration of approximately 5% (w / w) of the pharmaceutical composition, the formulation can be applied topically to the ocular surface and / or outer surface of the eyelid three times daily. In more severe cases, additional applications of PS can be applied approximately 0.5 hours after each application. Because PS can have a long-lasting analgesic effect, it can be administered less frequently. For example, PS can be administered topically less than once daily, e.g., once every two days. Indeed, for patients who experience long-term pain relief with a single administration, PS can be administered topically less than once a week, e.g., once every two weeks.

[0190] In some embodiments of topical administration to the ocular surface and / or outer surface of the eyelid, PS can have a long-lasting analgesic effect, so it can be administered less frequently.For example, PS can be topically administered to the ocular surface and / or outer surface of the eyelid less than once a day, for example, once every two days.In fact, for patients who experience long-term analgesia with a single administration, PS can be topically administered to the ocular surface and / or outer surface of the eyelid less than once a week, for example, once every two weeks.

[0191] In the case of topical administration of some pharmaceutical compositions, after applying the pharmaceutical composition, it is useful to cover the affected area with, for example, a bandage (for example, a plastic wrap or film) to ensure that an appropriate amount of the composition can be applied for an appropriate period of time.Therefore, after topical application of PS, the affected area may be bandaged.

[0192] In some embodiments, PS can be administered topically in the form of a patch, such as a medicated patch. The use of a patch can reduce the administration interval and / or frequency, for example, because the patch ensures controlled release of PS. Thus, the patch can be applied to the affected area once a day.

[0193] In some embodiments of topical administration to the outer surface of the eyelid, PS can be topically administered to the outer surface of the eyelid in the form of a patch, for example, a medicated patch.The use of a patch can reduce the administration interval and / or administration frequency, for example, because the patch ensures controlled release of PS.Therefore, the patch can be applied to the outer surface of the eyelid once a day.

[0194] PS may be orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight. In certain embodiments, PS may be administered at a dosage level of about 1 mg / kg to about 5 mg / kg, e.g., about 3 mg / kg of the subject's body weight.

[0195] PS may be orally administered at a dosage of about 1 mg to about 2000 mg. In some embodiments, PS may be orally administered at a dosage of about 100 mg to 1500 mg, e.g., about 200 mg to about 1000 mg. In some embodiments, PS may be orally administered at a dosage of about 50 mg to about 400 mg, e.g., about 100 mg to about 350 mg, e.g., about 150 mg to about 300 mg, e.g., about 150 mg to about 250 mg. In certain embodiments, PS is orally administered at a dosage of about 250 mg to about 300 mg, preferably about 250 mg. In some embodiments of multiple doses, equal amounts of PS may be administered with each dose. In other embodiments, a higher initial dose, followed by a lower maintenance dose, may be administered.

[0196] In some embodiments, PS can be orally administered once a day or more frequently.For example, PS can be orally administered twice a day, three times a day, four times a day, or more frequently as needed.In certain embodiments, PS can be orally administered twice or three times a day.

[0197] In certain embodiments, PS is orally administered twice daily at a dosage of about 150 mg to about 200 mg. Thus, a subject may be orally administered a daily dosage of about 300 mg to about 400 mg of PS.

[0198] In certain embodiments, PS is orally administered at a dosage of about 250 mg to about 300 mg (e.g., about 250 mg) two or three times daily. Thus, a subject may be orally administered PS at a daily dosage of about 500 mg to a maximum of about 900 mg.

[0199] Administration of PS may be continued as long as necessary. For example, PS may be administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, more than 28 days, more than 56 days, or more than 84 days. As described above, PS may be administered continuously, for example, chronically for at least 3 months, for chronically effective treatment. Thus, in some cases, continuous administration is achieved and maintained as long as necessary. PS may be administered intermittently in response to recurrence of pain and / or associated sensory symptoms associated with the indications described herein.

[0200] The PS can be used in mammals for the treatment (and prevention) of pain associated with the indications described herein. For example, the subject can be a human.

[0201] As mentioned above, PS can be formulated into a pharmaceutical composition suitable for administration to a subject with any one of the indications described herein (e.g., pain associated with central sensitization, PTPN, PHN, migraine (other headache disorders), or corneal neuropathic pain). Thus, PS can be administered in a suitable pharmaceutical composition according to the above-mentioned dosage regimen. In certain embodiments, PS, or a suitable pharmaceutical composition of PS, is administered as a monotherapy.

[0202] The dosing regimens disclosed herein are suitable for treating corneal pain, such as corneal pain caused by central sensitization and / or corneal pain that occurs at a central site of action. Indeed, the dosing regimens disclosed herein are applicable for use in any of the methods of treatment disclosed herein.

[0203] Those skilled in the art will understand that in certain embodiments, the dosage of such compounds may be adjusted depending on the mammal being treated. For example, the treatment of mice is described herein, and such dosage may or may not be modified when administering PS to humans. However, those skilled in the art may, if necessary, convert the dosages provided herein as set forth in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, USDapartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. The human equivalent dose (HED) may be determined from the animal dose and may be multiplied by the following conversion factors to obtain units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, micropig = 0.73, and minipig = 0.95.

[0204] Pharmaceutically acceptable forms of PS Pharmaceutical compositions comprising PS can contain pharmaceutically acceptable forms of PS, which can be solvates, derivatives, and / or prodrugs.

[0205] solvate As used herein, the term "solvate" refers to a compound that further contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable forms of PS can include solvates of PS, such as solvates of PS-I and / or PS-II. In some embodiments, the solvate contains at least one molecule of solvent. In some embodiments, the solvate contains less than one molecule of solvent. In some embodiments, the solvate is a hydrate.

[0206] Isotopes Pharmaceutically acceptable forms of PS can include isotopically labeled derivatives of PS-I. Pharmaceutically acceptable forms of PS can include isotopically labeled derivatives of PS-II. Isotopically labeled derivatives are compounds that are identical to PS except that one or more atoms have been replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, isotopically labeled derivatives of PS contain one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, isotopically labeled derivatives of PS contain one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine, respectively. 2 H, 3 H, 13 C. 14 C. 18 O. 17 O. 31 P, 32 P, 35 S, and 18 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of F. 2 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of H (e.g., deuterium). 3 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of H (e.g., tritium). 14 Contains one or more isotopes of C.

[0207] Derivatives and Prodrugs Pharmaceutically acceptable forms of PS can include derivatives of PS-I. Pharmaceutically acceptable forms of PS can include derivatives of PS-II. In some embodiments, a derivative of PS (e.g., PS-I or PS-II) is a metabolite. In other embodiments, a pharmaceutically acceptable form of PS is a prodrug of PS (e.g., a prodrug of PS-I or a prodrug of PS-II).

[0208] The sulfone group can be structurally represented as RS(=O)2-R'. In some embodiments, the derivative of PS is the sulfone form of PS.

[0209] PS contains an organophosphate functional group, which can be structurally represented as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR''). For example, O=P(OR)2(OR') can represent PS when R=CH2CH3 and R'= the remainder of the molecule conforms to PS in Formula I or II (e.g., PS-I, PS-II, or a derivative thereof).

[0210] In some embodiments, the derivative of PS is PS in which one of the ethoxy (e.g., -OCH2CH3) groups is an OH group, or a pharmaceutically acceptable salt thereof. In some embodiments, the derivative of PS is PS in which both of the ethoxy (e.g., -OCH2CH3) groups are OH groups, or a pharmaceutically acceptable salt thereof.

[0211] The activities of PS demonstrated herein may also be shared by pharmaceutically acceptable forms thereof. Accordingly, the present invention provides pharmaceutically acceptable forms of PS for use in the methods of the present invention.

[0212] While preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the present invention.

[0213] Numbered Embodiments The present invention further provides the following numbered embodiments:

[0214] 1. A method for treating pain associated with central sensitization, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the pain associated with central sensitization is treated.

[0215] 2. The method of embodiment 1, wherein said treating pain comprises reducing said pain.

[0216] 3. The method of any one of the preceding embodiments, wherein said treating pain comprises reducing one or more symptoms associated with central sensitization.

[0217] 4. The method of embodiment 3, wherein the one or more symptoms are selected from mood swings, fatigue, cognitive impairment, sleep changes, pain catastrophizing, memory complaints, depression, anxiety, photophobia, and / or phonophobia.

[0218] 5. The method of any one of the preceding embodiments, wherein said PS reduces neuronal signaling involved in pain sensation.

[0219] 6. The method of any one of the preceding embodiments, wherein said PS reduces centrally generated pain signaling.

[0220] 7. The method of any one of the preceding embodiments, wherein said PS reduces pain signaling originating in the dorsal horn of the spinal cord.

[0221] 8. The method of any one of the preceding embodiments, wherein said PS reduces pain signaling occurring in the CNS.

[0222] 9. The method of any one of the preceding embodiments, wherein said pain is allodynia.

[0223] 10. The method of embodiment 9, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0224] 11. The method of any one of the preceding embodiments, wherein said pain is hyperalgesia.

[0225] 12. A method for treating and / or preventing neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the neuropathic pain associated with PTPN is treated and / or prevented.

[0226] 13. The method of embodiment 12, wherein said treating neuropathic pain comprises reducing said neuropathic pain.

[0227] 14. The method of embodiment 12 or 13, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

[0228] 15. The method of any one of embodiments 12-14, wherein treating said neuropathic pain comprises reducing one or more of the sensory symptoms associated with PTPN.

[0229] 16. The method of any one of embodiments 12-15, wherein preventing said neuropathic pain comprises reducing the incidence of one or more of the sensory symptoms associated with said PTPN.

[0230] 17. The method of embodiment 15 or 16, wherein the one or more sensory symptoms are selected from paresthesia, burning sensation, and tingling sensation.

[0231] 18. The method of embodiment 17, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or crawling.

[0232] 19. The method of any one of embodiments 12-18, wherein said PS reduces neuronal signaling involved in pain sensation.

[0233] 20. The method of any one of embodiments 12-19, wherein the PS reduces pain that occurs via peripheral sensitization.

[0234] 21. The method of any one of embodiments 12 to 20, wherein the PS reduces pain that occurs via central sensitization.

[0235] 22. The method of any one of embodiments 12-21, wherein said PS reduces centrally generated pain signaling.

[0236] 23. The method of any one of embodiments 12-22, wherein said PS reduces pain signaling originating in peripheral nerves.

[0237] 24. The method of any one of embodiments 12-23, wherein said PS reduces pain signaling originating in the dorsal root ganglion.

[0238] 25. The method of any one of embodiments 12-24, wherein said PS reduces pain signaling originating in the dorsal horn of the spinal cord.

[0239] 26. The method of any one of embodiments 12-25, wherein said neuropathic pain is allodynia.

[0240] 27. The method of embodiment 26, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0241] 28. The method of any one of embodiments 12-27, wherein the neuropathic pain is hyperalgesia.

[0242] 29. The method of any one of embodiments 12 to 28, wherein the PTPN-associated neuropathic pain is caused by transient nerve conduction disorders, such as nerve compression injury.

[0243] 30. The method of any one of embodiments 12-29, wherein the PTPN-associated neuropathic pain is caused by axonal transection, such as a nerve crush injury.

[0244] 31. The method of any one of embodiments 12-30, wherein the neuropathic pain associated with PTPN is caused by one or more of the following: carpal tunnel syndrome, pronator teres syndrome, radial tunnel syndrome, suprascapular nerve entrapment, thoracic outlet syndrome, ulnar nerve entrapment (cubital tunnel syndrome or Guyon canal syndrome), dysesthesias of femoral neuralgia, peroneal nerve compression, pudendal nerve entrapment syndrome, sciatica, tarsal tunnel syndrome, cervical disc herniation, thoracic disc herniation, and / or lumbar disc herniation.

[0245] 32. A method for treating and / or preventing migraine pain, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the migraine pain is treated and / or prevented.

[0246] 33. The method of embodiment 32, wherein treating said pain comprises reducing said pain, e.g., throbbing headache.

[0247] 34. The method of embodiment 32 or 33, wherein preventing said pain comprises reducing the incidence of said pain, e.g., throbbing headache.

[0248] 35. The method of any one of embodiments 32-34, wherein treating pain comprises reducing one or more symptoms associated with migraine.

[0249] 36. The method of any one of embodiments 32-35, wherein preventing said pain comprises reducing the incidence of one or more symptoms associated with said migraine.

[0250] 37. The method of embodiment 35 or 36, wherein the one or more symptoms are selected from aura, nausea, vomiting, photophobia, phonophobia, and / or cranial autonomic symptoms.

[0251] 38. The method of embodiment 37, wherein the aura comprises one or more sensory disturbances, such as visual symptoms, tingling, and / or numbness.

[0252] 39. The head autonomic symptoms, bloodshot eyes or tearing, according to embodiment 37 or 38.

[0253] 40. The method of any one of embodiments 32-39, wherein the subject experiences cutaneous allodynia.

[0254] 41. The method of any one of embodiments 32-40, wherein said PS reduces neuronal signaling involved in pain sensation.

[0255] 42. The method of any one of embodiments 32-41, wherein the PS reduces pain that occurs via peripheral sensitization.

[0256] 43. The method of any one of embodiments 32-42, wherein the PS reduces pain that occurs via central sensitization.

[0257] 44. The method of any one of embodiments 32-43, wherein the PS reduces centrally generated pain signaling.

[0258] 45. The method of any one of embodiments 32-44, wherein the PS reduces pain signaling originating in the trigeminal nerve.

[0259] 46. ​​The method of any one of embodiments 32-45, wherein the PS reduces pain signaling originating in the trigeminal ganglion.

[0260] 47. The method of any one of embodiments 32-46, wherein the PS reduces pain signaling originating in the trigeminal nucleus caudalis.

[0261] 48. The method of any one of embodiments 32-47, wherein said PS reduces pain signaling occurring in higher neurons and / or pain-sensing areas of the brain, such as trigeminothalamic neurons.

[0262] 49. The method of any one of embodiments 32-48, wherein the pain is allodynia, such as cutaneous allodynia.

[0263] 50. The method of embodiment 49, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0264] 51. The method of any one of embodiments 32-50, wherein the pain is hyperalgesia.

[0265] 52. The method of any one of embodiments 32-51, wherein the migraine is episodic migraine or chronic migraine.

[0266] 53. The method of any one of embodiments 32-52, wherein the migraine is migraine with aura or migraine without aura.

[0267] 54. A method for treating and / or preventing neuropathic pain associated with postherpetic neuralgia (PHN), comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the neuropathic pain associated with said PHN is treated and / or prevented.

[0268] 55. The method of embodiment 54, wherein treating said neuropathic pain comprises reducing said neuropathic pain.

[0269] 56. The method of embodiment 54 or 55, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

[0270] 57. The method of any one of embodiments 54-56, wherein treating said neuropathic pain comprises reducing one or more of the sensory symptoms associated with PHN.

[0271] 58. The method of any one of embodiments 54-57, wherein preventing said neuropathic pain comprises reducing the incidence of one or more of the sensory symptoms associated with said PHN.

[0272] 59. The method of any one of embodiments 54-58, wherein the neuropathic pain is a sharp, burning, throbbing, or stabbing sensation.

[0273] 60. The method of any one of embodiments 57-59, wherein the one or more sensory symptoms are selected from itching or numbness.

[0274] 61. The method of any one of embodiments 54-60, wherein the PS reduces neuronal signaling involved in pain sensation.

[0275] 62. The method of any one of embodiments 54-61, wherein the PS reduces pain that occurs via peripheral sensitization.

[0276] 63. The method of any one of embodiments 54-62, wherein the PS reduces pain that occurs via central sensitization.

[0277] 64. The method of any one of embodiments 54-63, wherein the PS reduces centrally generated pain signaling.

[0278] 65. The method of any one of embodiments 54-64, wherein the PS reduces pain signaling occurring in peripheral nerves, such as nerves that innervate one or more dermatomes.

[0279] 66. The method of any one of embodiments 54-65, wherein the PS reduces pain signaling occurring in one or more spinal nerves, such as one or more cervical nerves, one or more thoracic nerves, one or more lumbar nerves, and / or one or more sacral nerves.

[0280] 67. The method of any one of embodiments 54-66, wherein the PS reduces pain signaling originating in the dorsal root ganglion.

[0281] 68. The method of any one of embodiments 54-67, wherein said PS reduces pain signaling originating in the dorsal horn of the spinal cord.

[0282] 69. The method of any one of embodiments 54-68, wherein the neuropathic pain is allodynia.

[0283] 70. The method of embodiment 69, wherein said allodynia is mechanical allodynia and / or thermal allodynia.

[0284] 71. The method of any one of embodiments 54-70, wherein the neuropathic pain is hyperalgesia.

[0285] 72. The method of any one of the preceding embodiments, wherein the subject is a human.

[0286] 73. The PS has formula I (PS-I): [ka] 10. The method of any one of the preceding embodiments, comprising:

[0287] 74. The PS has formula II (PS-II): [ka] 10. The method of any one of the preceding embodiments, comprising:

[0288] 75. The method of any one of the preceding embodiments, wherein the therapeutically effective amount of PS is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0289] 76. The method of embodiment 75, wherein the pharmaceutical composition comprising the PS is formulated for topical administration.

[0290] 77. The method of embodiment 76, wherein the pharmaceutical composition comprising the PS is formulated as a semi-solid.

[0291] 78. The method of embodiment 76, wherein the pharmaceutical composition comprising the PS is formulated as a liquid.

[0292] 79. The method of any one of embodiments 76 to 78, wherein the pharmaceutical composition comprising PS is a cream.

[0293] 80. The method of any one of embodiments 76 to 78, wherein the pharmaceutical composition comprising the PS is a gel, for example, the gel is a hydrogel.

[0294] 81. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a lotion.

[0295] 82. The method according to any one of embodiments 76 to 78, wherein the pharmaceutical composition comprising the PS is an ointment.

[0296] 83. The method of any one of embodiments 76-78, wherein the pharmaceutical composition comprising PS is a spray.

[0297] 84. The method according to embodiment 76, wherein the pharmaceutical composition comprising the PS is formulated as a patch.

[0298] 85. The method of any one of embodiments 75-84, wherein the pharmaceutical composition comprises the PS at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

[0299] 86. The method of embodiment 85, wherein the pharmaceutical composition comprises the PS at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0300] 87. The method of embodiment 86, wherein the pharmaceutical composition comprises the PS at a concentration of 8% (w / w) or less of the pharmaceutical composition, such as about 5% or about 3% (w / w) of the pharmaceutical composition.

[0301] 88. The method of embodiment 86, wherein the pharmaceutical composition comprises the PS at a concentration of about 3% (w / w) or less of the pharmaceutical composition, such as about 2% or about 1% (w / w) of the pharmaceutical composition.

[0302] 89. The PS has a viscosity of about 0.005 g / 10 cm 2 ~About 0.25g / 10cm 2 The method of any of embodiments 75-88, wherein the administration is at the affected site.

[0303] 90. The PS has a viscosity of about 0.005 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0304] 91. The PS has a viscosity of about 0.01 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0305] 92. The PS has a viscosity of about 0.05 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0306] 93. The PS has a viscosity of about 0.1 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0307] 94. The PS is about 0.15 g / 10 cm 290. The method of embodiment 89, wherein the administration is at the affected site.

[0308] 95. The PS is about 0.2 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0309] 96. The PS is about 0.25 g / 10 cm 2 90. The method of embodiment 89, wherein the administration is at the affected site.

[0310] 97. The method of any one of embodiments 75-96, wherein the PS is applied to the affected area and left on the affected area for about 1 hour to about 5 hours.

[0311] 98. The method of embodiment 97, wherein the PS is applied to the affected area and left on the affected area for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0312] 99. The method of embodiment 97 or 98, wherein the PS is removed from the affected area after the administration period, for example by washing it off.

[0313] 100. The method of embodiment 97 or 98, wherein after an administration period, a second or subsequent application of the PS is applied to the affected area.

[0314] 101. The method of any one of embodiments 75-100, wherein the PS is applied once a day.

[0315] 102. The method of any one of embodiments 75-100, wherein the PS is applied twice a day.

[0316] 103. The method of any one of embodiments 75 to 100, wherein the PS is applied three times a day.

[0317] 104. The method of any one of embodiments 75 to 100, wherein the PS is applied four times a day.

[0318] 105. The method of any one of embodiments 75 to 104, wherein the PS is administered in a pharmaceutical composition.

[0319] 106. A method for treating corneal neuropathic pain, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the corneal neuropathic pain is treated.

[0320] 107. The method of embodiment 106, wherein treating the corneal neuropathic pain comprises reducing the corneal neuropathic pain.

[0321] 108. The method of embodiment 106 or 107, wherein treating the corneal neuropathic pain comprises reducing one or more symptoms associated with the corneal neuropathic pain.

[0322] 109. The method of embodiment 108, wherein the one or more symptoms are selected from paresthesia, photosensitivity, photoallodynia, anxiety, depression, or apathy.

[0323] 110. The method of embodiment 109, wherein the paresthesia comprises one or more of numbness, tingling, prickling, or crawling.

[0324] 111. The method of any one of embodiments 106-110, wherein the PS reduces pain that occurs via central sensitization.

[0325] 112. The method of any one of embodiments 106-111, wherein said PS reduces centrally generated pain signaling.

[0326] 113. The method of any one of embodiments 106-112, wherein the PS reduces pain signaling originating in the trigeminal ganglion.

[0327] 114. The method of any one of embodiments 106-113, wherein the PS reduces pain signaling originating in the trigeminal nucleus caudalis.

[0328] 115. The method of any one of embodiments 106-114, wherein said PS reduces pain signaling occurring in higher neurons and / or pain-sensing areas of the brain, such as trigeminothalamic neurons.

[0329] 116. The method of any one of embodiments 106-115, wherein the corneal neuropathic pain is allodynia.

[0330] 117. The method of embodiment 116, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

[0331] 118. The method of any one of embodiments 106-117, wherein the corneal neuropathic pain is hyperalgesia.

[0332] 119. The method of any one of embodiments 106-118, wherein the subject is a human.

[0333] 120. The method of any one of embodiments 106-119, wherein the PS has formula I (PS-I).

[0334] 121. The method of any one of embodiments 106-120, wherein the PS has formula II (PS-II).

[0335] 122. The method of any one of embodiments 106 to 121, wherein the PS is administered to the ocular surface.

[0336] 123. The method of any one of embodiments 106 to 122, wherein the PS is administered to the outer surface of one or more eyelids, for example, the one or more eyelids are one or both upper eyelids and / or one or both lower eyelids.

[0337] 124. The method of any one of embodiments 106-123, wherein the therapeutically effective amount of PS is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0338] 125. The method of embodiment 124, wherein the pharmaceutical composition comprising the PS is formulated for topical administration.

[0339] 126. The method of embodiment 125, wherein the topical administration is to the ocular surface.

[0340] 127. The method of embodiment 125, wherein the topical administration is to the outer surface of one or more eyelids, for example, the one or more eyelids are one or both upper eyelids and / or one or both lower eyelids.

[0341] 128. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising the PS is formulated as a semi-solid.

[0342] 129. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising the PS is formulated as a liquid.

[0343] 130. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising PS is a cream.

[0344] 131. The method of any one of embodiments 125 to 127, wherein the pharmaceutical composition comprising PS is a gel, for example, the gel is a hydrogel.

[0345] 132. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising PS is a lotion.

[0346] 133. The method according to embodiments 125 to 127, wherein the pharmaceutical composition comprising PS is an ointment.

[0347] 134. The method according to embodiments 125-127, wherein the pharmaceutical composition comprising the PS is formulated as eye drops.

[0348] 135. The method of embodiment 134, wherein the eye drop composition is an eye drop solution or eye drop emulsion for dropwise administration to the eye.

[0349] 136. The method of embodiment 134 or 135, wherein the drop volume is about 10 to about 100 μL.

[0350] 137. The method of any one of embodiments 124-136, wherein the pharmaceutical composition comprises the PS at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

[0351] 138. The method of embodiment 137, wherein the pharmaceutical composition comprises the PS at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

[0352] 139. The method of embodiment 138, wherein the pharmaceutical composition comprises the PS at a concentration of 8% (w / w) or less of the pharmaceutical composition, such as about 5% or about 3% (w / w) of the pharmaceutical composition.

[0353] 140. The method of embodiment 139, wherein the pharmaceutical composition comprises the PS at a concentration of about 3% (w / w) or less of the pharmaceutical composition, such as about 2% or about 1% (w / w) of the pharmaceutical composition.

[0354] 141. The PS is about 0.005 mg / cm 2 ~about 0.25mg / cm 2 The method of any of embodiments 124-140, wherein the administration is on the ocular surface.

[0355] 142. The PS is about 0.005 mg / cm 2 , 0.01 mg / cm 2 , 0.05 mg / cm 2 , 0.1 mg / cm 2 , 0.15 mg / cm 2 , 0.2 mg / cm 2 , or 0.25 mg / cm 2The method of embodiment 141, wherein the administration is ocular surface.

[0356] 143. The PS is about 0.5 mg / cm 2 ~about 100mg / cm 2 The method of any of embodiments 124-140, wherein the administration is on the outer surface of the eyelid.

[0357] 144. The PS is about 0.5 mg / cm 2 , 5 mg / cm 2 , 10 mg / cm 2 , 25 mg / cm 2 , 50 mg / cm 2 , 75 mg / cm 2 or 100 mg / cm 2 The method of embodiment 143, wherein the administration is on the outer surface of the eyelid.

[0358] 145. The method of any one of embodiments 124-144, wherein the PS is applied to the ocular surface and / or the outer surface of the eyelid and left on the ocular surface and / or the outer surface of the eyelid for about 1 hour to about 5 hours.

[0359] 146. The method of embodiment 145, wherein the PS is applied to the ocular surface and / or the outer surface of the eyelid and left on the ocular surface and / or the outer surface of the eyelid for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0360] 147. The method of embodiment 145 or 146, wherein the PS is removed from the outer surface of the eyelid after the administration period, for example by washing it off.

[0361] 148. The method of any one of embodiments 145-147, wherein after an administration period, a second or subsequent application of the PS is applied to the ocular surface and / or the outer surface of the eyelid.

[0362] 149. The method of any one of embodiments 124-148, wherein the PS is applied once a day.

[0363] 150. The method of any one of embodiments 124-148, wherein the PS is applied twice a day.

[0364] 151. The method of any one of embodiments 124-148, wherein the PS is applied three times a day.

[0365] 152. The method of any one of embodiments 124-148, wherein the PS is applied four times a day.

[0366] 153. The method according to any one of embodiments 141-152, wherein the PS is administered to the ocular surface and / or the outer surface of the eyelid in a pharmaceutical composition.

[0367] 154. A method for treating and / or preventing an ocular disease or ocular condition, comprising administering a therapeutically effective amount of phosphosulindac (PS) to a subject in need thereof, such that the ocular disease or ocular condition is treated and / or prevented, wherein the PS is administered topically to the outer surface of one or more eyelids.

[0368] 155. The method of embodiment 154, wherein the one or more eyelids are one or both upper eyelids.

[0369] 156. The method of embodiment 154, wherein the one or more eyelids are one or both lower eyelids.

[0370] 157. The method of any one of embodiments 154-156, wherein the eye disease or eye condition is an inflammatory eye disease or eye condition.

[0371] 158. The method of any one of embodiments 154-157, wherein the eye disease or eye condition is dry eye disease (DED).

[0372] 159. The method of any one of embodiments 154-158, wherein the eye disease or eye condition is corneal pain, such as corneal neuropathic pain.

[0373] 160. A method for treating and / or preventing pain, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that said pain is treated and / or prevented.

[0374] 161. PS for use in the treatment of pain associated with central sensitization.

[0375] 162. PS for use in the treatment and / or prevention of pain due to migraine in a subject.

[0376] 163. PS for use in the treatment and / or prevention of neuropathic pain associated with PTPN.

[0377] 164. PS for use in the treatment and / or prevention of neuropathic pain associated with PHN.

[0378] 165. PS for use in the treatment of corneal neuropathic pain.

[0379] 166. A PS for use in the treatment and / or prevention of an ocular disease or condition, wherein the PS is administered topically to the outer surface of one or more eyelids.

[0380] 167. PS for use in the treatment and / or prevention of pain.

[0381] 168. Use of PS for the manufacture of a medicament for treating pain associated with central sensitization.

[0382] 169. Use of PS for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PTPN.

[0383] 170. Use of PS for the manufacture of a medicament for treating and / or preventing migraine pain in a subject.

[0384] 171. Use of PS for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PHN.

[0385] 172. Use of PS for the manufacture of a medicament for treating corneal neuropathic pain.

[0386] 173. Use of PS for the manufacture of a medicament for treating and / or preventing an ocular disease or condition, wherein the PS is administered topically to the outer surface of one or more eyelids.

[0387] 174. Use of PS for the manufacture of a medicament for treating and / or preventing pain.

[0388] 175. The method of any one of embodiments 1-75, 106-121, and 154-160, wherein the PS is administered orally.

[0389] 176. PS for use according to any one of embodiments 161 to 167, wherein the PS is administered orally.

[0390] 177. The use according to any one of embodiments 168 to 174, wherein the PS is administered orally.

[0391] 178. A method for treating and / or preventing neuropathic pain associated with CIPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the neuropathic pain associated with CIPN is treated and / or prevented, wherein the PS is administered orally.

[0392] 179. A method for treating and / or preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that the neuropathic pain associated with DPN is treated and / or prevented, wherein the PS is administered orally.

[0393] 180. The method, the PS for use, or the use according to any one of embodiments 175-179, wherein the PS is formulated as a liquid dosage form or a solid dosage form.

[0394] 181. The method, PS for use, or use according to embodiment 180, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup or elixir.

[0395] 182. The method, PS for use, or use according to embodiment 180, wherein the solid dosage form is a capsule, tablet, pill, powder, or granule.

[0396] 183. The method, the PS for use, or the use according to any one of embodiments 175 to 182, wherein the PS is orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight, for example, about 1 mg / kg to about 5 mg / kg, for example, about 3 mg / kg of the subject's body weight.

[0397] 184. The method, the PS for use, or the use according to any one of embodiments 175 to 183, wherein the PS is orally administered at a dosage of about 1 mg to about 2000 mg, about 100 mg to 1500 mg, about 200 mg to about 100 mg, about 50 mg to about 400 mg, for example, about 100 mg to about 350 mg, for example, about 150 mg to about 300 mg, for example, about 150 mg to about 250 mg.

[0398] 185. The method, the PS for use, or the use according to any one of embodiments 175 to 184, wherein the PS is orally administered in a dosage of about 250 mg to about 300 mg, preferably about 250 mg.

[0399] 186. The method, the PS for use, or the use according to any one of embodiments 175-185, wherein the PS is administered orally once a day.

[0400] 187. The method, the PS for use, or the use according to any one of embodiments 175-186, wherein the PS is administered orally at least twice a day, at least three times a day, or at least four times a day.

[0401] 188. The method, the PS for use, or the use according to any one of embodiments 175-187, wherein the PS is administered orally two or three times a day.

[0402] 189. The method, the PS for use, or the use according to any one of embodiments 175-188, wherein the PS is administered orally twice a day at a dosage of about 150 mg to about 200 mg.

[0403] 190. The method, the PS for use, or the use according to any one of embodiments 175-189, wherein the PS is administered orally in a daily dosage of about 300 mg to about 400 mg.

[0404] 191. The method, the PS for use, or the use according to any one of embodiments 175 to 190, wherein the PS is administered orally two or three times a day at a daily dosage of about 250 mg to about 300 mg (e.g., about 250 mg).

[0405] 192. The method, the PS for use, or the use according to any one of embodiments 175-191, wherein the PS is administered orally in a daily dosage of about 500 mg to a maximum of about 900 mg per day.

[0406] 193. The method of any one of claims 175-192, wherein the PS is administered orally in a pharmaceutical composition. [Example]

[0407] Embodiments encompassed herein will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather to encompass any and all variations that become evident as a result of the teachings provided herein.

[0408] Example 1: Effect of PS in treating pain associated with central sensitization method Central sensitization was established by intraperitoneally administering 10 mg / kg paclitaxel to C57 / BL mice. Paclitaxel was administered once daily for 3 days to all test groups. The results in Figure 2 demonstrate that paclitaxel causes a significant decrease in PWT compared to naive mice.

[0409] Mice were administered PS (as an 8% hydrogel) or vehicle control topically to both hind paws three times daily for 10 days, with the first dose administered 2 days after the last dose of paclitaxel.

[0410] The study groups were as follows: 1. Group 1: Paclitaxel only (n=9) 2. Group 2: Paclitaxel + vehicle (n=10) 3. Group 3: Paclitaxel + PS (n=10)

[0411] To determine treatment outcomes, pain threshold responses were measured using the well-established method of von Frey filaments. Specifically, a simplified up-down method for estimating paw withdrawal threshold (PWT) using von Frey filaments was used (as described by Bonin et al., Molecular Pain (2014); 10(26):1-10). Results of PWT tests are expressed as applied force (gm). PWT tests were performed at baseline (i.e., 4 days after the first dose of paclitaxel (day -1)) and then on the final day of treatment with PS or vehicle (i.e., day 10), approximately 30 minutes after the last application. Data are expressed as percent change from the respective baseline values.

[0412] Figure 1 provides an overview of the study.

[0413] result As shown in Figure 2, administration of vehicle in a background of paclitaxel had limited effect on PWT compared to treatment with paclitaxel alone, while administration of PS achieved a significant increase in PWT compared to vehicle and paclitaxel alone. These values, corresponding to Figure 2, are shown in Table 1. [Table 1]

[0414] conclusion Local administration of PS significantly increased PWT in mice with established pain associated with central sensitization, suggesting that PS treats pain associated with central sensitization.

[0415] In contrast to observations with typical NSAIDs, PS demonstrates pain-reducing effects in therapeutic models of pain associated with central sensitization. This remarkable activity of PS in certain animal models supports the observation that, unlike typical NSAIDs, PS can effectively treat pain associated with central sensitization.

[0416] Example 2: PS effectively treats pain associated with central sensitization caused by several different chemotherapeutic agents method animal Adult male C57BL / 6J mice, 8 weeks old and weighing 20–30 g at the start of the experiment, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Mice within each cage were randomly assigned to treatment groups. All studies were performed by investigators blinded to the identity of the treatment groups. Experiments were performed during the light cycle (7:00 AM–7:00 PM), and animals were euthanized by CO2 asphyxiation. The studies were approved by the relevant Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported in accordance with the ARRIVE guidelines.

[0417] phosphosulindac PS was formulated as an 8% hydrogel ointment for topical administration.

[0418] Pain induction associated with central sensitization Central sensitization was induced in mice using three different chemotherapeutic compounds using established protocols (Carozzi et al., Exp Neurol (2010); 226:301-309; Currie et al., PLoS Biol (2019); 17:e3000243; Eldridge et al., Toxicol Pathol (2020); 48:190-201). Each of the three chemotherapeutic compounds was prepared and administered as follows: Paclitaxel: Paclitaxel (purchased from MilliporeSigma, St. Louis, MO) was dissolved in a mixture of 1 volume ethanol / 1 volume Cremophor EL (EMD Millipore Corp, Burlington, MA) / 18 volumes distilled water. Paclitaxel was administered as four intraperitoneal injections of 8 mg / kg paclitaxel (in a volume of 1 ml / 100 g body weight) every other day for a cumulative dose of 32 mg / kg. Oxaliplatin: Oxaliplatin was dissolved in ddH2O. Oxaliplatin was injected intraperitoneally at 3 mg / kg daily for 5 days, followed by 5 days of no treatment, followed by another 5-day period of intraperitoneal injections of oxaliplatin daily as before, for a total of 10 injections for a cumulative dose of 30 mg / kg. All injections were administered intraperitoneally in a volume of 1 ml / 100 g body weight. Vincristine: Vincristine was dissolved in PBS. Two intraperitoneal injections of 1.5 mg / kg vincristine were given within one week for a total cumulative dose of 3 mg / kg. All injections were given intraperitoneally in a volume of 1 ml / 100 g body weight.

[0419] Protocol for the treatment of pain associated with established central sensitization with PS Once pain associated with central sensitization was established, as evidenced by a decrease in mechanical allodynia threshold, PS 8% or placebo hydrogel ointment was applied to the hind paws of mice three times daily for the duration of the evaluation period (see Figures 3-5). Mechanical allodynia was measured at the time points recorded in the figures.

[0420] Assessment of mechanical allodynia (von Frey test) Mechanical allodynia thresholds were determined using von Frey filaments according to established methods (Chaplan et al., J Neurosci Methods (1994); 53:55-63; Bagdas et al., Biochem Pharmacol (2015); 97:590-600). Briefly, mice were placed in a quiet room for 30 min, then placed in a Plexiglas cage with a mesh metal floor and allowed to acclimate for 30 min before testing. A series of calibrated von Frey filaments (Stoelting, Wood Dale, IL) with increasing stiffness were pressed perpendicularly against the paw with enough force to cause a slight bend and held for 2–3 s. This process was repeated five times at each stiffness level, with an interval of a few seconds between each. Paw withdrawal, licking, or shaking was considered a positive response. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animal responded.

[0421] statistical analysis Results are expressed as mean ± SEM. PK parameters were calculated using Microsoft Excel and PKSolver. Non-compartmental analysis was used. Analysis of variance (ANOVA) tests were performed, followed by Bonferroni post-hoc tests. Differences were considered significant at P<0.05.

[0422] result The effect of PS was evaluated in mice with pain associated with central sensitization caused by three different chemotherapeutic compounds, reflecting the clinical situation previously considered in Example 1, where patients present with pain associated with chronic central sensitization.

[0423] As shown in Figures 3-5, each of the three anticancer drugs tested induced significant neuropathic pain as evidenced by changes in mechanical allodynia. After neuropathic pain was established, topical treatment with PS 8% ointment was initiated three times daily.

[0424] Each of the different chemotherapeutic compounds is discussed separately below.

[0425] Paclitaxel (see Figure 3): At baseline, all four test groups of mice had essentially identical allodynia scores (range 2.24 ± 0.26 g to 2.49 ± 0.24 g; mean ± SEM for this and all subsequent values). Paclitaxel administered to the three test groups over 12 days significantly reduced their mechanical allodynia scores (approximately 85%), an indicator of pain associated with central sensitization. In contrast, the control group (non-paclitaxel, non-PS) showed minimal, statistically insignificant, allodynia score fluctuations throughout the study period.

[0426] When PS was applied to the paws of mice with paclitaxel-induced pain, their allodynia scores showed a gradual improvement from the lowest point at the beginning of treatment and returned to their baseline by day 16 (day 0 = 0.79 ± 0.08 g vs. day 16 = 2.49 ± 0.18 g; p = 1.6 × 10 -6 In contrast, the vehicle-treated group showed a mild worsening of allodynia scores (day 0 = 0.79 ± 0.11 g vs. day 16 = 0.56 ± 0.05 g; p = not significant). The paclitaxel-only treated group showed a change in allodynia scores similar to the vehicle group (day 0 = 0.78 ± 0.08 g vs. day 16 = 0.57 ± 0.05 g; p = not significant).

[0427] The difference between the PS-treated group and its vehicle control first became statistically significant on day 5 (PS = 1.17 ± 0.07 g, vehicle = 0.7 ± 0.07 g; p = 0.002), and the difference increased thereafter, reaching a maximum on day 16 (PS = 2.49 ± 0.18 g, vehicle = 0.56 ± 0.05 g; p = 2.1 × 10 -7 ).

[0428] Vincristine (see Figure 4): PS improved mechanical allodynia induced by the commonly used vincristine. In the three groups treated, vincristine reduced mechanical allodynia scores by 61% to 65% (day 0 = 0.7 ± 0.07 g for all, compared with day -7 scores ranging from 1.8 ± 0.18 g to 2.0 ± 0.24 g; p = 3.2 × 10). -6 In contrast, the control group given the vehicle alone showed no change in allodynia during these 7 days. PS treatment for 16 days in mice with vincristine-induced neuropathic pain significantly improved the allodynia score (114% increase compared to day 0; p = 1.3 × 10 -6 ), and their scores were identical to those of the control group (without vincristine).

[0429] The difference between the PS-treated group and its vehicle control was statistically significant on day 16 (PS = 1.5 ± 0.09 g, vehicle = 0.8 ± 0.09 g; p = 8.6 × 10 -6 In the vehicle and vincristine-only groups, there was no significant change in allodynia scores during the same period (0.7±0.07 g vs. 0.8±0.09 g for both).

[0430] Oxaliplatin (see Figure 5): As expected, during oxaliplatin administration, allodynia scores decreased by 65% ​​and 56% in the two study groups, respectively, on day 0.

[0431] PS treatment restored allodynia scores to baseline on day −15 (1.8 ± 0.09 g vs. 1.76 ± 0.13 g), whereas the vehicle group continued to show suppressed allodynia scores, which were 47% lower on day 22 compared with day −15. The difference between the PS and vehicle-treated groups became statistically significant on day 22 (p = 0.004).

[0432] Safety of PS During all studies, no local or systemic side effects were observed when PS ointment was applied to the hind paws of mice three times daily for up to 22 days, a finding consistent with the known safety profile of PS.

[0433] conclusion Local administration of PS significantly improved mechanical allodynia scores compared with those induced by three different chemotherapeutic compounds, thus treating pain associated with central sensitization by a variety of different chemotherapeutic agents.

[0434] Consistent with the observations in Example 1, PS demonstrates pain-reducing effects in therapeutic models of pain associated with central sensitization caused by chemotherapeutic compounds from different therapeutic classes.

[0435] Example 3: The activity of PS in treating pain associated with central sensitization is comparable to that of lidocaine and pregabalin, but not shared by sulindac The effects of PS on pain associated with central sensitization were compared with those of known centrally acting analgesics (lidocaine and pregabalin) and the parent compound of PS, sulindac. The pain treatment protocols corresponded to those described in Examples 1 and 2.

[0436] method Methods for animals, induction of pain associated with central sensitization (via paclitaxel), assessment of mechanical allodynia and statistical analysis correspond to those outlined in Example 2.

[0437] Pain was established in C57 / BL / 6J mice by administering paclitaxel to all test groups described below. 1. Group 1: Paclitaxel + vehicle (n=8) 2. Group 2: Paclitaxel + PS 5% (n=8) 3. Group 3: Paclitaxel + PS 1.2% (n=8) 4. Group 4: Paclitaxel + 0.7% sulindac (n=8) 5. Group 5: Paclitaxel + 5% lidocaine cream (n=8) 6. Group 6: Paclitaxel + Pregabalin (10 mg / kg) (n=8)

[0438] For treatment with PS, sulindac, and vehicle: PS hydrogel 5%, PS 1.2%, 0.7% sulindac, or vehicle was applied to both hind paws three times daily starting on day 0 and continuing through day 15. 0.7% sulindac was the highest concentration achievable and is equimolar to 1.2% PS.

[0439] Regarding lidocaine treatment: 5% lidocaine cream (positive control) was applied once to both hind paws of the mice 30 minutes before measuring PWT.

[0440] Regarding pregabalin treatment: 10 mg / kg pregabalin (positive control) was administered orally once 1 hour before measuring PWT.

[0441] To determine the outcome of the treatment, mechanical allodynia was assessed. Additionally, cold allodynia was assessed using the acetone test in groups of mice treated with vehicle or PS 5%. Both methods for assessing allodynia are described in Toma W, et al. Neuropharmacology 2017;117:305-15. Mechanical allodynia and cold allodynia were measured in the same animals at least one day apart.

[0442] Briefly, for mechanical allodynia, pain threshold responses were measured using the well-established method of von Frey filaments, as performed in the previous example. PWT tests were performed on day -8 (before the first dose of paclitaxel), the day treatment began (day 0, the day central sensitization was fully established), and day 14 (treatment continued until day 15). The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animals responded.

[0443] For cold allodynia, mice with paclitaxel-induced central sensitization were treated with PS 5% or vehicle for 15 days after the induction of pain associated with central sensitization. The acetone test was used. Briefly, acetone was applied to the plantar surface of each hind paw. The duration of time each mouse spent licking, lifting, and / or shaking its hind paw, recorded over a 60-second period, was used to score cold allodynia. Measurements were performed on day -8 (before the first paclitaxel injection), the day treatment began (day 0), and then on day 15.

[0444] result As expected, paclitaxel induced pain, as evidenced by a reduction in mechanical allodynia from a score of 1.83 ± 0.14 g (mean ± SEM for this and all subsequent values) before paclitaxel administration to 0.55 ± 0.05 g on study day 0 (when central sensitization was fully established). Paclitaxel also sensitized mice to cold allodynia, as evidenced by the change in scores before and after paclitaxel treatment (4.5 ± 0.24 s vs. 7.1 ± 0.4 s; p < 0.0001).

[0445] Treatment with PS improved the mechanical allodynia score in a dose-dependent manner (Fig. 6A). Similarly, treatment with 5% PS improved the cold allodynia score. The cold allodynia score in the PS-treated group was significantly lower than that in the vehicle-treated group (3.1 ± 0.4 vs. 9.3 ± 0.7; p < 0.0001) (Fig. 6B).

[0446] In contrast, administration of sulindac failed to demonstrate a significant effect on PWT, with scores similar to those of vehicle (0.62 ± 0.05 g vs. 0.56 ± 0.04 g; not statistically significant), whereas, as expected, both the lidocaine and pregabalin positive controls achieved significant increases in PWT compared to vehicle (Figure 6A). Importantly, PS 1.2%, an equimolar concentration to sulindac 0.7%, significantly ameliorated mechanical allodynia (p < 0.0001). The values ​​for mechanical allodynia corresponding to Figure 6A are provided in Table 2. [Table 2]

[0447] conclusion While PS has been shown to be effective in treating pain associated with central sensitization (see also Examples 1 and 2), strikingly, its unphosphorylated "parent" sulindac (a typical NSAID) failed to achieve rescue of PWT in this mouse model and therefore failed to treat pain associated with central sensitization. This was true despite sulindac being administered at the maximum nontoxic dose and in the same manner and formulation as PS. The positive controls lidocaine and pregabalin, known to have direct activity at neural and central sites of action in analgesia, demonstrated significant pain reduction, as expected. Thus, the efficacy observed for locally administered PS is more similar to that of a centrally acting positive control than to its closely related parent compound.

[0448] Thus, PS may be mechanistically distinct from its parent NSAID and act in a manner more similar to centrally acting drugs. These observations of the comparable efficacy of PS to pregabalin and lidocaine in treating and preventing pain associated with central sensitization reflect the central site of action of PS implied above (i.e., similar to the central site of action of pregabalin and lidocaine). These observations serve to demonstrate the potential of PS in treating pain associated with central sensitization, similar to typical centrally acting analgesics (e.g., pregabalin).

[0449] Example 4: Effects of PS in a rat model of central sensitization Central sensitization was induced in rats by increasing blood glucose using streptozotocin (STZ). This is a well-established model for generating chronic neuropathic pain in which STZ, an antibiotic extract from Streptomyces acromogenes, selectively damages pancreatic beta cells (see Morrow, Current Protocols in Neuroscience (2004); 29(1):1-11). As demonstrated, PS is effective in treating central sensitization generated in this additional model of chronic pain.

[0450] method Sprague-Dawley rats were fasted for 4-6 hours before receiving an intraperitoneal injection of 45 mg / kg of STZ. This was done for all experimental groups except the naive group. To prevent death due to hypoglycemia, rats were given 10% sucrose water as their only water source for the first 48 hours after injection. To ensure that only rats considered diabetic (i.e., with non-fasting plasma glucose levels >250 mg / dL) were included in the study, blood glucose was measured 72 hours after STZ injection.

[0451] Four weeks after STZ injection, rats were randomized to treatment groups. This delay between STZ injection and treatment allowed for the establishment of chronic pain (allodynia) associated with central sensitization. PS (as an 8% hydrogel) or vehicle control was administered topically to both hind paws of rats three times daily for three weeks, starting four weeks after STZ injection. 0.7% sulindac hydrogel was applied three times daily for one week, representing the highest safe concentration of sulindac for these animals. 5% lidocaine cream (positive control) was applied once to both hind paws of rats 30 minutes before PWT measurement. Finally, an additional positive control, pregabalin (at 10 mg / kg) or its vehicle, was administered orally once, one hour before PWT measurement.

[0452] The rats were divided into eight test groups as follows: the average weight of the rats in the experimental groups (1-4) was approximately 225 g, and the average weight of the rats in the control groups (5-8) was approximately 335 g. 1. Group 1: Naive rats (n=5) 2. Group 2: STZ only (n=6) 3. Group 3: STZ + vehicle (n = 6) 4. Group 4: STZ + PS (8% hydrogel) (n = 7) 5. Group 5: STZ + oral vehicle (n = 8) 6. Group 6: STZ + 0.7% sulindac hydrogel (n = 7) 7. Group 7: STZ + 5% lidocaine cream (n=8) 8. Group 8: STZ + pregabalin (10 mg / kg) (n = 7)

[0453] To determine treatment outcomes, mechanical allodynia was measured using the well-established method of von Frey filaments. Specifically, we used a simplified up-and-down method to estimate paw withdrawal thresholds (PWT) using von Frey filaments (as described in Bonin et al., Molecular Pain (2014); 10(26):1-10). Results of PWT tests are expressed as applied force (gm). PWT tests were performed at weeks 4, 5, and 7, depending on the administration protocol, with the first measurement representing baseline (i.e., demonstrating STZ's effectiveness in establishing pain associated with central sensitization). Measurements at weeks 5 and 7 were performed 30 minutes after the final treatment with sulindac or PS, respectively. For completeness, differences in the mean weights of rats in the experimental and control groups do not affect the ability to compare results from these groups (i.e., rats were simply obtained from different batches and responded similarly to the experimental procedures).

[0454] Figure 7 provides an overview of the study.

[0455] result As shown in Figure 8, administration of STZ resulted in a significant decrease in PWT 4 weeks after administration (p<0.02 vs. naive rats). Thus, as expected, pain associated with central sensitization was established in this model. Additional administration of vehicle had no significant effect on PWT compared to STZ alone, and the reduction in PWT compared to naive rats was similar to STZ alone. However, administration of PS achieved a significant increase in PWT compared to vehicle and STZ (p<0.04 and p<0.01, respectively), returning PWT to the threshold observed in naive rats (p<0.01). These values, corresponding to Figure 8, are provided in Table 3. [Table 3]

[0456] Furthermore, as shown in Figure 9, neither vehicle nor sulindac administration prevented the reduction in PWT caused by STZ (sulindac was not significantly different from vehicle). However, both lidocaine and pregabalin achieved significant increases in PWN compared to vehicle (p<0.03 and p<0.009, respectively). These values, corresponding to Figure 9, are provided in Table 4. [Table 4]

[0457] conclusion Local administration of PS is effective in normalizing pain associated with central sensitization induced by diabetes in one of the most reliable animal models of the disease. Indeed, PS significantly increased PWT in rats exhibiting central sensitization. Therefore, PS treats pain associated with central sensitization induced by additional mechanisms.

[0458] While PS was effective, notably, its unphosphorylated "parent" sulindac (a typical NSAID) failed to achieve rescue of PWT in a rat model and therefore failed to treat pain associated with central sensitization. This was true despite sulindac being administered at the maximal nontoxic dose and in the same manner and formulation as PS. The positive controls lidocaine and pregabalin, known to have direct activity at neural and central sites of action in analgesia, demonstrated significant reductions in pain associated with central sensitization, as expected. Thus, the efficacy observed with locally administered PS is more similar to its centrally acting positive control than to its closely related parent compound, correlating with observations demonstrating accumulation of PS at central sites of action.

[0459] Thus, PS may be mechanistically distinct from its parent NSAID and may act in a manner more similar to centrally acting drugs. These observations serve to demonstrate the potential of PS in established chronic pain associated with central sensitization.

[0460] Example 5: Effect of PS in treating neuropathic pain in a mouse model of CIPN Further building on the observations herein with topical administration of PS, this example demonstrates that oral administration of PS surprisingly treats neuropathic pain associated with CIPN, as demonstrated in an established animal model.

[0461] method Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 AM - 7:00 PM), and animals were euthanized by CO2 asphyxiation. Mice within each cage were randomly assigned to treatment groups. All tests were performed by an experimenter blinded to the identity of the treatment groups.

[0462] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported according to the ARRIVE guidelines (Kilkenny et al., 2010).

[0463] CIPN was induced in 8-week-old male C57BL / 6J mice (approximately 25 g). CIPN was induced in mice with chemotherapy using established protocols (Carozzi et al., 2010; Currie et al., 2019; Eldridge et al., 2020). Briefly, four intraperitoneal injections of 8 mg / kg paclitaxel were given every other day for a cumulative dose of 32 mg / kg. This paclitaxel administration regimen results in CIPN-associated pain with a time course similar to that of pain following paclitaxel administration in cancer patients.

[0464] PS and sulindac were administered by oral gavage three times daily for 7 days at the following doses: PS, 50 mg / kg; sulindac, 33 mg / kg (equimolar to PS).

[0465] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Naive mice (i.e., no paclitaxel, n=8) 2. Group 2: Paclitaxel only (n=8) 3. Group 3: Paclitaxel + vehicle (n=8) 4. Group 4: Paclitaxel + PS (n=8) 5. Group 5: Paclitaxel + Sulindac (n=8)

[0466] Mechanical allodynia was determined using the von Frey filament method as performed in the previous example. PWT testing was performed on day 7. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animals responded.

[0467] Additionally, thermal allodynia was determined for all test groups of mice as follows: 1. Group 1: Paclitaxel + vehicle (n=8) 2. Group 2: Paclitaxel + PS (n=8) 3. Group 3: Paclitaxel + Sulindac (n=8)

[0468] Briefly, the thermal allodynia test uses a radiant heat source (Hargreaves et al., 1988). Animals are placed in a plastic box with an elevated glass floor. The beam of a lamp probe is focused on the plantar surface of the paw until the animal withdraws its paw and the device's sensor blocks the lamp. The thermal allodynia threshold is defined as the latency to paw withdrawal (PWL) and is expressed in seconds (sec) or thermal allodynia threshold. Thermal allodynia responses to PS and sulindac were tested on the 16th day of treatment.

[0469] result As expected, administration of paclitaxel resulted in a significant decrease in PWT (p<0.001, vs. naive mice). Thus, chemotherapy-associated neuropathic pain, manifested as allodynia, was established in this model. Additional administration of vehicle had no significant effect on PWT compared with treatment with paclitaxel alone, while administration of PS achieved a significant increase in PWT compared with vehicle (p<0.003, vs. vehicle). In contrast, administration of sulindac failed to demonstrate a significant effect on PWT, with scores similar to those of vehicle (0.56±0.05 g vs. 0.54±0.03 g; not statistically significant). These values ​​are provided in Table 5. [Table 5]

[0470] To confirm the positive effect of PS assessed by mechanical allodynia, paw withdrawal latency (PWL) was evaluated in the thermal allodynia test in the CIPN mouse model. PS significantly increased PWL compared with the vehicle control (p<0.04). In contrast, the effect of sulindac was not significant compared with the vehicle control. PWL values ​​are provided in Table 6. [Table 6]

[0471] conclusion Similar to the observations with topically administered PS, oral administration of PS, in contrast to its parent compound, sulindac, resulted in significant increases in PWT and PWL. These positive results are surprising, especially in light of the ability of orally administered PS to achieve significant analgesic effects for pain originating at distal peripheral sites but persisting via central neuronal activity even in the absence of ongoing peripheral triggers. However, these observations confirm previous observations suggesting that PS acts centrally and demonstrate the broad applicability of PS in the treatment of various forms of neuropathic pain. Indeed, further observations herein demonstrate that orally administered PS reaches the central pain-generating site, thus confirming the unprecedented activity of PS as a direct-acting neuroanalgesic effective at the central site of action.

[0472] Example 6: Effect of PS in treating neuropathic pain associated with PTPN Preliminary in vivo evidence indicates that local administration of PS in the form of a hydrogel achieves significant analgesic effects on neuropathic pain associated with PTPN. This effect was surprising, but is consistent with data from WO2022 / 251805 and WO2022 / 251806, which showed that PS has direct analgesic effects on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN).

[0473] Example 7: Efficacy of locally administered PS in the treatment and / or prevention of neuropathic pain in a mouse model of PTPN The neuropathic pain associated with traumatic nerve injury can be reproduced in rat animal model by using chronic constriction injury (CCI) model.In this model, sciatic nerve is compressed to simulate peripheral nerve injury.This model produces the specific phenotype observed in human PTPN, including allodynia.

[0474] This model is performed according to the procedure developed by Bennett and Xie (Pain (1988); 33(1):87-107). Briefly, the sciatic nerve is exposed and four loose chromed catgut ligatures are placed around the nerve. The ligatures impede, but do not block, blood flow over the nerve. Three weeks following nerve injury, rats are evaluated for mechanical withdrawal threshold of the hindpaw, an indicator of mechanical allodynia. Sensory testing utilizes von Frey filaments with reproducible, calibrated buckling forces that vary from 0.4 to 10 g using the Chaplan up-and-down method. Allodynia is tested by touching the hindpaw perpendicularly, causing a slight buckling of the filament for approximately 5 seconds. Hindpaw withdrawal thresholds (g) are calculated based on the response pattern and the final filament force (Chaplan et al., Journal of neuroscience methods (1994); 53(1), 55-63).

[0475] The ability of a topical formulation of PS administered to the hind paw to reduce allodynia compared to its parent compound (sulindac) and a positive control is confirmed in this model system.

[0476] method Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 AM - 7:00 PM), and animals were euthanized by CO2 asphyxiation. Mice within each cage were randomly assigned to treatment groups. All tests were performed by an experimenter blinded to the identity of the treatment groups.

[0477] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported according to the ARRIVE guidelines (Kilkenny et al., 2010).

[0478] Chronic constriction injury-induced peripheral neuropathy (a form of posttraumatic peripheral neuropathy) was induced in 8-week-old male C57BL / 6J mice (approximately 25 g) under anesthesia. The left sciatic nerve was exposed by incising the skin and dissecting the connective tissue between the superficial gluteus maximus and biceps femoris muscles. Two chronic catgut ligatures of 7-0 suture were tied loosely around the sciatic nerve, 1 mm apart, just enough to obstruct but not stop blood flow over the nerve. In control sham-operated mice, a similar skin incision was made on the left side, but the sciatic nerve was not ligated. In both cases, the surgical wound was closed with muscle sutures and skin staples. Pain hypersensitivity testing was performed after 5–7 days of recovery from surgery.

[0479] PS (as a 5% gel), sulindac (as a 0.7% gel, the highest achievable concentration of sulindac), or vehicle control was administered topically to the left paw of mice three times daily for 14 days. Pregabalin (10 mg / ml) was administered once by oral gavage 1 h before determining mechanical allodynia and served as a positive control.

[0480] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Ligation only (i.e., surgical control without treatment, n = 5–7) 2. Group 2: Vehicle control (n = 5-7) 3.Group 3: PS5% (n=5~7) 4. Group 4: 0.7% sulindac (n = 5-7) 5. Group 5: Pregabalin (n = 5-7)

[0481] Briefly, to determine mechanical allodynia, pain threshold responses were measured using the well-established method of von Frey filaments, as performed in previous examples. PWT testing was performed on day 14. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animal responded.

[0482] Thermal allodynia was also determined for the following test groups of mice: 1. Group 1: Vehicle control (n=6) 2. Group 2: PS5% (n=6)

[0483] Thermal allodynia was determined using a radiant heat source as performed in previous examples (Hargreaves et al., 1988).

[0484] result PTPN was induced in 31 mice as described above, and 9 mice underwent a sham procedure. The induction of PTPN-associated neuropathic pain was confirmed by determining mechanical allodynia. At baseline (n = 40), PWT was 1.90 ± 0.14 g (mean ± SEM for this and all subsequent values). After ligation, PWT values ​​were as follows: sham-operated mice (n = 9), 1.04 ± 0.10 g; CCI mice (n = 31), 0.74 ± 0.05 g (p < 0.01 compared with sham-operated mice). These results are summarized in Figure 10A. Thus, the chronic constriction injury model ensured a significant reduction in PWT compared with sham-operated animals, confirming the establishment of central sensitization (manifested as allodynia). Mice were randomly assigned to the test groups.

[0485] As shown in Figure 10B, administration of vehicle had no significant effect on PWT, whereas pregabalin, as expected, significantly increased PWT compared to vehicle-treated mice. Sulindac did not alter PWT values ​​compared to vehicle controls. However, administration of PS achieved a significant increase in PWT compared to vehicle (p<0.005). PWT values ​​achieved in PS-treated mice were even greater than those achieved in pregabalin-treated mice (1.30±0.15 g vs. 1.1±0.10 g; mean±SEM). These values, corresponding to Figure 10B, are provided in Table 7. [Table 7]

[0486] To confirm the positive effect of PS assessed by mechanical allodynia, paw withdrawal latency (PWL) was assessed in the thermal allodynia test. PTPN was induced in 12 mice as described above. PS significantly increased PWL time compared with vehicle control (3.4±1.0 g vs. 9.1±2.9 g, p<0.05). PWL values ​​are provided in Table 8. [Table 8]

[0487] conclusion Local administration of PS significantly increased PWT in mice with chronic constriction injury, an established model of PTPN. It also significantly increased PWL in a thermal allodynia test. Thus, PS treats established pain associated with PTPN, further supporting the broad applicability of PS in the treatment of various forms of neuropathic pain.

[0488] While PS was effective in treating pain associated with central sensitization (manifested as allodynia) in this PTPN model, reflecting PS's ability to provide a direct analgesic effect on pain associated with central sensitization as observed in the previous examples, its unphosphorylated "parent," sulindac (a typical NSAID), failed to achieve rescue of PWT and therefore failed to treat PTPN-related pain in this mouse model. This was true despite sulindac being administered at the maximum nontoxic dose and in the same manner and formulation as PS. The positive control, pregabalin, known to have a central site of action in analgesia, demonstrated a significant reduction in PTPN-related pain, as expected. Thus, the efficacy observed with locally administered PS is more similar to its centrally acting positive control than to its closely related parent compound, correlating with observations demonstrating accumulation of PS at central sites of action.

[0489] Thus, PS may be mechanistically distinct from its parent NSAID and may act in a manner more similar to centrally acting drugs. These observations serve to demonstrate the potential of PS in established chronic pain associated with PTPN. Furthermore, these results, combined with the observation herein of PS accumulation at central sites of action, point to the unprecedented and surprising broad applicability of PS in the treatment and prevention of pain with a central mechanism (i.e., arising at a central site or due to central sensitization).

[0490] Example 8: Effect of locally administered PS at a distal site in the treatment and / or prevention of neuropathic pain in a mouse model of PTPN Previous examples in mice with PTPN-associated neuropathic pain (via a chronic constriction injury model) demonstrate the remarkable ability of PS to treat PTPN-associated pain. Remarkably, and consistent with other observations herein regarding the ability of PS to traverse along neurons to central sites, this example demonstrates that PS exerts its analgesic effect at a central site of action.

[0491] method In the first experiment, PTPN was induced in anesthetized 8-week-old male C57BL / 6J mice (approximately 25 g) using chronic constriction injury by ligating the left sciatic nerve, as previously described, to induce neuropathic pain manifested as allodynia affecting the left paw of the mice (i.e., decreasing paw withdrawal threshold).

[0492] PS (as an 8% gel), or vehicle control, was administered topically to the contralateral (i.e., right) hind paw of mice three times daily for 4 days before determining mechanical allodynia in the operated limb.

[0493] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Ligation only (i.e., no treatment surgery control, n=6) 2. Group 2: Vehicle control (n=6) 3.Group 3: PS8% (n=6)

[0494] Mechanical allodynia was determined by assessing the paw withdrawal threshold of the operated left paw using the von Frey filament method as performed in the previous example. PWT testing was performed on day 4. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animal responded.

[0495] Furthermore, in a second study, we assessed the speed with which PS could treat PTPN-associated pain by assessing its effect on mechanical allodynia immediately after local administration of PS. As described above, PTPN was induced in mice by chronic constriction injury (CCI) via ligation of the left sciatic nerve, which induces neuropathic pain manifested as allodynia affecting the left limb. PS (as a 5% gel) was applied only once to the contralateral (right) hind paw of the mice, and mechanical allodynia in the operated limb was then determined at different time points after administration.

[0496] Mechanical allodynia (via the PWT test) was determined for all test groups of mice as follows: 1. Group 1: Ligation only (i.e., no treatment surgery control, n=5) 2. Group 2: PS 5%, evaluated at t = 0.5 hours after administration (n = 5) 3. Group 3: PS 5%, evaluated at t = 1.0 hour after administration (n = 5) 4. Group 4: PS 5%, evaluated at t = 2.0 hours after administration (n = 5)

[0497] result In the first experiment, PTPN was induced in 18 mice as described above, and the mice were randomly assigned to test groups. As expected, treatment of mice with vehicle control did not result in a significant change from the PWT values ​​after ligation (0.52±0.09 g vs. 0.53±0.03 g). Strikingly, treatment of the contralateral paw with PS significantly increased PWT compared to both vehicle and surgical controls (p<0.001). These values ​​are provided in Table 9. [Table 9]

[0498] In a second experiment, PTPN was induced in 20 mice as described above, and the mice were randomly assigned to test groups. Building on the surprising results of the first experiment, a significant increase in PWT was observed across all time points tested, including the shortest time point of 0.5 hours after administration (p<0.0005). These values ​​are provided in Table 10. [Table 10]

[0499] conclusion Local administration of PS to the contralateral, unoperated paw of mice with PTPN-associated neuropathic pain achieved a significant increase in PWT. Consistent with our observations regarding PS's ability to traverse neurons toward central sites, this experiment confirms that PS accumulates at the central site of action in concentrations sufficient to directly inhibit neuronal pain signaling. Remarkably, a significant increase in PWT was observed just 0.5 hours after administration of PS to the contralateral paw. This suggests that PS has the ability to accumulate in therapeutically relevant amounts and rapidly act at central sites (as demonstrated by our pharmacokinetic analysis). Thus, PS can act directly on centrally located neurons to block pain signaling that occurs at central sites, e.g., via central sensitization, where pain is perceived even in the absence of ongoing noxious peripheral stimuli.

[0500] As shown in the previous example, PS's parent NSAID (i.e., sulindac) failed to treat neuropathic pain associated with PTPN. This example further confirms that PS acts in a distinctly different mechanistic manner compared to its parent NSAID. PS rapidly reaches its central site of action and has a direct effect on neuronal signaling, something that sulindac and other typical NSAIDs cannot achieve. These observations support the potential of PS to treat chronic pain indications in which pain is perceived as a result of the activity of centrally acting neurons.

[0501] Example 9: Effect of PS in treating neuropathic pain in a mouse model of PTPN Based on the results observed with topically applied PS and further observations herein demonstrating the broad applicability of PS as a centrally acting analgesic, orally administered PS was investigated in a mouse model of PTPN.

[0502] method Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 AM - 7:00 PM), and animals were euthanized by CO2 asphyxiation. Mice within each cage were randomly assigned to treatment groups. All tests were performed by an experimenter blinded to the identity of the treatment groups.

[0503] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported according to the ARRIVE guidelines (Kilkenny et al., 2010).

[0504] Chronic constriction injury-induced peripheral neuropathy (a form of post-traumatic peripheral neuropathy) was induced in anesthetized 8-week-old male C57BL / 6J mice (approximately 25 g) by ligating the left sciatic nerve as previously described, which establishes PTPN-associated neuropathic pain (manifested as allodynia).

[0505] PS was administered orally at 100 mg / kg three times a day for 6 days.

[0506] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Ligation only (i.e., no treatment surgery control, n=9) 2. Group 2: Vehicle (n=9) 3. Group 3: PS (n=9)

[0507] Mechanical allodynia was determined using the von Frey filament method as performed in the previous example. PWT testing was performed on day 6. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animals responded.

[0508] result As expected, treatment of mice with vehicle control did not result in a significant change in PWT values ​​after ligation. In contrast, treatment with orally administered PS significantly increased PWT compared to vehicle control treatment. These values ​​are provided in Table 11A. [Table 11A]

[0509] In another study using the same model system described herein, the parent compound, sulindac, was shown to be ineffective in treating neuropathic pain associated with PTPN. Indeed, oral administration of sulindac at 33 mg / kg had no significant effect on PWT compared with vehicle (Table 11B). [Table 11B]

[0510] conclusion Similar to observations with topically administered PS, 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 falls short of achieving analgesia in this challenging pain model. The analgesic effect of orally administered PS compared with vehicle in this animal model was improved compared with topically administered PS.

[0511] These positive results support the data herein using topical PS in this model and confirm that PS is not acting as a local analgesic but instead can reach a central site of action to achieve significant effects on pain known to be associated with central sensitization manifested as allodynia. The ability of PS to affect centrally generated pain, even when administered orally, is particularly surprising and is supported by further observations herein showing that orally administered PS reaches central pain-generating sites. These results further confirm the broad applicability of PS, which appears to be a direct-acting neuroanalgesic, in the treatment of various forms of neuropathic pain.

[0512] Example 10: Efficacy of orally administered PS and failure of sulindac in treating neuropathic pain in a mouse model of PTPN To confirm the observations in the previous examples, lower doses of orally administered PS were tested for efficacy in treating neuropathic pain associated with PTPN and compared to the parent compound, sulindac.

[0513] method We used chronic constriction injury to induce PTPN-associated neuropathic pain. Neuropathic pain was induced in 8-week-old male C57BL / 6J mice (approximately 25 g) under anesthesia by ligating the left sciatic nerve, as previously described. This established PTPN-associated neuropathic pain (expressed as allodynia).

[0514] PS, sulindac, or vehicle control was administered orally once daily for 6 or 14 days as shown in the table below. The dose of PS was 50 mg / kg, and the dose of sulindac was 33 mg / kg (equimolar to PS).

[0515] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Ligation only (i.e., no treatment surgery control, n=9) 2. Group 2: Vehicle (n=9) 3. Group 3: PS (n=9) 4. Group 4: Sulindac (n=9)

[0516] Mechanical allodynia was determined using von Frey filaments as performed in the previous example. PWT testing was performed on days 6 or 14, as indicated. Mechanical thresholds, expressed as g, indicate the force of the von Frey filaments to which the animals responded.

[0517] result As expected, treatment of mice with vehicle control did not result in a significant change from PWT values ​​compared to ligation alone. This failure persisted through 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 increased over the longer 14-day administration period (1.62±0.13 g vs. 0.56±0.03 g, p<0.00001). In contrast, sulindac failed to achieve any significant change compared to vehicle control at any time point. These values ​​are provided in Table 12. [Table 12]

[0518] conclusion These results confirm the remarkable efficacy of higher doses of PS in treating pain associated with PTPN as observed herein. Notably, oral administration of PS at both lower doses and less frequent administration still resulted in significant increases in PWT in the mouse model of PTPN. Such effects are surprising and demonstrate that PS, even when administered orally, is a particularly effective compound in treating established neuropathic pain. This effect is enhanced over longer treatment periods, at which point its efficacy is comparable to the higher doses used in previous examples. These positive results further support the clinical applicability of orally administered PS in treating difficult pain indications, including those in which neuropathic pain is established and has a central site of action. Indeed, these observations point to the usefulness of lower doses of PS over long-term dosing intervals.

[0519] As consistently observed herein, the anti-inflammatory activity of sulindac is completely insufficient for treating the complex neuropathic pain generated in this animal model, and the success of orally administered PS further indicates the direct activity of PS on centrally located neurons involved in persistent pain signal transduction.Thus, when orally administered, PS, even at lower doses, shows distinct and unexpected activity compared to its parent compound in additional models of neuropathic pain.This confirms the observation that PS acts in a distinctly different mechanistic manner compared to its parent NSAID.

[0520] Example 11: Notes on Observations Related to PTPN Preliminary in vivo observations demonstrate unprecedented analgesic activity of PS in the treatment of neuropathic pain associated with PTPN. While these observations are surprising, they are consistent with data from WO2022 / 251805 and WO2022 / 251806 (both of which are incorporated herein by reference in their entireties), which show that PS has direct analgesic effects on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN). In light of the potent analgesic effects of PS in two pathophysiologically distinct forms of neuropathic pain, the inventors hypothesized (without wishing to be bound by theory) that PS may have more broadly applicable analgesic activity in other forms of neuropathic pain, possibly based on the ability of PS to traverse to central sites of action and directly affect neural signaling associated with central sensitization. Our initial observations and further data presented herein in appropriate animal models of PTPN-associated pain confirm this hypothesis, demonstrating unprecedented analgesic activity of PS in treating PTPN-associated neuropathic pain. Such broad applicability as an analgesic across various forms of neuropathic pain is not guaranteed; indeed, gabapentin exhibits variable efficacy in treating various forms of neuropathic pain. Further experiments described herein using well-established animal models of PTPN-associated neuropathic pain confirm these observations. We predict that PS may have a direct effect on neuronal pain signaling generated by trauma inflicted on peripheral nerves, preventing pain generation at central sites by reducing signaling caused by central sensitization. This is suggested by evidence demonstrating the ability of PS to reduce PTPN-associated allodynia even when administered at a site distal to the peripheral pain-generating site, and the observed ability of PS to traverse along centrally projecting neurons to and remain stable at the central site of action, even when administered orally.Remarkably, local administration of PS to one paw achieved a significant reduction in allodynia (a symptom of central sensitization) induced by posttraumatic peripheral neuropathy in the contralateral paw of a PTPN animal model. Thus, PS appears to achieve its analgesic effect by targeting neuronal activity at the central site of action and, therefore, may be therapeutically effective even when administered distally (or, indeed, orally). Such therapeutic applicability of PS is unprecedented. In light of the ability of PS to traverse to the central site of action upon local administration, these findings represent a significant contribution to providing a straightforward treatment for PTPN-associated neuropathic pain. Indeed, the local route allows for low systemic clearance, reduced drug interactions, increased patient tolerability, and easy coadministration with oral medications. PS may also be administered orally for the treatment of PTPN-associated neuropathic pain. Indeed, remarkably, oral administration achieved analgesia in appropriate animal models.

[0521] These observations demonstrate previously unrecognized activities and therapeutic utility of PS, a compound that falls within the broader class of NSAIDs but does not share all of the properties of this compound family. Indeed, unlike typical NSAIDs, PS does not inhibit COX-1 or COX-2 activity or block prostaglandin synthesis or activity. Instead, PS has been shown to induce increased COX activity and a significant increase in PGE2 levels (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32). Preliminary observations suggest a role for PS as an analgesic targeting pain signaling associated with PTPN, an activity distinct from the established roles of PS as an anti-inflammatory agent and typical NSAIDs. Indeed, such anti-inflammatory activity has been shown to be ineffective in treating peripheral neuropathic pain (Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1-25)), and NSAIDs, such as ketorolac, have shown limited analgesic activity against neuropathic pain associated with PTPN.

[0522] Previous observations regarding the activity of PS have been limited to its anti-inflammatory activity. For example, WO 2019 / 067919 suggested a role for PS in the treatment of DED using an acute DED model in which concanavalin A (ConA) was administered simultaneously with PS into the lacrimal glands of rabbits. In this context, the anti-inflammatory activity of PS resulted in a limited inflammatory response to ConA, thus preventing the establishment of DED. These observations confirm the anti-inflammatory activity of PS and suggest its usefulness in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model fall short of providing any evidence of PS's ability as an analgesic, capable of acting directly on nerves to reduce neural signaling caused by neuropathic pain. Any reduction in pain in this acute DED model could be attributed solely to PS inhibiting the inflammatory response (i.e., the underlying pathology that triggers the activation of pain sensors). On the contrary, the results in the DED model suggest that PS improves corneal sensitivity, implying increased nociception, an effect opposite to that desired for an analgesic. Of course, regardless of any indication toward an analgesic activity of PS, such activity observed in the acute DED model does not provide any indication of a corresponding activity in neuropathic pain, let alone in the neuropathic pain associated with PTPN.

[0523] The observations herein demonstrate that PS has therapeutic utility beyond the scope of the anti-inflammatory activity associated with typical NSAIDs. In contrast, certain NSAIDs, such as ketorolac, are ineffective analgesics in treating neuropathic pain associated with PTPN. Furthermore, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1-25) outlined that NSAIDs have no therapeutic efficacy in peripheral neuropathic pain. The activity of PS suggested herein contrasts with the inability of typical NSAIDs to provide direct analgesic effects on damaged neurons in neuropathic pain, as observed in the prior art. Without wishing to be bound by theory, it is likely that the reason for the lack of response to typical NSAIDs in the prior art is that pain is caused by neuropathic nerve damage, not inflammation (i.e., the anti-inflammatory activity of any typical NSAID is insufficient to prevent or treat neuropathic pain). Thus, the analgesic activity of PS demonstrated herein is unique and not shared by typical NSAIDs. Any alleged analgesic activity of NSAIDs observed in the prior art reflects their anti-inflammatory activity (i.e., halting potential pain triggers) rather than actual analgesic activity directed against nerve signaling (i.e., which would result in a reduction in pain caused by nerve injury and sensitization). For example, WO 2008 / 014066 implicates sulindac in the treatment of pain associated with a chronic constriction injury model, but concludes that any alleged effects are due to a reduction in pro-inflammatory cytokines rather than an effect on the pain signaling pathway itself. Indeed, as noted above, the anti-inflammatory activity of typical NSAIDs is considered to have no therapeutic utility in the treatment of neuropathic pain. In any event, any alleged activity of sulindac cannot be extrapolated to PS in light of the distinctly different activities of sulindac and PS. The observations herein demonstrate the usefulness of PS in the treatment of neuropathic pain associated with PTPN.Any suggestion that typical NSAIDs have analgesic activity is related to the requirement for inhibition of the COX pathway and prostaglandin synthesis (i.e., activities of typical NSAIDs that are not shared by PS). Without wishing to be bound by theory, the observations herein indicate that PS effectively treats neuropathic pain associated with PTPN by targeting neuronal signaling that occurs via central sensitization, a major component of PTPN-associated neuropathic pain.

[0524] Thus, the inventors have demonstrated a new and surprising activity for PS in the treatment and / or prevention of neuropathic pain associated with PTPN. As outlined above, these observations imply an activity of PS that goes beyond the range of anti-inflammatory activities previously observed for PS and related NSAIDs. Furthermore, the ease with which PS can be administered (e.g., topically) and its limited adverse effects (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32) make PS an improved therapy for neuropathic pain associated with PTPN.

[0525] Moreover, surprisingly, the analgesic activity of PS was maintained even when administered orally in an animal model with established neuropathic pain associated with PTPN. The ability of PS to affect neuropathic pain associated with PTPN is particularly surprising and is supported by further observations herein showing that orally administered PS reaches central pain-generating sites.

[0526] Example 12: Effect of PS in the treatment of migraine pain Preliminary in vivo evidence indicates that topical administration of PS in the form of a hydrogel achieves significant analgesic effects on migraine pain. This effect was surprising, but is consistent with data from WO2022 / 251805 and WO2022 / 251806, which show that PS has direct analgesic effects on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN).

[0527] Example 13: Efficacy of PS and failure of sulindac in treating and / or preventing pain in a mouse model of migraine The nitroglycerin (NTG)-induced migraine mouse model (Bates et al., 2010) is a particularly useful and clinically relevant animal model of migraine. NTG induces activation and sensitization of primary afferent neurons and second-order trigeminovascular neurons. These pathophysiologies are thought to be the underlying mechanisms of migraine (thought to arise in patients with episodic migraine due to repeated activation of dural afferent fibers) and many craniofacial nociceptive symptoms. NTG also mediates facial cutaneous hypersensitivity and hindpaw hypersensitivity to innocuous peripheral stimuli, indicative of allodynia, a symptomatic manifestation of central sensitization. Thus, the ability of NTG to induce central sensitization makes this model applicable to both migraine and, more generally, other pain disorders associated with central sensitization. In this model, rats are tested for mechanical allodynia (painful response to normally non-painful stimuli) using von Frey fibers, small, calibrated fibers that deliver calibrated amounts of force.

[0528] Historical data from this model demonstrates that mechanical nociceptive sensitivity is attenuated by current standard therapeutic compounds, suggesting that this model has clinical application. As predicted above, sensitivity to innocuous stimuli is called allodynia and has been shown to be a potential clinical correlate in migraine patients. In fact, patients with chronic or transformed migraine exhibit facial allodynia even on headache-free days (Cooke et al., The Journal of Head and Face Pain (2007); 47(4), 531-539). Improvement of allodynia, as indicated by an increase in paw withdrawal threshold in this model, correlates with treatment of pain similar to that experienced by migraine patients.

[0529] The ability of a topical formulation of PS to reduce allodynia compared to its parent compound (sulindac) and a positive control is confirmed in this model system.

[0530] method Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 AM - 7:00 PM), and animals were euthanized by CO2 asphyxiation. Mice within each cage were randomly assigned to treatment groups. All tests were performed by an experimenter blinded to the identity of the treatment groups.

[0531] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported according to the ARRIVE guidelines (Kilkenny et al., 2010).

[0532] We used a mouse model of NTG-induced migraine similar to that described by Bates et al., 2010. Specifically, instead of intraperitoneal injection of NTG, a 0.4 mg finely ground NTG tablet (Greenstone Brand) was administered sublingually. As a control, a 0.4 mg Practi-Nitroglycerin sublingual tablet was used. Mechanical nociceptive thresholds were reduced as early as 30 minutes after NTG administration and persisted for approximately 24 hours.

[0533] PS (as an 8% gel), sulindac 5.3% (solubilized in DMSO), or vehicle control gel was administered topically to both hind paws of each mouse 30 minutes after administration of NTG.

[0534] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Vehicle control (n=6) 2. Group 2: PS8% (n=6) 3. Group 3: Sulindac 5.3% (n=6)

[0535] To determine mechanical allodynia, pain threshold responses were measured using the well-established method of von Frey filaments, as performed in previous examples. The PWT test to assess mechanical allodynia was performed 30 minutes after treatment. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animal responded.

[0536] result First, we validated the NTG migraine model, and then evaluated the effects of PS and sulindac in treating migraine pain. In the first study, six separate groups of mice were used, three at 30 minutes and three at 60 minutes, because determining mechanical allodynia in the same animals within 30 minutes can affect the results. As shown in the table below, administration of NTG produces allodynia within 30 minutes of NTG administration, consistent with the understanding that this compound rapidly induces neuronal activity corresponding to central sensitization. For completeness, the oral NTG placebo control had no effect on PWT (i.e., did not produce allodynia) compared to baseline (see Table 13A). [Table 13A]

[0537] As expected, and as summarized in Table 13B, following migraine induction, vehicle-treated mice had lower PWT values ​​compared to the baseline values ​​measured in mice that did not receive NTG. These results are consistent with migraine induction via the activity of NTG. Topical administration of PS achieved a significant increase in PWT compared to vehicle (p<0.003). In contrast, the parent compound, sulindac, failed to improve PWT compared to vehicle. These values ​​are provided in Table 13B. [Table 13B]

[0538] conclusion Local administration of PS significantly increased PWT in mice with NTG-induced migraine compared with vehicle controls. Thus, strikingly, PS treats migraine-related pain. Consistent with other observations herein, this experiment confirms that the parent compound, sulindac, fails to treat migraine-related pain, even at particularly high concentrations, indicating that mere anti-inflammatory activity is insufficient in this animal model of migraine pain. Indeed, allodynia associated with NTG administration is due to activation of neural signaling via the trigeminal nucleus caudalis, confirming the observation herein that the analgesic activity of PS is distinct from any anti-inflammatory activity and more closely resembles the direct neural activity of centrally acting drugs. Without wishing to be bound by theory, the ability of PS to treat pain induced by NTG administration further confirms its activity in combating pain associated with central sensitization, both through a direct effect on pain-generating neural signaling. Furthermore, consistent with the observations herein regarding the rapid accumulation of PS at the central site of action, these results confirm the ability of PS to traverse from peripheral administration sites to distal pain-generating sites to achieve analgesic effects.

[0539] Example 14: Efficacy of orally administered PS in treating pain in a mouse model of migraine Building on the results observed with topically applied PS for the treatment of migraine pain and pain associated with central sensitization, as well as further observations herein demonstrating the broad applicability of PS as a centrally acting analgesic, orally administered PS was investigated in a mouse model of migraine pain.

[0540] method Consistent with previous examples, migraine was induced using 0.4 mg of NTG administered sublingually in the form of a finely ground 0.4 mg NTG tablet (Greenstone Brand). Mechanical allodynia in response to NTG develops in 30 minutes and persists for less than 24 hours. The ability of NTG to induce central sensitization, manifested as allodynia, makes this model applicable to both migraine and other pain disorders more generally associated with central sensitization.

[0541] PS and sulindac were orally administered to each mouse. PS was administered at 50 mg / kg, and sulindac was administered at 33 mg / kg (equimolar to the PS dose), 30 minutes after NTG administration.

[0542] Mechanical allodynia was determined for all test groups of mice as follows: 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)

[0543] Mechanical allodynia was determined using the von Frey filament method as described in the previous example. PWT testing was performed 30 minutes after administration of PS or vehicle control. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animals responded.

[0544] result As expected, following migraine induction, vehicle-treated mice had lower PWT values ​​compared to baseline values ​​measured before migraine induction (i.e., sublingual administration of NTG establishes allodynia that is not reversed by vehicle administration). These results are consistent with migraine induction. Oral administration of PS achieved a significant increase in PWT compared to vehicle (p<0.002). Administration of oral sulindac did not significantly increase PWT compared to vehicle. These values ​​are provided in Table 14. [Table 14]

[0545] conclusion Similar to the observations with topically administered PS, oral administration of PS resulted in a significant increase in PWT compared with vehicle controls in a mouse model of migraine, in contrast to oral sulindac administration, which had no significant effect. These positive results support the data herein using topical PS in this model, confirming that PS is not acting as a local analgesic but instead reaches a central site of action to achieve significant effects on pain known to originate centrally (e.g., via central sensitization). The ability of PS to affect centrally generated pain, even when administered orally, is particularly surprising and is supported by further observations herein showing that orally administered PS reaches the central pain-generating site. The failure of orally administered sulindac to treat pain in this pain model, which generates pain associated with central sensitization, corresponds to observations with topical sulindac in other models of centrally generated pain, demonstrating that the mere anti-inflammatory activity of sulindac is insufficient to abrogate pain signaling in this model. Sulindac, of course, does not act as an analgesic against neuronal pain signaling, let alone pain signaling originating at a central site of action. In contrast, and without wishing to be bound by theory, these results confirm the broad applicability of PS, which appears to be a direct-acting neuroanalgesic, in the treatment of various forms of neuropathic pain and pain with a central site of origin. Indeed, the allodynia associated with NTG administration is due to activation of neuronal signaling via the trigeminal nucleus caudalis, confirming the observation herein that the analgesic activity of PS is distinct from any anti-inflammatory activity and is more akin to the direct neuroactive activity of centrally acting drugs.

[0546] Example 15: Effects of topiramate, sumatriptan, propranolol, and gabapentin in a mouse model of migraine pain To confirm their clinical applicability in a mouse model of migraine pain, we tested the ability of four compounds, topiramate, sumatriptan, propranolol, and gabapentin, to reduce allodynia. These compounds are widely used in the treatment or prevention of migraine-related pain, and their administration was confirmed to reduce allodynia in this mouse model of migraine pain.

[0547] method Consistent with previous examples, migraine headaches were induced using 0.4 mg of NTG administered sublingually in the form of a finely ground 0.4 mg NTG tablet (Greenstone Brand). Mechanical allodynia in response to NTG developed in 30 minutes and persisted for less than 24 hours.

[0548] 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 at the indicated doses 30 min after migraine induction.

[0549] Mechanical allodynia was determined for all test groups of mice (5 mice per group): 1. Group 1: Baseline (i.e., no NTG treatment) 2. Group 2: Vehicle 3. Group 3: Topiramate 4. Group 4: Sumatriptan 5. Group 5: Propranolol 6. Group 6: Gabapentin

[0550] Mechanical allodynia was determined using the von Frey filament method as described in the previous example. PWT tests were performed 30 minutes after administration of compound or vehicle control. The mechanical threshold, expressed as g, indicates the force of the von Frey filament to which the animal responded.

[0551] result As expected, following migraine induction, vehicle-treated mice had lower PWT values ​​compared to the baseline values ​​measured before migraine induction (i.e., sublingual administration of NTG establishes allodynia that is not reversed by vehicle administration). These results are consistent with the induction of pain by migraine. Administration of all four compounds achieved a significant increase in PWT compared to vehicle. These values ​​are provided in Table 15. [Table 15]

[0552] conclusion The administration of all four compounds, which are known to be effective in treating migraine pain, results in a significant increase in PWT compared with vehicle control in the mouse model of migraine.These data confirm the clinical applicability of this mouse model to determine the therapeutic potential of compounds in treating migraine pain.This further supports the conclusion in previous example that PS is suitable for treating migraine pain, as well as various forms of neuropathic pain and pain with central origin.

[0553] Notably, these clinical compounds are known to act directly on central neurons through mechanisms that include reducing action potential firing, thereby attenuating pain signaling. As mentioned above, persistently elevated action potential firing is associated with central sensitization that occurs upon administration of NTG in this model. Therefore, the use of PS as disclosed in the Examples herein achieves analgesic activity similar to that observed with direct neuroactive clinical therapeutics for migraine pain. These observations further support the hypothesis that PS achieves the treatment of pain, such as migraine pain, through a direct effect on neurons, particularly neurons involved in the generation of pain associated with central sensitization.

[0554] Example 16: Efficacy of orally administered PS and failure of sulindac in treating pain in a mouse model of chronic migraine Building on the observations herein in a mouse model of migraine pain, the analgesic efficacy of orally administered PS was investigated in mice with chronic (i.e., ongoing) migraine pain episodes. In contrast to previous experiments, the pain established in this model is chronic, producing further episodes of central sensitization, thus creating a more challenging pain model.

[0555] method We used an NTG-induced chronic migraine model (Pradhan et al., 2014) (Moye & Pradhan, 2017). Specifically, mice received sublingual NTG 0.4 mg in the form of finely ground 0.4 mg NTG tablets (Greenstone Brand) every 2 days for a total of five doses. Control mice received an NTG placebo (Practi-Nitroglycerin sublingual 0.4 mg placebo tablet) in the same manner. Chronic administration of NTG ensures that the effects of central sensitization occur over a longer period, allowing us to examine the efficacy of PS in treating pain associated with ongoing sensitization from centrally located neurons.

[0556] As with the migraine pain model considered elsewhere herein, the ability of NTG to induce central sensitization manifested as allodynia makes this model applicable to both migraine and more generally other pain disorders associated with central sensitization.

[0557] PS and sulindac were orally administered to each mouse at 50 mg / kg and 33 mg / kg (equimolar to the PS dose) once daily for 11 days, simultaneously with NTG administration.

[0558] Mechanical allodynia was determined for all test groups of mice as follows: 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)

[0559] Mechanical allodynia was determined using von Frey filaments as described in the previous example. PWT tests were performed before administration of NTG (or placebo NTG), as indicated, to determine baseline values. PWT tests were then performed 30 minutes after administration of PS, Sulindac, or vehicle control. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animals responded.

[0560] result As expected, following administration of NTG, mice had lower PWT values ​​compared to the baseline values ​​measured before 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. Placebo NTG did not significantly alter baseline values. For vehicle-treated mice, there was no significant difference in PWT values ​​compared to NTG-treated mice after 11 days (i.e., sublingual administration of NTG establishes allodynia that is not reversed by vehicle administration). However, oral administration of PS 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, consistent with observations elsewhere herein, administration of oral sulindac did not significantly increase PWT compared to vehicle. These values ​​are provided in Table 16. [Table 16]

[0561] conclusion Similar to the observations with orally administered PS in the migraine pain model herein, oral administration of PS resulted in a significant increase in PWT compared with vehicle control in a mouse model of chronic migraine, in contrast to oral sulindac, which had no significant effect. These remarkable results confirm the data herein that orally administered PS can treat pain associated with central sensitization expressed in this migraine pain model.

[0562] Furthermore, these data demonstrate that orally administered PS can continue to treat pain associated with central sensitization, resulting in persistent pain onset and nociception (i.e., corresponding to pain manifestations in chronic migraine) over an extended period of time. These observations are particularly striking because continued administration of NTG causes consistent activation of centrally located neurons, corresponding to the isolated neuronal signaling experienced during central sensitization, further supporting the role of PS in directly acting on neuronal signaling occurring at central sites, consistent with further observations herein.

[0563] Example 17: Effect of topiramate and sumatriptan in a mouse model of chronic migraine Similar to the short-term migraine pain experiments, the ability of topiramate and sumatriptan to reduce allodynia was tested to confirm the clinical applicability of the chronic migraine pain model.

[0564] method The NTG-induced chronic migraine model was used as previously described.

[0565] Twelve days after the first dose of NTG, a single intraperitoneal dose of topiramate (30 mg / kg), sumatriptan (600 μg / kg), or vehicle was administered.

[0566] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: NTG + vehicle (n = 8) 2. Group 2: NTG + topiramate (n=8) 3. Group 3: NTG + sumatriptan (n=8)

[0567] Mechanical allodynia was determined using von Frey filaments, as in the previous example. PWT tests were performed before administration of NTG to determine baseline values, and also before administration of compound on day 12, as indicated. PWT tests were then performed 30 minutes after administration of topiramate or sumatriptan. The mechanical threshold, expressed in g, indicates the force of the von Frey filaments to which the animals responded.

[0568] result As expected, following administration of NTG, vehicle-treated mice had lower PWT values ​​compared to the baseline values ​​measured before administration of NTG. These results are consistent with the induction of migraine pain. Both topiramate and sumatriptan administration achieved a significant increase in PWT compared to vehicle. These values ​​are provided in Table 17. [Table 17]

[0569] conclusion Similar to the observations in the short-term migraine pain model, administration of topiramate and sumatriptan, compounds known to be effective in treating migraine pain, likely through direct effects on neuronal signaling, resulted in significant increases in PWT compared with vehicle controls in this chronic migraine pain model. Thus, these data confirm the clinical applicability of this long-term NTG administration model for determining the therapeutic potential of compounds in the treatment of chronic migraine pain.

[0570] Example 18: Notes on observations related to migraine pain Preliminary in vivo observations demonstrate unprecedented analgesic activity of PS in the treatment of migraine pain. These observations are surprising, but are consistent with data from WO2022 / 251805 and WO2022 / 251806 (both of which are incorporated herein by reference in their entireties), which show that PS has direct analgesic effects on two distinct types of neuropathic pain (i.e., associated with CIPN and DPN). In light of the potent analgesic effects of PS in two pathophysiologically distinct forms of neuropathic pain, the inventors hypothesized that PS may have more broadly applicable analgesic activity, possibly (without wishing to be bound by theory) based on PS's ability to reach central sites of action and directly affect neural signaling associated with central sensitization. The inventors' initial observations, along with further data in appropriate animal models of migraine pain presented herein, confirm this hypothesis, demonstrating unprecedented analgesic activity of PS in the treatment of migraine pain. Further experiments described herein using well-established animal models confirm these observations. We predict that PS has a direct effect on neuronal pain signaling generated by migraine pathophysiology, specifically preventing pain generation at central sites by reducing signaling caused by central sensitization. This is suggested by evidence demonstrating PS's ability to reduce allodynia and supported by its observed ability to traverse centrally projecting neurons to and remain stable at central sites of action, even when administered orally. Such therapeutic applicability of PS is unprecedented. In light of PS's ability to traverse central sites upon topical administration, these findings represent a significant contribution to providing a straightforward treatment for pain associated with a wide range of headache disorders. Indeed, the topical route allows for low systemic clearance, reduced drug interactions, increased patient tolerability, and easy coadministration with oral medications. PS may also be administered orally for the treatment of migraine pain. Indeed, surprisingly, oral administration in appropriate animal models achieved analgesia.

[0571] These observations demonstrate previously unrecognized activities and therapeutic utility of PS, a compound that falls within the broader class of NSAIDs but does not share all of the properties of this compound family. Indeed, unlike typical NSAIDs, PS does not inhibit COX-1 or COX-2 activity or block prostaglandin synthesis or activity. Instead, PS has been shown to induce increased COX activity and significant increases in PGE2 levels (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32). As explained herein, migraine is not considered an inflammatory disorder; instead, it is considered to have a pathophysiology of pain resulting from neuronal dysfunction and sensitization within the trigeminal pathway. Therefore, purely anti-inflammatory activity would not achieve the analgesic effect required to treat migraine pain. Indeed, although NSAIDs are hypothesized to treat migraine, studies have demonstrated that members of this class of compounds are not effective analgesics for this indication. For example, naproxen has been shown to be clinically ineffective for treating migraine headaches (Law et al. Cochrane Database of Systematic Reviews (2013); 10:1-45). To the extent that NSAIDs have been suggested for the treatment of migraine-associated pain (i.e., not inflammation), this activity is limited to their ability to inhibit prostaglandin synthesis by blocking the COX pathway. As explained above, PS does not share these activities of typical NSAIDs. Thus, the analgesic activity of PS in the treatment of migraine pain is unexpected. Naturally, the treatment of pain itself, as suggested by the preliminary observations herein, is distinct from the established role of PS and typical NSAIDs as anti-inflammatory agents.

[0572] Previous observations regarding the activity of PS have been limited to its anti-inflammatory activity. For example, WO 2019 / 067919 suggested a role for PS in the treatment of DED using an acute DED model in which concanavalin A (ConA) was administered simultaneously with PS into the lacrimal glands of rabbits. In this context, the anti-inflammatory activity of PS resulted in a limited inflammatory response to ConA, thus preventing the establishment of DED. These observations confirm the anti-inflammatory activity of PS and suggest its usefulness in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model fall short of providing any evidence of PS's ability as an analgesic that could act directly on nerves to reduce the neuronal signaling dysfunction and central sensitization associated with migraine pain. Any reduction in pain in this acute DED model could be attributed solely to PS inhibiting the inflammatory response (i.e., the underlying pathology that triggers the activation of pain sensors). On the contrary, the results in the DED model suggest that PS improves corneal sensitivity, implying increased nociception, an effect opposite to that desired for an analgesic. Of course, regardless of any indications toward an analgesic activity of PS, such activity observed in the acute DED model does not provide any indication of a corresponding activity in migraine pain.

[0573] The observations herein demonstrate that PS has therapeutic utility beyond the scope of anti-inflammatory activity suggested for typical NSAIDs. Such NSAIDs, such as naproxen, are ineffective in reducing migraine pain (Law et al., Cochrane Database of Systematic Reviews (2013); 10:1-45), and this failure is likely a result of the purely anti-inflammatory activity of typical NSAIDs. As explained above, such anti-inflammatory activity is insufficient to treat migraine pain, which is a purely neuronal disorder. Any suggestion of the activity of typical NSAIDs in treating migraine pain (rather than the inflammatory response) is related to the requirement for inhibition of the COX pathway and prostaglandin synthesis (i.e., activities of typical NSAIDs not shared by PS). Without wishing to be bound by theory, the observations herein indicate that PS effectively treats migraine-related pain by targeting neuronal signaling that occurs via central sensitization, a key component of migraine-related pain.

[0574] Thus, the inventors have demonstrated a new and surprising activity for PS in the treatment and / or prevention of migraine-related pain. As outlined above, this activity represents a mechanism unique to PS compared to typical NSAIDs. Furthermore, the ease with which PS can be administered (e.g., topically) and its limited adverse effects (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32) make PS an improved therapy for migraine pain.

[0575] Moreover, surprisingly, the analgesic activity of PS was maintained even when administered orally in an animal model of migraine pain. The ability of PS to affect migraine pain in an animal model that induces pain and central sensitization is particularly surprising and is supported by further observations herein showing that orally administered PS reaches the central pain-generating site.

[0576] Example 19: Effect of PS in treating neuropathic pain associated with PHN Preliminary in vivo evidence indicates that topical administration of PS in the form of a hydrogel achieves significant analgesic effects on neuropathic pain associated with PHN. This effect was surprising, but is consistent with data from WO2022 / 251805 and WO2022 / 251806, which show that PS has a direct analgesic effect on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN).

[0577] Example 20: Efficacy of PS and failure of sulindac in treating and / or preventing neuropathic pain in a mouse model of PHN Neuropathic pain associated with PHN can be reproduced in a rat animal model using injection of varicella-zoster virus (VZV) into the footpad of rats. VZV reaches the dorsal root ganglion and produces symptoms corresponding to allodynia and hyperalgesia. Therefore, this model produces certain phenotypes observed in human PHN, including, for example, allodynia.

[0578] This model is performed according to the procedure originally developed by Sadzot-Delvaux et al. (Neurology (1995); 45(12 Suppl 8):S18-20). Briefly, rats are inoculated subcutaneously in the footpad with VZV and then subjected to behavioral testing, including measurement of paw withdrawal latency in response to mechanical or thermal stimuli. Paw withdrawal thresholds are significantly reduced within 3-5 days after injection, remain low for 1 month, and resolve within 100 days after injection. After the onset of allodynia, rats are evaluated for the mechanical withdrawal threshold of the hind paw, an indicator of mechanical allodynia. Sensory testing utilizes von Frey filaments. Allodynia is tested by touching the hind paw perpendicularly, causing a slight buckling of the filament. Based on the response pattern and the final filament force, the hind paw withdrawal threshold is calculated.

[0579] As described herein, a corresponding mouse model is available.

[0580] method Adult male BALB / c mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were housed in groups of four in an AAALAC-accredited facility. Food and water were available ad libitum. Experiments were performed during the light cycle (7:00 AM - 7:00 PM), and animals were euthanized by CO2 asphyxiation. Mice within each cage were randomly assigned to treatment groups. All tests were performed by an experimenter blinded to the identity of the treatment groups.

[0581] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal studies are reported according to the ARRIVE guidelines (Kilkenny et al., 2010).

[0582] PHN was induced in mice by infecting them with HSV-1 KOS strain virus and following established protocols (Ou et al., Front Immunol, 14, 1026269, 2023; Takasaki et al., Anesthesiology, 96(5), 1168-74, 2002).

[0583] Briefly, BALB / c male mice were anesthetized with isoflurane (2%), their mid-flank and right leg were clipped, and hair was removed with a chemical hair remover (Veet Hair Remover; Reckitt Benckiser). Three days later, HSV-1 (10 in 20 μl of PBS) was injected. 6PFU) were inoculated onto the right hind paw shank (5 × 5 mm) after a sandpaper wound. The virus was applied directly to the wound area. The contralateral hind paw was not inoculated. Mock infections were performed using the same virus that had been heat-inactivated at 60°C for 1 hour.

[0584] At the onset stage of skin lesions (3–5 days after inoculation), numerous small blisters appeared on the backs of the mice and surrounding the inoculated area, characterized as mild to moderate zosteriform lesions.

[0585] Five days after inoculation, PS (as a 5% gel) or vehicle control was administered topically to both hind paws of mice three times daily for three days.

[0586] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Sham vaccination (n=5~7) 2. Group 2: Vehicle control (n = 5-7) 3.Group 3: PS5% (n=5~7)

[0587] In a second experiment, the effects of the parent compound, sulindac, were tested in the same mouse model. Five days after inoculation, mice were given topical sulindac (as a 5% gel) or vehicle control three times daily for three days in both hind paws.

[0588] Mechanical allodynia was determined for all test groups of mice as follows: 1. Group 1: Vehicle control (n=5-7) 2. Group 2: Sulindac 5% (n=5-7)

[0589] To determine mechanical allodynia, pain threshold responses were measured using the well-established method of von Frey filaments, as performed in previous examples. PWT tests to assess mechanical allodynia were performed either before inoculation, 5 days after inoculation, or 3 days after treatment, as indicated. The mechanical threshold, expressed as g, indicates the force of the von Frey filaments to which the animals responded.

[0590] result Allodynia was evident in both hind paws, i.e., ipsilateral and contralateral to the viral inoculation site, with no statistically significant difference in intensity between them, as previously reported (Chen & Pan, Brain Res, 1042(1), 108-13, 2005).

[0591] As expected, as shown in Table 18A, mock-inoculated mice have similar PWT values ​​compared with pre-inoculated mice, indicating that mock inoculation does not lead to the development of any pain.Five days after induction, a significant decrease in PWT values ​​was observed in both inoculated groups, reflecting the successful induction of PHN-associated neuropathic pain.Remarkably, administration of PS can achieve a significant increase in PWT after treatment compared with vehicle (p<0.0001).The results are shown in Table 18A. [Table 18A]

[0592] In the second experiment, administration of sulindac after inoculation did not improve PWT values ​​compared to vehicle controls (0.56±0.06 vs. 0.65±0.07; not significant). These values ​​are provided in Table 18B. [Table 18B]

[0593] conclusion Local administration of PS significantly increased PWT in mice with PHN compared with vehicle controls. Thus, remarkably, PS treats pain associated with PHN, a form of neuropathic pain known to be particularly difficult to treat.

[0594] As discussed herein, pain associated with PHN is associated with central sensitization as manifested by the development of allodynia. Thus, these results, combined with the observation herein of the accumulation of PS at central sites of action, point not only to the analgesic activity of PS in treating neuropathic pain associated with PHN, but also to the unprecedented and surprising broad applicability of PS for treating and preventing pain with central mechanisms (i.e., arising at a central site or due to central sensitization), even in particularly challenging neuropathic pain models.

[0595] In contrast, the parent compound, sulindac, failed to improve PWT values ​​compared to vehicle controls, despite the use of high relative concentrations of sulindac, again confirming that the anti-inflammatory activity of typical NSAIDs is insufficient to treat the difficult pain encountered in these models.

[0596] Example 21: Notes on Preliminary Observations Related to PHN Preliminary in vivo observations demonstrate unprecedented analgesic activity of PS in the treatment of neuropathic pain associated with PHN. These observations are surprising, but are consistent with data from WO2022 / 251805 and WO2022 / 251806 (both of which are incorporated herein by reference in their entireties), which show that PS has direct analgesic effects on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN). In light of the potent analgesic effects of PS in two pathophysiologically distinct forms of neuropathic pain, the inventors hypothesized that PS may have more broadly applicable analgesic activity in other forms of neuropathic pain, possibly (without wishing to be bound by theory) based on the ability of PS to traverse to central sites of action and directly affect neural signaling associated with central sensitization. The inventors' initial observations herein confirm this hypothesis, demonstrating the unprecedented analgesic activity of PS in the treatment of neuropathic pain associated with PHN. Such broad applicability as an analgesic across various forms of neuropathic pain is not guaranteed; indeed, gabapentin exhibits variable efficacy in treating various forms of neuropathic pain. Further experiments using well-established animal models of PHN-associated neuropathic pain will confirm these observations. The inventors predict that PS has a direct effect on neuronal pain signaling that occurs in response to VZV reactivation and viral replication, which cause nerve damage both peripherally and centrally, and may prevent pain generation at central sites by reducing signaling caused by central sensitization. Such therapeutic applicability of PS is unprecedented. In light of the ability of PS to traverse to central sites upon local administration, these findings represent a significant contribution to providing a simple and straightforward treatment for PHN-associated neuropathic pain. Indeed, the local route allows for low systemic clearance, reduced drug interactions, increased patient tolerability, and easy combination with oral medications.

[0597] These observations demonstrate previously unrecognized activities and therapeutic utility of PS, a compound that falls within the broader class of NSAIDs but does not share all of the properties of this compound family. Indeed, unlike typical NSAIDs, PS does not inhibit COX-1 or COX-2 activity or block prostaglandin synthesis or activity. Instead, PS has been shown to induce increased COX activity and a significant increase in PGE2 levels (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32). The observations herein demonstrate a role for PS as an analgesic targeting pain signaling associated with PHN, an activity distinct from the established roles of PS as an anti-inflammatory agent and typical NSAIDs. Indeed, such anti-inflammatory activity has been shown to be ineffective in treating neuropathic pain associated with PHN (Moore et al. (Cochrane Database of Systematic Reviews (2015);10:1-25)).

[0598] Previous observations regarding the activity of PS have been limited to its anti-inflammatory activity. For example, WO 2019 / 067919 suggested a role for PS in the treatment of DED using an acute DED model in which concanavalin A (ConA) was administered simultaneously with PS into the lacrimal glands of rabbits. In this context, the anti-inflammatory activity of PS resulted in a limited inflammatory response to ConA, thus preventing the establishment of DED. These observations confirm the anti-inflammatory activity of PS and suggest its usefulness in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model fall short of providing any evidence of PS's ability as an analgesic, capable of acting directly on nerves to reduce neural signaling caused by neuropathic pain. Any reduction in pain in this acute DED model could be attributed solely to PS inhibiting the inflammatory response (i.e., the underlying pathology that triggers the activation of pain sensors). On the contrary, the results in the DED model suggest that PS improves corneal sensitivity, implying increased nociception, an effect opposite to that desired for an analgesic. Of course, regardless of any indication toward an analgesic activity of PS, such activity observed in the acute DED model does not provide an indication of a corresponding activity in neuropathic pain, let alone in the neuropathic pain associated with PHN.

[0599] The observations herein indicate that PS has therapeutic utility beyond the scope of the anti-inflammatory activity associated with typical NSAIDs. In contrast, certain NSAIDs are ineffective analgesics in treating neuropathic pain associated with PHN. Indeed, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1-25) reviewed that NSAIDs have no therapeutic efficacy in peripheral neuropathic pain associated with PHN. The activity of PS suggested herein contrasts with the inability of typical NSAIDs to provide a direct analgesic effect on damaged neurons in neuropathic pain, as observed in the prior art. While not 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 rather than inflammation (i.e., the anti-inflammatory activity of any typical NSAID is insufficient to prevent or treat neuropathic pain). Thus, the analgesic activity of PS demonstrated herein is unique and not shared by typical NSAIDs. Any alleged analgesic activity of NSAIDs observed in the prior art reflects their anti-inflammatory activity (i.e., stopping potential triggers that cause pain) rather than actual analgesic activity directed against nerve signaling (i.e., which would result in a reduction in pain caused by nerve damage and sensitization). Indeed, as discussed above, the anti-inflammatory activity of typical NSAIDs is considered to have no therapeutic utility in treating neuropathic pain associated with PHN. In any case, any alleged activity of typical NSAIDs in treating neuropathic pain associated with PHN cannot be extrapolated to PS in light of the distinctly different activity of PS compared to typical NSAIDs. The observations herein demonstrate the usefulness of PS in treating neuropathic pain associated with PHN. Any suggestion that typical NSAIDs have analgesic activity is related to the requirement for inhibition of the COX pathway and prostaglandin synthesis (i.e., activities of typical NSAIDs not shared by PS).Without wishing to be bound by theory, the observations herein indicate that PS effectively treats neuropathic pain associated with PHN by targeting neuronal signaling that occurs via central sensitization, a major component of neuropathic pain associated with PHN.

[0600] Thus, the inventors demonstrate new and surprising activity for PS in the treatment and / or prevention of neuropathic pain associated with PHN. As outlined above, preliminary observations imply activity of PS that goes beyond the range of anti-inflammatory activity previously observed for PS and related NSAIDs. Furthermore, the ease with which PS can be administered (e.g., topically) and its limited adverse effects (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32) make PS an improved therapy for neuropathic pain associated with PHN.

[0601] Example 22: Effect of PS in the treatment of corneal neuropathic pain Preliminary in vivo evidence indicates that topical administration of PS to the ocular surface achieves significant analgesic effects on corneal neuropathic pain. Furthermore, topical administration of PS to the outer surface of the eyelid dramatically reduced chronic pain in subjects undergoing LASIK. This effect was surprising, but is consistent with data from WO2022 / 251805 and WO2022 / 251806, which showed that PS has a direct analgesic effect on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN).

[0602] Example 23: Evaluation of the efficacy of PS in treating corneal neuropathic pain in a rabbit model Animal models involving injury to the ocular surface rely heavily on the induction of corneal inflammation, which can prevent observations regarding the treatment of corneal neuropathic pain. Alternatively, corneal neuropathic pain can be generated in a rabbit model by ligating the ciliary branches that innervate the cornea. Nerve compression causes sensitization, leading to pain hypersensitivity.

[0603] This model is a modified version of the procedure developed by Seyed-Razavi et al. (Investigative Ophthalmology & Visual Science (2017); 58:3951). The model used herein uses rabbits rather than mice. Briefly, following lateral canthotomy, two temporary nylon sutures are placed, and the lateral conjunctival fornix is ​​incised circumferentially (90 degrees). The globe is rotated nasally by gently pressing the nasal conjunctival fornix with curved, blunt-tip forceps. Silk sutures are placed and tied around the exposed optic nerve and surrounding ciliary nerve branches, and ligated without cutting the ciliary nerve. Rabbits undergoing all surgical steps but lacking suture ligation serve as sham controls. Following this procedure, two nylon sutures are used to reattach the eyelids. Various behavioral responses can then be monitored to demonstrate the establishment of central sensitization, an indicator of corneal neuropathic pain, without any associated peripheral corneal pathology. Exemplary behavioral responses include eye rubbing, blinking, and / or squinting. For completeness, these behaviors can be further induced by instillation of hyperosmolar saline solution. Indeed, as observed in Seyed-Razavi et al., mice subjected to nerve ligation exhibit an increased frequency of nociceptive paw rubbing over the affected eye. Therefore, this is an appropriate model for determining the efficacy of analgesics in treating corneal neuropathic pain. Because this occurs as a result of dysfunction of centrally located neurons (i.e., central sensitization), acute-acting analgesics (i.e., active against corneal nociceptors) will not effectively resolve hypersensitivity in this model of corneal neuropathic pain.

[0604] Example 24: Notes on preliminary observations related to corneal neuropathic pain Preliminary in vivo observations demonstrate unprecedented analgesic activity of PS in the treatment of corneal neuropathic pain. These observations are surprising, but are consistent with data from WO2022 / 251805 and WO2022 / 251806 (both of which are incorporated herein by reference in their entireties), which show that PS has direct analgesic effects on two distinct types of neuropathic pain (i.e., those associated with CIPN and DPN). In light of the potent analgesic effects of PS in two pathophysiologically distinct forms of neuropathic pain, the inventors hypothesized that PS may have more broadly applicable analgesic activity in other forms of neuropathic pain, likely based on its ability to traverse to central sites of action (even when administered topically to the eyelid) and directly affect neural signaling associated with central sensitization. The inventors' initial observations herein confirm this hypothesis, demonstrating the unprecedented analgesic activity of PS in the treatment of corneal neuropathic pain. Indeed, PS demonstrated a significant reduction in corneal neuropathic pain experienced by subjects after LASIK surgery. Such broad applicability as an analgesic across various forms of neuropathic pain is not guaranteed; indeed, gabapentin exhibits variable efficacy in treating various forms of neuropathic pain. Further experiments using animal models of corneal neuropathic pain will confirm these observations. Without wishing to be bound by theory, the inventors predict that PS has a direct effect on neuronal pain signaling generated by central sensitization associated with corneal neuropathic pain. Such therapeutic applicability of PS is unprecedented. Given the ability of PS to traverse to its central site of action upon topical administration (even to the outer surface of the eyelid), these findings represent a significant contribution to providing a straightforward treatment for corneal neuropathic pain. Indeed, the topical route (certainly via the outer surface of the eyelid) allows for low systemic clearance, reduced drug interactions, increased patient tolerability, and easy combination with oral medications.

[0605] These observations demonstrate previously unrecognized activities and therapeutic utility of PS, a compound that falls within the broader class of NSAIDs but does not share all of the properties of this compound family. Indeed, unlike typical NSAIDs, PS does not inhibit COX-1 or COX-2 activity or block prostaglandin synthesis or activity. Instead, PS has been shown to induce increased COX activity and a significant increase in PGE2 levels (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32). The observations herein demonstrate a role for PS as an analgesic targeting pain signaling associated with corneal neuropathic pain, an activity distinct from the established roles of PS as an anti-inflammatory agent and typical NSAIDs. Indeed, such anti-inflammatory activity has been shown to be ineffective in treating neuropathic pain (Moore et al. (Cochrane Database of Systematic Reviews (2015);10:1-25)). Consistent with this, anti-inflammatory drugs are not effective for patients with corneal neuropathic pain.

[0606] Previous observations regarding the activity of PS have focused on its anti-inflammatory activity and have not provided any indication of analgesic activity in corneal neuropathic pain. For example, WO 2019 / 067919 suggested a role for PS in the treatment of DED using an acute DED model in which concanavalin A (ConA) was administered simultaneously with PS into the lacrimal glands of rabbits. In this context, the anti-inflammatory activity of PS resulted in a limited inflammatory response to ConA, thus preventing the establishment of DED. These observations confirm the anti-inflammatory activity of PS and suggest its usefulness in preventing the establishment and maintenance of the inflammatory components of DED. The observations in this acute DED model do not provide any evidence of PS's ability to directly act on nerves to reduce neural signaling caused by neuropathic pain. Any reduction in pain in this acute DED model could be attributed solely to PS inhibiting the inflammatory response (i.e., the underlying pathology that triggers the activation of pain sensors). In addition to demonstrating the anti-inflammatory activity of PS in DED, the authors of WO2019 / 067919 suggest that PS reduces corneal sensitivity in an acute corneal sensation model. These observations regarding the alleged decreased sensitivity to acute stimuli that do not apparently produce persistent pain (i.e., sensation occurring in the absence of peripheral stimulation) do not suggest the ability of PS to treat pain associated with central sensitization, a mechanism known to be involved in corneal neuropathic pain. Indeed, the effects of PS in this acute model were observed immediately, implying a local action of PS, not dissimilar to the activity observed for ketorolac, a typical NSAID, in the same model. Such peripheral activity does not demonstrate the efficacy of PS in treating pain generated at a central site of action. Indeed, clinical guidance in the field recommends avoiding the use of NSAIDs to treat types of pain associated with central sensitization (e.g., neuropathic pain), and ketorolac has been shown to have limited analgesic activity in such pain models. Furthermore, results from the DED model suggest that PS restores suppressed corneal sensitivity, implicating a role for PS in increasing rather than reducing nociception.Of course, regardless of any indications towards analgesic activity of PS, such activity observed in the acute DED model does not provide any indication of a corresponding activity in corneal neuropathic pain.

[0607] The observations herein demonstrate that PS has therapeutic utility beyond the scope of the anti-inflammatory activity associated with typical NSAIDs. In contrast, NSAIDs are ineffective analgesics in the treatment of neuropathic pain. Indeed, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10:1-25) reviewed that NSAIDs have no therapeutic efficacy in neuropathic pain. The activity of PS suggested herein contrasts with the inability of typical NSAIDs to provide a direct analgesic effect on sensitized neurons in neuropathic pain, as observed in the prior art. While not 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 rather than inflammation (i.e., the anti-inflammatory activity of any typical NSAID is insufficient to prevent or treat neuropathic pain). Therefore, the analgesic activity of PS demonstrated herein is unique and not shared by typical NSAIDs. Any alleged analgesic activity of NSAIDs observed in the prior art reflects their anti-inflammatory activity (i.e., stopping potential triggers that cause pain) rather than actual analgesic activity directed against nerve signaling (i.e., that would result in a reduction in pain caused by sensitization). In any event, any alleged activity of typical NSAIDs cannot be extrapolated to PS in light of the distinctly different activity of PS. Any suggestion that typical NSAIDs have analgesic activity is related to the requirement for inhibition of the COX pathway and prostaglandin synthesis (i.e., activities of typical NSAIDs that are not shared by PS). Without wishing to be bound by theory, the observations herein indicate that PS treats corneal neuropathic pain by targeting nerve cell signaling that occurs via central sensitization, a major component of corneal neuropathic pain.

[0608] Thus, the present inventors have demonstrated a new and surprising activity for PS in the treatment of corneal neuropathic pain. As outlined above, these observations imply an activity of PS that exceeds the range of activity previously observed for PS and related NSAIDs. Furthermore, the ease with which PS can be administered (e.g., topically) and its limited adverse effects (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32) make PS an improved therapy for corneal neuropathic pain, particularly via topical administration to the outer surface of the eyelid.

[0609] Example 25: Pharmacokinetics and biodistribution of PS As demonstrated herein, given the broad applicability of PS for the treatment and / or prevention of pain with a central site of action, such as pain associated with central sensitization, neuropathic pain associated with PTPN, migraine pain, neuropathic pain associated with PHN, and corneal neuropathic pain, this may reflect the ability of PS to reach and remain stable at a specific site of action. Therefore, the site of action of PS was investigated. Despite being administered locally, PS was found to traverse from the periphery to the central site within the nerve.

[0610] method PS 8% ointment was applied topically to each hind paw by gentle rubbing (50 μl per paw). At 0.5, 1, 3, 5, 12, 18, and 24 hours, mice (n = 4-5 mice per time point) were euthanized by CO2 inhalation. Blood was collected immediately after death. Tissues, including skin from both paws, foot muscles, leg muscles, sciatic nerves, and lumbar DRG, were quickly dissected, immediately frozen in liquid nitrogen, and stored at -80°C until analysis.

[0611] In a separate experiment, eight mice with paclitaxel-induced PN were treated with PS 8% ointment three times daily for two weeks. Mice were euthanized as described above 30 minutes after the final administration of PS. Both sciatic nerves were harvested from these mice and divided into proximal and distal halves. The corresponding halves from each pair of animals were combined for drug level assays.

[0612] As previously described (Wen et al., Int J Pharm (2019); 557:273-279), each plasma sample was mixed with a double volume of acetonitrile and centrifuged at 13,200 rpm for 15 minutes. Tissue samples were weighed, and ddHO (100–300 μL depending on the tissue weight) was added and homogenized. As reported (Wen et al., 2019), after adding acetonitrile (twice the volume of the homogenate), the mixture was sonicated for 10 minutes, centrifuged at 13,200 rpm for 15 minutes, and analyzed by HPLC. The limits of quantification were 0.1 μM for PS and 0.05 μM for sulindac, sulindac sulfone, sulindac sulfide, and their glucuronidated derivatives.

[0613] result PS can be rapidly metabolized both in vitro and in vivo to several metabolites, including PS sulfide, PS sulfone, sulindac, sulindac sulfide, and sulindac sulfone (Figure 11). The glucuronide of sulindac and its metabolites (formed primarily in the liver) have also been identified. Because the metabolism and PK / biodistribution of PS vary depending on its route of administration, both were studied in normal mice receiving local administration of PS to the hind paw, with particular attention to the sciatic nerve and dorsal root ganglion (DRG) as examples of peripheral and more centrally located neuronal sites.

[0614] As shown in Figure 12 and Table 19, PS was detected in the paw skin, the application site, the muscle under the skin, the leg muscle, the sciatic nerve, and the DRG. As expected (Xie et al., Br J Pharmacol (2012a); 165: 2152-2166), PS was not detected in the systemic circulation.

[0615] The concentration of PS increases from the skin to its most distal DRG, max (194.7±5.3μM to 0.3±0.1μM) and AUC 0-24h The T of PS decreased progressively as evidenced by the respective values ​​of both (1,609.8 μM h to 4.5 μM h). max is the same (0.5 hours) for all tissues except for the DRG, which, as discussed below, exhibits a prolonged T, possibly reflecting the manner in which the PS arrives at it. max Another interesting feature was the skin and muscle 1 / 2 The difference was within a relatively narrow range (11.4-20.6 hours), in contrast to the much more extended value of 57.4 hours in the sciatic nerve and possibly even more extended values ​​in the DRG (which could not be determined with reasonable accuracy).

[0616] These differences indicate that there is a difference in metabolic capacity for PS between nerves and skin and muscle. [Table 19]

[0617] Only three metabolites of PS were detected: sulindac, sulindac sulfone, and sulindac sulfide (Figure 13 and Table 20). The glucuronic acid product was not detected. Sulindac was the quantitatively predominant metabolite, with sulindac sulfide and sulindac sulfone levels <20% of the sulindac level. Sulindac levels were approximately 25% of the PS level in all tissues except the sciatic nerve (higher) and DRG (equal). [Table 20]

[0618] Absence of PS in circulation, T in DRG max The significantly higher levels of PS in the DRG compared with those in the sciatic nerve suggest that PS reaches the DRG by traversing the sciatic nerve from the skin.

[0619] To further explore this conclusion, we compared PS levels in the proximal and distal halves of mouse sciatic nerves 30 minutes after application to the hindpaw. The two values ​​were significantly different, with the distal half being 18.5-fold higher than the proximal half (17 ± 5.1 μM vs. 0.9 ± 0.3 μM; Table 21). Concentrations of three metabolites of PS (sulindac, sulindac sulfide, and sulindac sulfone) were also higher (4.5- to 8.5-fold higher) in the distal half compared to the proximal half. These findings support the idea that PS reaches the DRG from its application site by direct tissue translocation or transport, rather than via the circulation. [Table 21]

[0620] conclusion These experiments demonstrate that locally administered PS can reach key sites of action known to be involved in the generation of pain associated with 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 from other headache disorders), and corneal neuropathic pain). Furthermore, in light of its rapid metabolism in the bloodstream, these results demonstrate that PS reaches these sites of action by traversing peripheral neurons toward the central nervous system, where it is found at significant concentrations in the DRG. Thus, without wishing to be bound by theory, these observations confirm that PS likely exerts its analgesic activity in the indications disclosed herein directly on neurons and possibly within a central site of action, similar to the activity of neurodirected and centrally acting analgesics such as lidocaine and pregabalin. Indeed, based on the ability of local PS to traverse peripheral neurons toward the central site of action in these experiments, it would be expected that local administration of PS to the skin near a peripheral nerve would allow PS to accumulate in higher-order neurons involved in chronic signaling associated with central sensitization. For example, in PTPN, local administration of PS to the skin near an injured peripheral nerve would be expected to allow PS to accumulate in proximal peripheral neurons or in higher-order neurons involved in chronic signaling associated with central sensitization. For example, in PHN, local administration of PS to the skin of one or more thoracic dermatomes would be expected to allow PS to accumulate in one or more thoracic nerves or in higher-order neurons involved in chronic signaling associated with central sensitization. For example, in the case of migraine, local administration of PS to the skin near trigeminal neurons would be expected to allow PS to accumulate in neurons of the trigeminal pathway, such as the trigeminal ganglion, or further into the CNS, in the trigeminal nucleus caudalis within the trigeminocervical complex (TCC).

[0621] The observation of PS accumulation at the central site of action is supported by the observation that PS clearly inhibits neuronal pain signaling at the central site of action (e.g., its analgesic effect on NTG-induced central sensitization, its analgesic effect when administered to the contralateral unoperated paw, and the ability of orally administered PS to reach central pain-generating sites and achieve meaningful analgesia).

[0622] Example 26: Pharmacokinetics and biodistribution of PS when adm...

Claims

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

2. 10. The method of claim 1, wherein treating the neuropathic pain comprises reducing the neuropathic pain.

3. 3. The method of claim 1 or 2, wherein preventing said neuropathic pain comprises reducing the incidence of said neuropathic pain.

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

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

6. 6. The method of claim 4 or 5, wherein the one or more sensory symptoms are selected from paresthesia, a burning sensation, and a tingling sensation.

7. 7. The method of claim 6, wherein the abnormal sensations include one or more of numbness, tingling, prickling, or crawling.

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

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

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

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

12. 10. The method of any one of the preceding claims, wherein the PS reduces pain signaling originating in peripheral nerves.

13. 10. The method of any one of the preceding claims, wherein the PS reduces pain signaling originating in the dorsal root ganglion.

14. 10. The method of any one of the preceding claims, wherein the PS reduces pain signaling originating in the dorsal horn of the spinal cord.

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

16. 16. The method of claim 15, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

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

18. 10. The method of any one of the preceding claims, wherein the PTPN-associated neuropathic pain is caused by transient nerve conduction disorders, such as nerve compression injury.

19. 10. The method of any one of the preceding claims, wherein the PTPN-associated neuropathic pain is caused by axonal transection, e.g., nerve crush injury.

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

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

22. The PS is of formula I (PS-I) 【Chemistry 1】 10. The method of any one of the preceding claims, comprising:

23. The PS is represented by formula II (PS-II): 【Chemistry 2】 10. The method of any one of the preceding claims, comprising:

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

25. 25. The method of claim 24, wherein the pharmaceutical composition comprising the PS is formulated for topical administration.

26. 26. The method of claim 25, wherein the pharmaceutical composition comprising PS is formulated as a semi-solid.

27. 26. The method of claim 25, wherein the pharmaceutical composition comprising PS is formulated as a liquid.

28. The method according to any one of claims 25 to 27, wherein the pharmaceutical composition comprising PS is a cream.

29. The method according to any one of claims 25 to 27, wherein the pharmaceutical composition comprising PS is a gel, for example, the gel is a hydrogel.

30. The method according to any one of claims 25 to 27, wherein the pharmaceutical composition comprising PS is a lotion.

31. The method according to any one of claims 25 to 27, wherein the pharmaceutical composition comprising PS is an ointment.

32. The method according to any one of claims 25 to 27, wherein the pharmaceutical composition comprising PS is a spray.

33. 26. The method of claim 25, wherein the pharmaceutical composition comprising the PS is formulated as a patch.

34. 34. The method of any one of claims 24 to 33, wherein the pharmaceutical composition comprises the PS at a concentration of about 0.5% to about 15% (w / w) of the pharmaceutical composition.

35. 35. The method of claim 34, wherein the pharmaceutical composition comprises the PS at a concentration of about 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (w / w) of the pharmaceutical composition.

36. 36. The method of claim 35, wherein the pharmaceutical composition comprises the PS at a concentration of 8% (w / w) or less of the pharmaceutical composition, for example, about 5% or about 3% (w / w) of the pharmaceutical composition.

37. 37. The method of claim 36, wherein the pharmaceutical composition comprises the PS at a concentration of about 3% (w / w) or less of the pharmaceutical composition, for example about 2% or about 1% (w / w) of the pharmaceutical composition.

38. The PS has a viscosity of about 0.005 g / 10 cm ２ ~Approx. 0.25g / 10cm ２ The method according to any one of claims 24 to 37, wherein the method is administered at an affected site.

39. The PS has a viscosity of about 0.005 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

40. The PS is about 0.01 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

41. The PS is about 0.05 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

42. The PS is about 0.1 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

43. The PS is about 0.15 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

44. The PS is about 0.2 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

45. The PS is about 0.25 g / 10 cm ２ 39. The method of claim 38, wherein the administration is at the affected site.

46. 46. ​​The method of any one of claims 24 to 45, wherein the PS is applied to the affected area and left on the affected area for about 1 hour to about 5 hours.

47. 47. The method of claim 46, wherein the PS is applied to the affected area and left on the affected area for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

48. 48. The method of claim 46 or 47, wherein the PS is removed from the affected area after the administration period, for example by washing it off.

49. 48. The method of claim 46 or 47, wherein after an administration period, a second or subsequent application of the PS is applied to the affected area.

50. 50. The method of any one of claims 24 to 49, wherein the PS is applied once a day.

51. 50. The method of any one of claims 24 to 49, wherein the PS is applied twice daily.

52. 50. The method of any one of claims 24 to 49, wherein the PS is applied three times a day.

53. 50. The method of any one of claims 24 to 49, wherein the PS is applied four times a day.

54. The method of any one of claims 38 to 53, wherein the PS is administered in a pharmaceutical composition.

55. The method of any one of claims 1 to 24, wherein the PS is administered orally.

56. 56. The method of claim 55, wherein the PS is formulated as a liquid or solid dosage form.

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

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

59. 59. The method of any one of claims 55 to 58, wherein the PS is orally administered at a dosage level of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight, e.g., about 1 mg / kg to about 5 mg / kg, e.g., about 3 mg / kg of the subject's body weight.

60. 59. The method of any one of claims 55 to 58, wherein the PS is orally administered at a dosage of about 1 mg to about 2000 mg, about 100 mg to 1500 mg, about 200 mg to about 100 mg, about 50 mg to about 400 mg, such as about 100 mg to about 350 mg, for example about 150 mg to about 300 mg, such as about 150 mg to about 250 mg.

61. 61. The method of any one of claims 55 to 60, wherein the PS is administered orally in a dosage of about 250 mg to about 300 mg, preferably about 250 mg.

62. 62. The method of any one of claims 55 to 61, wherein the PS is administered orally once daily.

63. 63. The method of any one of claims 55-62, wherein the PS is administered orally at least twice a day, at least three times a day, or at least four times a day.

64. 64. The method of claim 63, wherein the PS is administered orally two or three times daily.

65. 65. The method of any one of claims 55-64, wherein the PS is administered orally at a dosage of about 150 mg to about 200 mg twice daily.

66. 66. The method of any one of claims 55 to 65, wherein the PS is administered orally at a daily dosage of about 300 mg to about 400 mg.

67. 67. The method of any one of claims 55-66, wherein the PS is administered orally at a daily dosage of about 250 mg to about 300 mg (e.g., about 250 mg) two or three times daily.

68. 68. The method of any one of claims 55-67, wherein the PS is administered orally at a daily dosage of about 500 mg to a maximum of about 900 mg daily.

69. 69. The method of any one of claims 55 to 68, wherein the PS is administered orally in a pharmaceutical composition.

70. PS for use in the treatment and / or prevention of neuropathic pain associated with PTPN.

71. The PS for use according to claim 70, wherein the PS is administered by a method according to any one of claims 1 to 65.

72. Use of PS for the manufacture of a medicament for treating and / or preventing neuropathic pain associated with PTPN.

73. 73. The use of PS according to claim 72, wherein the PS is administered by the method according to any one of claims 1 to 65.

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