Nitroxoline for use in the treatment and / or prevention of pain

Abstract

The present invention relates to a compound of nitroxoline its use in therapy, particularly for the treatment and / or prevention of pain.

Description

[0001] NITROXOLINE FOR USE IN THE TREATMENT AND / OR PREVENTION OF PAIN

[0002] FIELD OF THE INVENTION

[0003] This invention relates to new uses of nitroxoline.

[0004] BACKGROUND OF THE INVENTION

[0005] Pain is a complex and multifaceted symptom that significantly impacts the quality of life of individuals. It can arise from a variety of conditions, including genetic disorders, injury / trauma, chronic conditions (e.g. arthritis, diabetic neuropathy), injury to nervous system (e.g. spinal / nerve injury, stroke, MS, radiculopathy, trigeminal neuralgia, herniated disc), psychosocial (e.g. depression), autoimmune disorders (Guillain-Barre Syndrome, Chronic Inflammatory Demyelinating Polyneuropathy), lifestyle (e.g. overweight), aging (in particular of musculoskeletal system), iatrogenic (e.g. surgery), infections (e.g. shingles, HIV / AIDS), chemotherapy-associated neuropathy (e.g. platinum, antibody-drug conjugates), idiopathic / other. Genetic disorders associated with neuropathic pain include neurofibromatosis, schwannomatosis, plexiform neurofibroma, cutaneous neurofibroma, acoustic neuroma, cancer. Furthermore, pain can take many forms such as nociceptive pain, neuropathic pain, hypertrophic neuropathic pain and inflammatory pain.

[0006] Current pain management strategies for pain are largely symptomatic and include the use of analgesics, anti-inflammatory drugs, anticonvulsants, and antidepressants and non-drug interventions e.g. neurostimulation, implantable devices, nerve blocks. However, these treatments often provide limited relief and are associated with significant side effects. There is an unmet need for effective and targeted therapies that can alleviate pain.

[0007] SUMMARY OF THE INVENTION

[0008] The present invention is a composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment and / or prevention of pain. The inventors have surprisingly found that the composition is expected to have a therapeutic benefit for the treatment and / or prevention of pain. As will be evident from the in vivo data below, the composition of the present invention provides therapeutic options in treating and / or preventing pain.

[0009] A first aspect of the present invention is a composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment and / or prevention of pain.

[0010] A second aspect of the invention is a composition comprising nitroxoline, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pain, wherein nitroxoline is the only active agent in the composition. A third aspect of the invention is use of nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for use in the treatment and / or prevention of pain.

[0011] A fourth aspect of the invention is a method of treating and / or preventing pain comprising administering to a patient in need thereof an effective amount of a composition comprising nitroxoline or a pharmaceutically acceptable salt or prodrug thereof.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 shows mechanical allodynia assessed by Von Frey method in animals following chronic constriction injury of the sciatic nerve.

[0014] Figure 2 shows thermal allodynia assessed by cold plate method in animals following chronic constriction injury of the sciatic nerve.

[0015] DETAILED DESCRIPTION OF THE INVENTION

[0016] In the present invention and as demonstrated by the below in vivo data, nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof of the invention has been shown to have utility for the treatment and / or prevention of pain and is therefore, expected to offer therapeutic options for treating and / or preventing pain.

[0017] Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skills in the art to which this invention pertains.

[0018] The term "comprises" or "comprising" will take its usual meaning in the art, namely indicating that the component includes but is not limited to the relevant features (i.e. including, among other things). As such, the term "comprises" will include references to the component consisting essentially of (such as consisting of) the relevant features. The term "consists of" or "consisting of" will take its usual meaning in the art, namely indicating that the component includes and is limited to the relevant features.

[0019] The term "treatment" or "treating" as used herein, refers to therapeutic (curative) treatment including amelioration. Treatment also includes stopping the disease, ailment or symptom from developing or slowing further progression of the disease, ailment or symptom. For example, treatment may include preventing pain from worsening. An intensity of pain or quality of life assessment may be used to determine the presence of pain.

[0020] The term "prevention" or "preventing" as used herein, refers to "prophylactic" treatment. For example, this may include administering the composition of the invention to a patient that has mutated (e.g. NF1 deficient) non-myelinating Schwann cells or diagnosed with a condition, such as neurofibromatosis. The mutated (e.g. NF1 deficient) non-myelinating Schwann cells may have begun to proliferate, such as to proliferate rapidly. Prevention may also include the composition being administered after successful treatment of the pain, and to prevent the pain from reoccurring.

[0021] The terms "patient" and "subject" are used interchangeably and refer to a subject of treatment and / or prevention to be administered the nitroxoline. Preferably, the subject is human. Suitably, the subject has neurofibromatosis. In one embodiment the patient is a paediatric patient, preferably a paediatric patient 2 years of age and older, preferably the paediatric patient has neurofibromatosis.

[0022] As used herein, a "pharmaceutically acceptable salt" is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, salicylic, stearic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aryl amines or heterocyclic amines.

[0023] The present invention is directed to a composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment and / or prevention of pain.

[0024] In an alternative embodiment, the present invention is directed to a composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment and / or prevention of pain, wherein nitroxoline is the only active agent in the composition. By only active agent it is meant that the composition does not contain other components which may be used in the treatment and / or prevention of pain.

[0025] In an alternative embodiment, the composition further comprises a second active agent for treating and / or preventing pain. Preferably, the second active agent is a MEK inhibitor.

[0026] In an alternative embodiment, the present invention is directed to a composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in combination with a second composition comprising a MEK inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, wherein the two compositions are administered to the subject simultaneously, separately or sequentially. The term, "separate administration" means that the drugs are administered as part of the same overall dosage regimen (which could comprise a number of days), but preferably on the same day. The term "simultaneously" means that the drugs are to be taken together or formulated as a single composition. The term "sequentially" means that the drugs are administered at about the same time, and preferably within about 1 hour of each other. Preferably, the drugs are administered simultaneously i.e. taken together or formulated as a single composition. Most preferably, they are formulated as a single composition.

[0027] Compositions of the invention may be prepared or employed in the form of a pharmaceutically acceptable salt, including the therapeutically active non-toxic acid addition salts that the nitroxoline is able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the free base form with such appropriate acids in a suitable solvent or mixture of solvents. Appropriate acids comprise, for example, ethanesulfonic, maleic, malonic, L-tartaric, fumaric, citric, succinic, acetic, triphenyl acetic, hydrochloric, sulfuric, phosphoric, l-hydroxy-2-naphthoic, hydrobromic, methanesulfonic, tartaric, palmitic, isethionic, pamoic, formic, cinnamic benzoic, ascorbic, galactaric, lactic, malic, oxalic, para- toluenesulfonic, benzenesulphonic, propionic, furoic, phosphonic and glutaric.

[0028] The present invention also provides a pharmaceutical composition comprising nitroxoline according to the invention optionally in combination with one or more pharmaceutically acceptable diluents or carriers.

[0029] By "pharmaceutically acceptable diluent or carrier" is meant any diluent or excipient, such as fillers or binders, that is compatible with the other ingredients of the composition, and which is not deleterious to the recipient. The pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices. Diluents and carriers may include those suitable for parenteral, oral, topical including by inhalation via the mouth into the lungs or inhalation via the nose, mucosal and rectal administration, and may be different depending on the route of administration.

[0030] Compounds of the invention include pharmaceutically acceptable prodrugs thereof. The term "pharmaceutically acceptable prodrug" refers to a biologically inactive compound which can be metabolized in the body to produce a drug. Suitably, nitroxoline of the invention is administered in the form of a prodrug which is converted to the active form during absorption into the body. Suitably, the nitroxoline prodrug of the present invention is an ester, carbonate, carbamate, amide, phosphate or oxime prodrug.

[0031] Accordingly, nitroxoline or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising nitroxoline according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, may be used for the treatment and / or prevention of pain.

[0032] The term "schwannomatosis" has its normal meaning in the art. It refers to a distinct genetic disorder characterized by the development of multiple schwannomas, which are benign tumors originating from Schwann cells that insulate and protect peripheral nerves. The condition primarily manifests through chronic pain, which can be severe and debilitating, along with potential neurological deficits depending on the tumor's location. Schwannomatosis is considered a rare condition and presents significant challenges in pain management and treatment.

[0033] The term "neurofibromatosis" has its normal meaning in the art. It refers to genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin, surrounding bone or nerves. Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by pathogenic germline alterations at the NF1 locus on chromosome 17 responsible for encoding a tumor suppressor protein neurofibromin, its dysregulation leading to a wide range of clinical manifestations including plexiform neurofibromas (PN) and cutaneous neurofibromas (CN) affecting an estimated 50% and 90% of adults with NF1 respectively. Neurofibromatosis type 2 (NF2) is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band qll-13.1. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas.

[0034] The term "nociceptive pain" has its normal meaning in the art. It refers to a type of pain arising from the activation of nociceptors, which are sensory receptors that respond to potentially harmful stimuli by sending signals to the spinal cord and brain. This pain results from actual or threatened damage to non-neural tissue and is typically associated with inflammation, mechanical damage, or thermal injury. It can be further classified into somatic pain, originating from skin, muscles, and joints, and visceral pain, arising from internal organs. Nociceptive pain is often described as aching, throbbing, or sharp and is a protective response to prevent further injury and promote healing. Effective management of nociceptive pain is crucial for improving patient outcomes and quality of life.

[0035] The term "neuropathic pain" has its normal meaning in the art. It refers to a complex, chronic pain resulting from damage to or dysfunction of the nervous system, including peripheral nerves, spinal cord, or brain. This type of pain is characterized by sensations such as burning, shooting, or electric shock-like pain, often accompanied by tingling, numbness, and increased sensitivity to normally non-painful stimuli (allodynia). Neuropathic pain can arise from various conditions, including diabetes, shingles, multiple sclerosis, spinal cord injury, and certain genetic disorders such as neurofibromatosis. The term "localized hypertrophic neuropathic pain" has its normal meaning in the art. It refers to a specific type of neuropathic pain characterized by abnormal nerve growth and thickening at a localized site, leading to chronic pain. This condition arises from nerve damage or dysfunction, resulting in altered nerve signalling and heightened sensitivity to stimuli. Patients typically experience persistent, burning, or shooting pain in the affected area, often accompanied by symptoms such as tingling, numbness, or muscle weakness.

[0036] The term "cutaneous neurofibroma" has its normal meaning in the art. It refers to a benign tumor that develops from the peripheral nerve sheath and is commonly associated with neurofibromatosis type 1 (NF1). Cutaneous neurofibromas are composed of a mix of Schwann cells, fibroblasts, and mast cells, and they can vary in size and number. They can cause discomfort, itching, and cosmetic concerns. In some cases, cutaneous neurofibromas can become numerous and significantly impact a patient's quality of life, necessitating effective management strategies.

[0037] The term "plexiform neurofibroma" has its normal meaning in the art. It refers to a complex, benign tumor arising from multiple nerve bundles and is commonly associated with neurofibromatosis type 1 (NF1). These tumors are characterized by their diffuse, infiltrative growth pattern, often extending along the length of nerves and involving multiple fascicles. Plexiform neurofibromas can affect deep tissues, including muscles, bones, and internal organs, leading to significant morbidity. They may cause pain, neurological deficits, and disfigurement due to their size and propensity to grow.

[0038] The term "acoustic neuroma" has its normal meaning in the art. It refers to a benign tumor that develops from Schwann cells covering the vestibulocochlear nerve, which connects the inner ear to the brain. This tumor typically arises in the internal auditory canal and can grow to exert pressure on adjacent structures, including the brainstem and cranial nerves. Symptoms of an acoustic neuroma often include hearing loss, pain, tinnitus (ringing in the ears), and balance disturbances. As the tumor enlarges, it can cause facial numbness or weakness and, in severe cases, life-threatening complications due to brainstem compression.

[0039] The term "diabetic neuropathy" has its normal meaning in the art. It refers to nerve damage that occurs as a complication of diabetes mellitus, resulting from chronic high blood sugar levels. It primarily affects peripheral nerves, leading to symptoms such as pain, tingling, numbness, and loss of sensation, typically in the feet and hands. Diabetic neuropathy can also impact autonomic nerves, causing gastrointestinal, cardiovascular, and genitourinary dysfunctions. The condition is progressive and can significantly impair a patient's quality of life, increasing the risk of ulcers, infections, and amputations. The term "postoperative" in the context of pain following a surgical operation refers to the acute pain experienced by patients following surgical operations, resulting from tissue injury, inflammation, and the body's response to operational trauma. This type of pain can vary in intensity and duration depending on the type of surgery, the patient's health condition, and the surgical technique used. Effective management of postoperative pain is crucial for enhancing patient recovery, reducing the risk of complications such as chronic pain development, and improving overall outcomes.

[0040] A malignant peripheral nerve sheath tumour (MPNST) is a form of cancer of the connective tissue surrounding nerves. A sarcoma is defined as a MPNST when at least one of the following criteria is met: it arises from a peripheral nerve, it arises from a pre-existing benign nerve sheath tumor (neurofibroma) or it demonstrates Schwann cell differentiation on histologic examination. MPNSTs are considered aggressive and are associated with a low survival rate.

[0041] In a particular embodiment, the pain is associated with and / or caused by neurofibromatosis or schwannomatosis. Suitably, the neurofibromatosis is neurofibromatosis type 1 or neurofibromatosis type 2, preferably neurofibromatosis type 1. Suitably the schwannomatosis is NF2-related schwannomatosis or non-NF2 schwannomatosis, or LZTR1- or SMARCBl-related schwannomatosis. Suitably, the subject of treatment and / or prevention has neurofibromatosis, such as NF1 or NF2. Suitably, the subject of treatment and / or prevention has schwannomatosis such as NF2-related schwannomatosis or non-NF2 schwannomatosis or LZTR1- or SMARCBl- related schwannomatosis.

[0042] In a particular embodiment, the pain is associated with and / or caused by itching. The exact cause of itching in neurofibromatosis is unclear. Some health professionals believe it is because of a cell in our body releasing a chemical called histamine. It might also be due to nerve endings feeling pain (pain receptors).

[0043] In a particular embodiment, the pain is nociceptive pain or neuropathic pain. In a particular embodiment, the neuropathic pain is localized hypertrophic neuropathic pain.

[0044] In a particular embodiment, the pain is associated with and / or caused by a neurofibroma, such as a cutaneous neurofibroma or a plexiform neurofibroma. Suitably, the subject of treatment and / or prevention has a cutaneous neurofibroma. Suitably, the subject of treatment and / or prevention has a plexiform neurofibroma.

[0045] In a particular embodiment, the pain is associated with and / or caused by a neuroma or a schwannoma, (such as an acoustic neuroma), or meningioma. Suitably, the subject of treatment and / or prevention has an acoustic neuroma, or meningioma. In a particular embodiment, the pain is associated with and / or caused by a tumour such as a malignant peripheral nerve sheath tumour (MPNST), nerve sheath tumour, gastrointestinal stromal tumour or optic glioma. Suitably, the subject of treatment and / or prevention has a benign peripheral nerve sheath tumour or malignant peripheral nerve sheath tumour, gastrointestinal stromal tumour or optic glioma.

[0046] In a particular embodiment, the pain is associated with and / or caused by diabetic neuropathy, inflammation, cancer, and / or is postoperative.

[0047] In a particular embodiment, the pain is associated with and / or caused by Atypical Neurofibromatosis Neoplasms of Uncertain Biological Potential (ANNUBP). Atypical neurofibromas and atypical neurofibromatous neoplasms of uncertain biologic potential (collectively AN / ANNUBP) refer to neurofibromas with atypical histological features. They are considered premalignant with an increased risk of progressing to a malignant peripheral nerve sheath tumour.

[0048] In a particular embodiment, the subject of treatment and / or prevention has depression, anxiety and / or impaired cognitive functioning.

[0049] Suitably, the subject of treatment and / or prevention displays pain associated with one or more signs or symptoms selected from mechanical allodynia, thermal hyperalgesia, pins and needles, burning sensations, stabbing pains, twitching, headaches, migraines, muscle cramps, scoliosis and muscle weakness or paralysis.

[0050] In a particular embodiment, the pain to be treated and / or prevented is chronic pain.

[0051] Suitably, the pain occurs in at least one of the following areas selected from: abdominal, midscapular, rib head, lower back, appendage, epigastric, ocular, craniofacial, neck, temporomandibular and maxillary, distal thigh and leg, pelvic, perineal, and urethral.

[0052] In addition to the commonly described symptoms of NF1, patients also report worsened mental health, sleep, and pain as a result of the disorder; however, chronic pain is a severely understudied phenomenon of NF1. The prevalence of pain in NF1 patients is unknown but quality of life-based questionnaires in Australia, South America, Europe, and North America consistently identify both the intensity and quality of pain as having a major impact on NF patients.

[0053] The etiology of pain associated with these diseases, especially with neurofibromatosis is generally unknown. Pain as a symptom of NF1, for example, plays a role in creating not just physical agony but psychological and social distress, subsequently lowering the quality of life of patients. While most of the research on neurofibromatosis focuses on the tumour component of the disease, pain remains largely understudied.

[0054] Suitably, the intensity of pain and quality of life in the subject of treatment and / or prevention have been evaluated by completion of at least one assessment selected from: Generic QOL Scale, Paediatric QOL Inventory 4.0 Generic Core Scale, PedsQL Disease Specific NF1 Module, Numerical Rating Scale-NF Version 11 (NRS-ll-NF), Pain Interference Index (PII), Patient and Clinician Global Impression of Change (GIC), Plexiform Neurofibroma (PN) Symptom Checklist, PN Clinician Morbidity Checklist, Neurofibromatosis Pain Module and cNF-Skindex.

[0055] In one embodiment, the subject of the treatment and / or prevention is a mammal, preferably a human.

[0056] In the present invention, the composition may be administered in a variety of dosage forms. In one embodiment, the composition may be formulated in a format suitable for oral administration.

[0057] In an alternative embodiment, the composition may formulated in a format suitable for rectal, intravenous, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository.

[0058] The composition may be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferably, the composition is formulated such that it is suitable for oral administration, for example tablets and capsules. Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents and surfactants such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form.

[0059] The composition may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.

[0060] The composition may also be administered by inhalation. An advantage of inhaled medications is their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.

[0061] The present invention also provides an inhalation device containing the composition of the present invention. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.

[0062] The composition may also be administered by intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability. Further, the present invention also provides an intranasal device containing the composition according to the present invention.

[0063] The composition may also be administered by transdermal administration. For topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions or suspensions may be employed. The present invention therefore also provides a transdermal patch containing the composition.

[0064] The composition may also be administered by sublingual administration. The present invention therefore also provides a sub-lingual tablet comprising the composition.

[0065] The composition may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.

[0066] Liquid dispersions for oral administration may be syrups, emulsions and suspensions.

[0067] Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

[0068] Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. In an embodiment of the invention, the composition is administered in an effective amount to treat and / or prevent pain. An effective dose will be apparent to one skilled in the art and is dependent on a number of factors including age, sex, weigh, which the medical practitioner will be capable of determining.

[0069] The composition may be administered once a day, twice a day, three times a day or four times a day. Suitably the composition comprises 125 mg of nitroxoline. Suitably the composition is administered up to six times a day, such as 6 times a day. Suitably the composition is administered up to four times a day, such as 4 times a day or 3 times a day.

[0070] In an embodiment, the composition is administered at least once a day. Preferably, the single daily dose is 300 mg to 900 mg, preferably 400 mg to 600 mg, more preferably 500 mg to 850 mg, yet more preferably 600 mg to 775 mg, most preferably 700 mg to 800 mg of nitroxoline, such as about 750 mg. Suitably the single daily dose may be about 500 mg or 375 mg.

[0071] In an embodiment, the composition is administered twice daily. Preferably, each dose is 30 mg to 600 mg, preferably 50 mg to 500 mg, more preferably 100 mg to 400 mg, yet more preferably 150 mg to 350 mg, most preferably 200 mg to 300 mg of nitroxoline, such as 250 mg of nitroxoline.

[0072] In an embodiment of the invention, the composition is administered three times daily. Preferably, each dose is 5 mg to 350 mg, preferably 10 mg to 300 mg, more preferably 25 mg to 250 mg, yet more preferably 50 mg to 200 mg, most preferably 75 mg to 150 mg of nitroxoline, such as 125 mg of nitroxoline.

[0073] In an embodiment of the invention, the composition is administered three times daily. Preferably, each dose is 30 mg to 600 mg, preferably 50 mg to 500 mg, more preferably 100 mg to 400 mg, yet more preferably 150 mg to 350 mg, most preferably 200 mg to 300 mg of nitroxoline, such as 225 mg to 275 mg or 250 mg of nitroxoline.

[0074] Preferably, the dosage regime is such that the total daily dosage of nitroxoline does not exceed 1000 mg, more preferably 750 mg.

[0075] Suitably the dosage of nitroxoline may be between 1 and 15 mg / kg, more preferably between 1.5 and 10 mg / kg, even more preferably between 2 and 5 mg / kg, such as between 3 and 4 mg / kg.

[0076] Suitably the effective dose of nitroxoline results in a concentration of 1 to 150 pM, preferably 10 to 100 pM, more preferably 25 to 50 pM in cells. Suitably the composition comprising nitroxoline and the second composition comprising the second active agent, preferably a MEK inhibitor, are a single daily dose. Suitably the two compositions are administered simultaneously i.e. nitroxoline and the MEK inhibitor are taken together. The compositions may also be administered sequentially i.e. at about the same time, and preferably within about 1 hour of each other.

[0077] In order to treat and / or prevent a pain, the composition comprising nitroxoline is used in a chronic dosage regime i.e. chronic, long-term treatment. Suitably the regime lasts for at least 4 weeks, suitably at least 8 weeks, such as at least 12 weeks, for example at least 16 weeks. Suitably the regime lasts for at least 48 weeks.

[0078] The present invention also relates to the of nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for use in the treatment and / or prevention of pain. This embodiment may have any of the preferred features described above.

[0079] The present invention also relates to a method of treating and / or preventing pain comprising administering to a patient in need thereof an effective amount of a composition comprising nitroxoline or a pharmaceutically acceptable salt or prodrug thereof. This embodiment of the invention may have any of the preferred features described above. The method of administration may be according to any of the routes described above. Suitably the patient has reported a reduction in the pain after being administered nitroxoline and is therefore administered further dosages of nitroxoline. The reduction in pain may be reported by the patient as measured by any of the intensity of pain and quality of life assessments mentioned above.

[0080] For the avoidance of doubt, the present invention also embraces prodrugs which react in vivo to give a compound of the present invention.

[0081] The following examples illustrate the invention.

[0082] EXAMPLES

[0083] Abbreviations

[0084] Abbreviations as used herein will be known to those skilled in the art. In particular, the following abbreviations may be used herein:

[0085] Abbreviation Definition

[0086] BID bis in die (twice a day)

[0087] CCI Chronic constriction injury

[0088] CN Cutaneous Neurofibroma MRI Magnetic Resonance Imaging

[0089] NF1 Neurofibromatosis type 1

[0090] PN Plexiform Neurofibroma

[0091] PO per os (by oral administration)

[0092] TID ter in die (three times daily)

[0093] PRO(s) Patient Reported Outcome(s)

[0094] Example 1 - Evaluation of nitroxoline efficacy in the model of chronic constriction injury

[0095] Background

[0096] To evaluate the efficacy of nitroxoline in a model of neuropathic pain induced by chronic constriction injury (CCI) of the rat sciatic nerve. Chronic constriction injury was induced by a surgery, and pain responses were measured by Von Frey and cold plate tests.

[0097] Study design

[0098] Male Sprague-Dawley rats of 180-200g were used in this study. The surgery was performed on study day 0. Animals were anesthetized with a combination of sodium ketamine 35 mg / kg intraperitoneal injection and xylazine 8 mg / kg intraperitoneal injection. While under anesthesia, the mice were placed in a prone position and the left sciatic nerve was exposed at a location above the femoral joint. Three loose knots with silk 4-0 suture material were applied to the sciatic nerve with about 1-mm spacing. Great care was taken to tie the ligatures, such that the diameter of the nerve will be seen to be just barely constricted (Bennett & Xie, 1988). The skin was then closed by a clamp. The proinflammatory environment causes the nerve to swell and constrict against the sutures and creates a partial nerve crush, which triggers chronic pain behaviours. On study day 13, the animals' response to Von Frey was measured and animals that exhibited a paw withdrawal threshold of <15g were included in this study. On study day 28, the animals' response to Von Frey and cold plate was measured at 1 and 1.5 hours post dosing, respectively.

[0099] For both tests, nitroxoline was dosed at two different doses, of 30 mg / kg and 60 mg / kg, via PO BID on study days 14-28. Vehicle was administered via PO BID on study days 14-28. Gabapentin, the positive control, was dosed once on the study day 28 at a dose of 150 mg / kg via PO.

[0100] Mechanical Allodynia Evaluation (Von Frey testing)

[0101] Allodynic response to tactile stimulation was assessed using the Von Frey apparatus (Touch Test®). Graded Von Frey filaments were applied to the hind paw to assess the 50% paw withdrawal threshold using the Dixon Up-Down Method (Chaplan et al., 1994). The Von Frey test was performed on all animals on day -1 (baseline, pre-surgery), 13 (pre-dosing) and 28 (post-dosing). Testing for mechanical allodynia was performed 1 hour post dosing of Nitroxoline, Gabapentin or vehicle on Day 28. Measurements were done at baseline prior to surgery, 13 days after the surgery but prior to treatment start, and 28 days after the surgery, following single dose gabapentin, or 2 weeks of dosing with 30 or 60 mg / kg BID of nitroxoline.

[0102] As shown by Figure 1, chronic constriction injury surgery induced substantial mechanical allodynia by 13 days post-surgery, as demonstrated by a reduction in the 50% paw withdrawal threshold in the Von Frey test. Mechanical allodynia at day 28 was not alleviated with vehicle treatment. Treatment with a single dose of the positive control, gabapentin, 150 mg / kg PO, led to a significant increase in the 50% paw withdrawal threshold, compared to vehicle treatment at day 28 (p<0.0001, using two-way ANOVA, followed by Dunnett's test). Treatment with nitroxoline for 2 weeks (starting on day 14) with both 30 and 60 mg / kg BID significantly increased the 50% paw withdrawal threshold on testing day 28 compared to the vehicle treatment (p<0.0001, using two-way ANOVA, followed by Dunnett's test).

[0103] Cold Allodynia Evaluation CCold plate 0°C)

[0104] Animals were placed on the cold plate (0°± l°C) and the latency time to withdrawal, shaking or licking the paws were recorded, with an upper limit of 30s. Cold plate evaluation was performed on all animals on day -1 (pre-surgery), 13 (pre-dosing) and 28 (post-dosing). Measurements were done at baseline prior to surgery, 13 days after the surgery but prior to treatment start, and 28 days after the surgery, following single dose gabapentin, or 2 weeks of dosing with 30 or 60 mg / kg BID of nitroxoline.

[0105] As shown by Figure 2, chronic constriction injury surgery induced cold allodynia by day 13, as demonstrated by a reduction in the latency of first paw response using the cold plate method. Cold allodynia at day 28 was not alleviated with vehicle treatment. Treatment with a single dose of the positive control, gabapentin at 150 mg / kg PO, significantly increased the time to first paw response on testing day 28 compared with vehicle treatment (p<0.01). Treatment with nitroxoline for 2 weeks (starting on day 14) with both 30 and 60 mg / kg BID significantly increased time to first paw response on testing day 28, compared to vehicle treatment (p<0.01 for 30 mg / kg and p<0.001 for 60 mg / kg, using two-way ANOVA, followed by Dunnett's test).

[0106] Conclusion

[0107] Under the conditions of this study, treatment with test item nitroxoline at doses of 30 mg / kg and 60 mg / kg was effective in reducing mechanical and cold allodynia induced by Chronic Constriction Injury of the sciatic nerve in rats. Efficacy was comparable to a single treatment with gabapentin, which is the current first line treatment in neuropathic pain. Therefore, the inventors have surprisingly found that nitroxoline provides therapeutic options in treating and / or preventing pain. Example 2 - A Phase 2, Open-Label, Single Arm, Non-Controlled, Single-Stage Study to

[0108] Evaluate the Safety and Effects of Nitroxoline in Patients with Plexiform Neurofibroma and Neurofibromatosis Type 1

[0109] Study Design

[0110] This is a phase 2, open-label, single arm, non-controlled, single-stage study. Following a four- week screening period, eligible participants are enrolled onto a 12 cycle (~12 month) treatment period with nitroxoline. Participants with radiographic or clinical response were allowed to continue to receive treatment for an additional 12 cycles.

[0111] The study includes 20 male or female participants, aged 16 years and over and with a diagnosis of NF1 and a PN that is progressive or caused significant morbidity. In this study, nitroxoline is administered orally at a maximum dose of 750 mg per day, in 3 divided doses of 250 mg. Cycles are 4 weeks duration (28 days) and nitroxoline is administered continuously.

[0112] Participants are provided written informed consent prior to beginning any protocol-related assessments for eligibility. Participants under 18 years old are provided assent supported by their legally authorized representative consent prior to the start of any protocol-related procedures. All participants are required to return to the clinical site for safety assessments biweekly during cycle 1 of study, every cycle for cycles 2, 3, 4, and every other cycle for cycles 5- 12. For participants who continued to receive an additional 12 cycles of treatment, visits occurred every 3 cycles (15, 18, 21, 24). Clinical trial assessments included the following: Laboratory testing (Heme and Chemistry); Physical Examination and Vital signs; MRI with STIR imaging for volumetric response assessment according to REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) recommendation; ECG; Urinalysis / Urine pregnancy test; Eye examination (see footnote 8 in the Table of Assessments (Appendix I) for specific requirements for the ophthalmology assessment); Blood for PK trough; and Pain evaluation and quality of life assessed through the administration and completion of PROs by the participants and caregivers and observer- re ported outcomes by study clinicians.

[0113] Dosina and Administration

[0114] Participants take an oral dose (in the fed state preferred) of 250 mg (2 x 125 mg tablets) three times a day (TID or 750 mg / day) for 12 cycles. A cycle is defined as 28 days. Participants with a partial response (> 20% volumetric MRI reduction of the target lesion) or stable disease with a previously progressive tumor and / or clinical improvement are allowed to continue therapy for an additional 12 cycles for a total of 24 cycles.

[0115] Experimental Design

[0116] Baseline evaluations are conducted within 2-4 weeks prior to the beginning of treatment according to the intensity of pain and quality of life assessments detailed above. The treatment is started with nitroxoline by administering a dose of 250 mg nitroxoline three times daily. The treatment was continued for 12 cycles.

[0117] Volumetric MRI analysis was performed every 4 cycles. An EKG and eye exam are performed after 1 cycle, then every 4 cycles with MRI. Patient reported outcomes are assessed every 4 cycles. A clinical and PK assessment is completed.

[0118] Any partial response or stable disease with clinical improvement is assessed. The treatment is then continued for an additional 12 cycles with a total of 24 cycles.

[0119] During the subsequent 12 cycles, volumetric MRI analysis is performed every 6 cycles, an EKG and eye exam performed every 6 cycles, a clinical assessment and lab assessment completed every 3 cycles and a patient reported outcome completed every 6 cycles.

[0120] Patient Reported Outcomes

[0121] Pain evaluation and quality of life are assessed through the administration and completion of the following PROs by the participants and caregivers and observer- re ported outcomes by study clinicians: NRS-ll-NF to measure pain intensity; Pain interference index (PII); PedsQL Generic Quality of Life Scale; PedsQL Disease Specific NF1 Module; Patient and Clinician Global Impression of Change (for patients on the CN photography optional study, this will be completed for both the PN and CNs at the Cycle 12 and Cycle 24 visits); PN Symptom Checklist; PN Clinician Morbidity Checklist; and cNF-Skindex.

[0122] Generic QOL Scale: The Pediatric Quality of Life Inventory 4.0 Generic Core Scales are multidimensional child self-report and parent proxy-report scales to assess health-related quality of life (QOL) in children, adolescents, and adults ages 2 years and older. It is a brief standardized QOL scale with good reliability and validity, which includes both generic and disease specific modules. It consists of a 23-item core measure of generic QOL that has four subscales: physical functioning, emotional functioning, social functioning, and school functioning. The domain of physical functioning will be used as a specific exploratory outcome measure for this study. There are parallel self-report forms for ages 5 years and older (young child: 5-7; child: 8-12; teen: 13-18; young adult: 18-25; adults: 26 and older). The self-report Teen, Young Adult and Adult forms will be administered in this study. It takes approximately 5 minutes to complete.

[0123] NF1 Disease Specific QOL Module: In addition to the generic PedsQL noted above, the PedsQL™ NF1 Module 3.0 Acute Version also will be administered to evaluate disease specific QOL. It is a 104-item a self-report instrument to assess NF1 disease-specific quality of life (QOL) in ages 5 years of age and older. It is comprised of 18 scales: 1) Skin Itch Bother (6 items) 2) Skin Sensations (3 items), 3) Pain (6 items), 4) Pain Impact (16 items), 5) Pain Management (2 items) 6) Cognitive functioning (15 items), 7) Speech (4 items), 8) Fine Motor (6 items), 9) Balance, 10) Vision (5 items), 11) Perceived Physical Appearance, 12) Communication, 13) Worry (10 items), 14) Treatment (6 items), 15) Medicines (3 items), 16) Stomach Discomfort (3 items), 17) Constipation (3 items), 18) Diarrhea (2 items)42. It has parallel versions for different age groups. This study will utilize the Young Adult: (18-25) and Adult (26 and older) forms.

[0124] The PedsQL™ NF1 Module format, instructions, and Likert response scale are similar to the PedsQL™ 4.0 Generic Core Scales and other PedsQL™ Disease-Specific Modules. The instructions ask how much of a problem each item has been during the past week. A 5-point response scale is used for all items (0= never a problem, 1= almost never a problem, 2= sometimes a problem, 3= often a problem, 4= almost always a problem). Items are reverse scored and linearly transformed to a scale of 0-100 similar to PedsQL™ 4.0 Generic Core Scales (0= 100, 1= 75, 2= 50, 3=25, 4=0). Higher scores indicate better HRQOL and fewer symptoms or problems. The total scale score is computed as the sum of all items on the PedsQL™ NF1 Module divided by the number of items answered (this accounts for missing data). Subscale scores are computed as the sum of the items divided by the number of items that were answered in that scale. If more than 50% of the items in the scale are missing, the scale score is not computed.

[0125] The PedsQL NF1 Module Total Scale Scores demonstrated excellent reliability for the patient selfreport version (a = 0.98) and good to excellent reliability for the 18 individual scales.

[0126] Tumor Pain Intensity: The Numerical Rating Scale-NF Version 11 (NRS-l l-NF) is a self-report segmented 11-point numeric scale that assesses pain intensity. It consists of a horizontal line with 0 representing "no tumor pain" at the right end of the line and 10 representing "worst tumor pain possible" at the left end. Participants are asked to circle the one number from 0 to 10 that best describes the pain intensity of their physician-selected "target tumor" at its worst during the past week. It takes less than 1 minute to complete. The NRS-ll-NF is recommended as a core outcome measure of pain intensity for clinical trials, and this adapted version for NF was used successfully in the SPRINT trial.

[0127] Paint Interference: The Pain Interference Index (PII) is a 6-item measure that assesses the degree to which pain has interfered with daily activities in the past week. This measure was developed in Sweden and validated in Swedish with a group of children and adolescents with longstanding idiopathic pain. Then the measure was translated into English, modified to make the wording more readable and to shorten the response time frame to one week, and adapted to create a parallel parent version. Results of validation studies in children with NF1 and their parents indicate that the internal consistency and construct validity of the PII are good and support the use of the PII to assess pain interference in children and young adults with NF1 and PNs. For this study, participants from 16 years of age and older will complete self-report PII. Patient Global Impression of Change: The Patient Global Impression of Change (GIC) Scale is a PRO measure that evaluates the clinical significance of changes in pain intensity or other morbidities. An adapted version of the GIC Scale will be administered at the follow-up PRO evaluations only (it should not be given pre-study because it assesses change from baseline). On the adapted GIC, participants will rate their overall impression of change in level of their top 1 or 2 self-selected morbidities (from a list) and in all their tumor-related morbidities from before initiation of the study drugs to the current evaluation point. The GIC Scale has been used in several research studies on chronic pain in adults and more recently children. It has been recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) for clinical trials involving chronic pain.

[0128] Clinician Global Impression of Change: The GIC has been adapted for clinicians to rate change in PN morbidities for each participant from before the initiation of the study drugs to the current evaluation point based on their history and physical examination. This global measure of change will be completed for participants of all ages by a clinician (familiar with the participant).

[0129] Background Information Form: To allow for more meaningful analysis of the QOL data, the participant will complete a background information form at study entry and each subsequent QOL evaluation. This form will collect general information such as the participant's level of education, work status, psychiatric diagnoses, and pain medications, as well as the perceived visibility of NF1 tumors and severity of NF1 symptoms.

[0130] PN Symptom Checklist: To allow for more accurate tracking of PN-related symptoms during treatment, the participant will complete the PN Symptom Checklist at study entry and each subsequent QOL evaluation. This form asks participants to rate how much PN-related symptoms (such as fatigue, constipation, and numbness) have been a problem for them in the past 2 weeks on a 5-point scale (ranging from not at all to a lot). cNF-Skindex: The cNF-Skindex is an 18 item measures that assesses individuals' emotions, symptoms, and functioning related to cutaneous neurofibromas52. The measure has excellent test-retest reliability in individuals with NF1 and has demonstrated construct validity through high correlations with the EQ-5D. Participants are asked to rate how bothered they have been by cutaneous neurofibroma issues on a 7-point scale ranging from never bothered to always bothered. A total score is calculated by summing the responses to all items. Scores range from 0 to 108, with higher scores indicating worse cNF-related QOL. Subscale scores assessing emotions, functioning, and symptoms are also available. Primary Objective

[0131] To evaluate the efficacy of nitroxoline on PN response rate after 12 cycles assessed by volumetric MRI imaging. The endpoint is assessed as a complete or partial response of the target PN according to REiNS criteria after 12 cycles using volumetric MRI analysis.

[0132] Secondary Objectives

[0133] To evaluate the effect of nitroxoline on Duration of Response and Time to Response after 12 cycles, as assessed by volumetric MRI imaging. The endpoint is assessed as the Duration of Response i.e., duration between first complete or partial response until disease progression or death due to any cause and the Time to Response i.e., time between first dose until first complete or partial response.

[0134] To evaluate the safety and tolerability of nitroxoline in terms of adverse events and serious adverse events. The endpoint is assessed as the incidence of adverse events (AEs) and serious adverse events (SAEs) reported during the study and the change from baseline for physical examinations and assessment of vital signs, clinical laboratory evaluations and electrocardiogram (ECG) measurements at regular intervals.

[0135] To evaluate the effect of nitroxoline on PN response rate after 24 cycles, assessed by volumetric MRI imaging. The endpoint is assessed as complete or partial response of the target PN according to REiNS criteria after 24 cycles using volumetric MRI analysis.

[0136] To assess the pharmacokinetics of nitroxoline. The endpoint is assessed as serial and / or trough nitroxoline plasma concentration measurements at multiple timepoints.

[0137] Stable Disease (SD) is defined as neither sufficient decrease in the volume of the target lesion to qualify for PR, nor sufficient increase in the target lesion to qualify for PD. Progressive Disease (PD) is > 20% increase in the volume of the target or non-target PN compared to the pretreatment volume. If the participant had PN outside of target lesion, up to two non-target lesions were selected and imaged at the same recommended intervals and submitted for analysis.

[0138] Participants with six or more CNs on the back are given the opportunity to enrol in a sub-cohort investigating the exploratory objective of CN response to nitroxoline. Whole body 3D photographic images are taken and the CNs are measured with a study specific ruler as per the Table of Assessments. Participants also complete a global impression of change questionnaire specific to their CNs at baseline, cycle 12 and 24 visits. An additional optional cohort (5 participants maximum) have nitroxoline measurements in the plasma and in CN tumors through biopsy as per. In this cohort, biopsy samples are obtained from one CN from participants for nitroxoline PK measurements at 3 different time points. If participants are enrolled on both CN optional studies, the 3 CNs undergoing biopsy are different from the CNs selected for measurement in the CN photography study. A third optional cohort of participants (5 participants maximum) have serial blood PK levels drawn at two time points. All participants are given the opportunity to bank biological specimens (blood, PN and CN tumor tissue) during the study.

[0139] Exploratory Objectives

[0140] To evaluate the effect of nitroxoline on PN response rate after 4, 8, 12, 18 and 24 cycles, assessed by volumetric MRI imaging. The endpoint is assessed as complete or partial response of the target PN according to REiNS criteria after 4, 8, 12, 18 and 24 cycles using volumetric MRI analysis. A partial response (PR) is defined as > 20% decrease in the volume of target PN and a complete response (CR) is defined as complete resolution of the target PN.

[0141] To evaluate the effect of nitroxoline on quality of life, pain and morbidity in participants with PN. The endpoint is assessed as a mean change in clinical assessments from baseline using patient- reported outcome measures and observer- re ported outcomes by study clinicians.

[0142] To evaluate the effect of nitroxoline on CN, as assessed by 3D visual images and ruler measurements. The endpoint is assessed as an evaluation of whole body CNs in terms of number and appearance, an evaluation of a pre-defined region of CNs in terms of surface area, an evaluation of global impression of change as reported by participant, clinician and blinded investigator based on the 3D photographs and an evaluation of a pre-defined region of CNs in terms of volume.

[0143] To assess nitroxoline in CN biopsy concentrations. The endpoint is assessed as a plasma to tissue biopsy concentration ratio and tissue accumulation ratio at three timepoints.

[0144] Statistical Plan

[0145] In this single-stage clinical trial, the primary endpoint was PN response after 12 cycles. The null hypothesis tested is that response rate was < 5% vs. the alternative hypothesis that the response rate was > 25%. With one sided type I error of 0.05, a sample size of 16 evaluable participants provided 80% power to test this hypothesis. If the number of responders is 3 or more, the null hypothesis was rejected suggesting efficacy of the treatment. If the number of responders is 2 or fewer, the null hypothesis was not rejected. A maximum non-evaluable percentage of 20% is anticipated, 20 participants are enrolled into the study to achieve at least 16 evaluable participants.

[0146] Target Population

[0147] Participants 16 years of age or older with a diagnosis of NF1 and a PN that is progressive or caused significant morbidity. CLAUSES

[0148] Particular embodiments of the invention are illustrated by clauses below.

[0149] 1. A composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment and / or prevention of pain.

[0150] 2. The composition for use according to clause 1, wherein the pain is associated with and / or caused by neurofibromatosis or schwannomatosis.

[0151] 3. The composition for use according to clause 1 or clause 2, wherein the pain is associated with and / or caused by itching.

[0152] 4. The composition for use according to any one of the preceding clauses, wherein the pain is nociceptive pain.

[0153] 5. The composition for use according to any one of the preceding clauses, wherein the pain is neuropathic pain.

[0154] 6. The composition for use according to clause 5, wherein the neuropathic pain is localized hypertrophic neuropathic pain.

[0155] 7. The composition for use according to any one of the preceding clauses, wherein the pain is associated with and / or caused by a neurofibroma, such as a cutaneous neurofibroma or a plexiform neurofibroma.

[0156] 8. The composition for use according to any one of the preceding clauses, wherein the pain is associated with and / or caused by a neuroma or a schwannoma, such as an acoustic neuroma.

[0157] 9. The composition for use according to any one of the preceding clauses, wherein the pain is associated with and / or caused by a tumour such as a malignant peripheral nerve sheath tumour (MPNST), nerve sheath tumour, gastrointestinal stromal tumour or optic glioma.

[0158] 10. The composition for use according to any one of the preceding clauses, wherein the pain is associated with and / or caused by diabetic neuropathy, inflammation, cancer, and / or is postoperative.

[0159] 11. The composition for use according to any one of the preceding clauses, wherein the pain is associated with and / or caused by Atypical Neurofibromatosis Neoplasms of Uncertain Biological Potential (ANNUBP). The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention has neurofibromatosis, schwannomatisis, diabetic neuropathy, inflammation, cancer, preferably the subject of treatment and / or prevention has neurofibromatosis or schwannomatisis. The composition for use according to clause 2 or 12, wherein the neurofibromatosis is neurofibromatosis type 1 or neurofibromatosis type 2, preferably neurofibromatosis type 1, or wherein the schwannomatisis is LZTR1- and SMARCBl-related schwannomatosis. The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention has a cutaneous neurofibroma. The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention has a plexiform neurofibroma. The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention has a benign peripheral nerve sheath tumour or malignant peripheral nerve sheath tumour. The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention has an acoustic neuroma. The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention has depression, anxiety and / or impaired cognitive functioning. The composition for use according to any one of the preceding clauses, wherein the subject of treatment and / or prevention displays pain associated with one or more signs or symptoms selected from mechanical allodynia, thermal hyperalgesia, pins and needles, burning sensations, stabbing pains, twitching, headaches, migraines, muscle cramps, scoliosis and muscle weakness or paralysis. The composition for use according to any one of the preceding clauses, wherein the pain is chronic pain. The composition for use according to any one of the preceding clauses, wherein the pain occurs in at least one of the following areas selected from: abdominal, midscapular, rib head, lower back, appendage, epigastric, ocular, craniofacial, neck, temporomandibular and maxillary, distal thigh and leg, pelvic, perineal, and urethral. 22. The composition for use according to any one of the preceding clauses, wherein the subject of the treatment and / or prevention is human.

[0160] 23. The composition for use according to any one of the preceding clauses, wherein the composition comprises 30 mg to 600 mg, preferably 50 mg to 500 mg, more preferably 100 mg to 400 mg, yet more preferably 150 mg to 350 mg, most preferably 200 mg to 300 mg of nitroxoline.

[0161] 24. The composition for use according to any one of the preceding clauses, wherein administration is by a dose two times per day.

[0162] 25. The composition for use according to any one of clauses 1-22, wherein the dose is 10 mg to 400 mg, preferably 30 mg to 350 mg, more preferably 50 mg to 300 mg, yet more preferably 75 mg to 250 mg, most preferably 100 mg to 150 mg of nitroxoline.

[0163] 26. The composition for use according to any of clauses 1 to 23 or 25, wherein administration is by a dose three times per day.

[0164] 27. The composition for use according to any one of the preceding clauses, to be administered orally.

[0165] 28. The composition for use according to any of clauses 1-26, to be administered by intravenous, parenteral, transdermal, sublingual, rectal or inhaled administration.

[0166] 29. The composition for use according to any one of the preceding clauses, wherein the intensity of pain and quality of life in the subject of treatment and / or prevention have been evaluated by completion of at least one assessment selected from: Generic QOL Scale, Paediatric QOL Inventory 4.0 Generic Core Scale, PedsQL Disease Specific NF1 Module, Numerical Rating Scale-NF Version 11 (NRS-ll-NF), Pain Interference Index (PII), Patient and Clinician Global Impression of Change (GIC), Plexiform Neurofibroma (PN) Symptom Checklist, PN Clinician Morbidity Checklist, Neurofibromatosis Pain Module and cNF-Skindex.

[0167] 30. The composition for use according to clause 29, wherein the assessment according to the Generic Quality of Life Scale or Paediatric Quality of Life Inventory 4.0 Generic Core Scale comprises an assessment of the four subscales, physical functioning, emotional functioning, social functioning and school functioning. 31. The composition for use according to clause 29, wherein the assessment according to the PedsQL Disease Specific NF1 Module comprises assessing the following 18 scales: skin itch bother, skin sensations, pain, pain impact, pain management, cognitive functioning, speech, fine motor, balance, vision, perceived physical appearance, communication, worry, treatment, medicines, stomach discomfort, constipation and diarrhoea.

[0168] 32. The composition for use according to clause 29, wherein the assessment according to NRS-ll-NF is a segmented 11-point numeric scale that assesses tumour pain intensity, wherein 0 represents no tumour pain and 10 represents the worst tumour pain possible.

[0169] 33. The composition for use according to clause 29, wherein the assessment according to PII is a 6-item measure that assesses the degree to which pain has interfered with daily activities in the past week.

[0170] 34. The composition for use according to clause 29, wherein the assessment according to the GIC scale comprises: asking the subject of the treatment and / or prevention to rate their overall impression of change in level of their top 1 or 2 self-selected morbidities from a list and in all their tumour-related morbidities from before initiation of the study drugs to the current evaluation point; wherein the assessment is completed at the follow-up evaluation after the treatment and / or prevent has been completed.

[0171] 35. The composition for use according to clause 29, wherein the subject of treatment and / or prevention has completed a background information form prior to treatment and / or prevention and at each subsequent QOL evaluation, and wherein general information such as the level of education, work status, psychiatric diagnoses, pain medications, perceived visibility of NF1 tumours and severity of NF1 symptoms is collected in the form.

[0172] 36. The composition for use according to clause 29, wherein the assessment according to the PN symptom checklist comprises asking the subject of treatment and / or prevention to rate how much PN-related symptoms such as fatigue, constipation and numbness have been a problem for them in the past 2 weeks on a 5-point scale.

[0173] 37. The composition for use according to clause 29, wherein the assessment according to the cNF-Skindex comprises: asking the subject of treatment and / or prevention to rate how bothered they have been by cutaneous neurofibroma issues on a 7-point scale ranging from never bothered to always bothered; and calculating a total score by adding the scores of all items; wherein cNF-Skindex is based on 18 measures related to individuals' emotions, symptoms, and functioning related to cutaneous neurofibromas, and wherein a higher total score indicates worse cNF-related QOL.

[0174] 38. The composition for use according to any one of clause 29-37, wherein the assessment is completed prior to (and optionally during) treatment and / or prevention.

[0175] 39. A composition comprising nitroxoline, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pain, wherein nitroxoline is the only active agent in the composition.

[0176] 40. Use of nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for use in the treatment and / or prevention of pain.

[0177] 41. Use according to clause 40, having any of the additional features of clauses 2-39.

[0178] 42. A method of treating and / or preventing pain comprising administering to a patient in need thereof an effective amount of a composition comprising nitroxoline or a pharmaceutically acceptable salt or prodrug thereof.

[0179] 43. A method according to clause 42, wherein the patient has reported a reduction in pain as measured by one of the pain assessments outlined in any one of clauses 29 to 39.

[0180] 44. The method according to clause 42 or 43, having any of the additional features of clauses 2-39.

Claims

CLAIMS1. A composition comprising nitroxoline, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment and / or prevention of pain.

2. The composition for use according to claim 1, wherein the pain is associated with and / or caused by neurofibromatosis or schwannomatosis.

3. The composition for use according to claim 1 or claim 2, wherein the pain is associated with and / or caused by itching.

4. The composition for use according to any one of the preceding claims, wherein the pain is nociceptive pain.

5. The composition for use according to any one of the preceding claims, wherein the pain is neuropathic pain.

6. The composition for use according to claim 5, wherein the neuropathic pain is localized hypertrophic neuropathic pain.

7. The composition for use according to any one of the preceding claims, wherein the pain is associated with and / or caused by a neurofibroma, such as a cutaneous neurofibroma or a plexiform neurofibroma.

8. The composition for use according to any one of the preceding claims, wherein the pain is associated with and / or caused by a neuroma or a schwannoma, such as an acoustic neuroma.

9. The composition for use according to any one of the preceding claims, wherein the pain is associated with and / or caused by a tumour such as a malignant peripheral nerve sheath tumour (MPNST), nerve sheath tumour, gastrointestinal stromal tumour or optic glioma.

10. The composition for use according to any one of the preceding claims, wherein the pain is associated with and / or caused by diabetic neuropathy, inflammation, cancer, and / or is postoperative.

11. The composition for use according to any one of the preceding claims, wherein the pain is associated with and / or caused by Atypical Neurofibromatosis Neoplasms of Uncertain Biological Potential (ANNUBP).

12. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention has neurofibromatosis, diabetic neuropathy, inflammation, cancer, preferably the subject of treatment and / or prevention has neurofibromatosis.

13. The composition for use according to claim 2 or 12, wherein the neurofibromatosis is neurofibromatosis type 1 or neurofibromatosis type 2, preferably neurofibromatosis type 1.

14. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention has a cutaneous neurofibroma.

15. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention has a plexiform neurofibroma.

16. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention has a benign peripheral nerve sheath tumour or malignant peripheral nerve sheath tumour.

17. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention has an acoustic neuroma.

18. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention has depression, anxiety and / or impaired cognitive functioning.

19. The composition for use according to any one of the preceding claims, wherein the subject of treatment and / or prevention displays pain associated with one or more signs or symptoms selected from mechanical allodynia, thermal hyperalgesia, pins and needles, burning sensations, stabbing pains, twitching, headaches, migraines, muscle cramps, scoliosis and muscle weakness or paralysis.

20. The composition for use according to any one of the preceding claims, wherein the pain is chronic pain.

21. The composition for use according to any one of the preceding claims, wherein the pain occurs in at least one of the following areas selected from: abdominal, midscapular, rib head, lower back, appendage, epigastric, ocular, craniofacial, neck, temporomandibular and maxillary, distal thigh and leg, pelvic, perineal, and urethral.

22. The composition for use according to any one of the preceding claims, wherein the subject of the treatment and / or prevention is human.

23. The composition for use according to any one of the preceding claims, wherein the composition comprises 30 mg to 600 mg, preferably 50 mg to 500 mg, more preferably100 mg to 400 mg, yet more preferably 150 mg to 350 mg, most preferably 200 mg to 300 mg of nitroxoline.

24. The composition for use according to any one of the preceding claims, wherein administration is by a dose two times per day.

25. The composition for use according to any one of claims 1-22, wherein the dose is 10 mg to 400 mg, preferably 30 mg to 350 mg, more preferably 50 mg to 300 mg, yet more preferably 75 mg to 250 mg, most preferably 100 mg to 150 mg of nitroxoline.

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