Postoperative arthralgia treatment with polysulfated polysaccharides

Abstract

The present invention relates to medical uses of polysulfated polysaccharides and compositions thereof in the treatment of postoperative arthralgia of mammals. In particular, the present invention relates to the use of polysulfated polysaccharides and compositions thereof in the treatment of sterile persistent pain after joint replacement in mammals.

Description

[0001] This application is a divisional application of a patent application with an application date of February 27, 2019, application number 201980016173.3, and invention name “Polysulfated polysaccharides for the treatment of postoperative joint pain”. Technical Field

[0002] The present invention relates to the medical use of polysulfated polysaccharides and compositions thereof in treating postoperative joint pain in mammals, and in particular, the present invention relates to the use of polysulfated polysaccharides in treating aseptic persistent pain after joint replacement surgery. Background Art

[0003] Pain after joint replacement surgery

[0004] Joint replacement or arthroplasty offers patients an opportunity to escape the pain of debilitating diseases such as end-stage osteoarthritis and rheumatoid arthritis, where nonsurgical treatments have proven unsuccessful. Nevertheless, despite the excellent pain relief and improved quality of life achieved with joint replacement, up to 20% of patients complain of persistent pain [1]. In particular, aseptic persistent pain may not resolve even one year after surgery. This obviously results in dissatisfaction among patients who choose joint replacement for pain relief. Furthermore, unsatisfactory clinical outcomes increase costs to the healthcare system.

[0005] Early and accurate diagnosis of postoperative joint pain is key to optimizing treatment. The diagnosis of infectious pain or pain caused by periprosthetic fracture is relatively obvious, while the diagnosis of sterile pain is unclear. Therefore, it is difficult to successfully treat sterile persistent postoperative joint pain.

[0006] A recent study showed that aseptic persistent joint pain after total knee arthroplasty may be caused by extra-articular causes, such as extra-articular osteoarthritis or avascular necrosis, or in most cases by a variety of intra-articular causes, including component loosening, component wear, instability, recurrent hemarthrosis, patellar maltracking, tendon rupture, and stiffness. Treatment of aseptic persistent pain has been reported to ultimately involve revision surgery [1].

[0007] Revision surgery is complex, carries the risk of unrelieved pain, and may be harmful in some cases. Another option is standard nonsurgical management, which includes the use of analgesics or anti-inflammatory drugs, as well as reduced weight bearing and physical therapy [2]. However, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have been shown to have negative effects on bone healing and cartilage metabolism ([3]–[6]). The risk of both traumatic and spontaneous fractures has been increased in subjects who have been continuously treated with corticosteroids [5].

[0008] Therefore, medications that do not have the negative effects of NSAIDs or corticosteroids are needed to expand the limited number of options currently available for the management of postoperative joint pain, particularly aseptic persistent pain that is difficult to diagnose and difficult to treat.

[0009] Polysulfated polysaccharides

[0010] Heparin and structurally related polysulfated polysaccharides such as pentosan polysulfate, chitosan polysulfate, and fucoidan have been used as anticoagulants for many years [7–12]. Pentosan polysulfate (PPS) is a less potent anticoagulant than heparin [7, 9, 11] but has been used as a thrombolytic agent postoperatively and in prophylaxis

[12] . PPS has been used to treat interstitial cystitis (bladder inflammation) by oral and intrathecal routes [13–15]. In fact, PPS is a drug PPS is an active agent in the treatment of interstitial cystitis. Other studies have described the potential use of PPS in the treatment of inflammatory conditions such as asthma, allergic rhinitis, and / or chronic obstructive pulmonary disease (COPD)

[16] , as well as the use of PPS in osteoporosis

[17] and the use of PPS in bone marrow edema

[18] . Summary of the invention

[0011] The present invention is based on the surprising discovery that PPS treatment reduces persistent postoperative pain in subjects after joint replacement surgery. The present invention is also based on the surprising discovery that PPS treatment reduces osteoarthritis pain and persistent postoperative joint pain in subjects. In addition to reducing pain, PPS treatment was found to improve joint function and reduce bone marrow edema lesions, with no adverse events reported.

[0012] Therefore, PPS may be an improved alternative to NSAIDs and corticosteroids with potential pain-relieving activity. These findings suggest the potential effectiveness of PPS as a treatment option for subjects with postoperative pain, and as a treatment option in subjects with postoperative pain and arthritis, such as osteoarthritis.

[0013] According to a first aspect, there is provided a method for treating postoperative joint pain in a mammal, the method comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal.

[0014] According to a second aspect, a composition is provided, comprising a polysulfated polysaccharide or an acceptable salt thereof, and an acceptable excipient, wherein the composition is used for treating postoperative joint pain in mammals.

[0015] According to a third aspect, a composition is provided, comprising a polysulfated polysaccharide or an acceptable salt thereof, and an acceptable excipient, wherein the composition is used for treating postoperative joint pain in a mammal.

[0016] According to a fourth aspect, there is provided a use of a polysulfated polysaccharide or an acceptable salt thereof in treating postoperative joint pain in a mammal.

[0017] According to a fifth aspect, provided is a use of a polysulfated polysaccharide or an acceptable salt thereof in the preparation of a medicament for treating postoperative joint pain in a mammal.

[0018] Unless otherwise defined herein, scientific and technical terms used in conjunction with this application shall have the meanings commonly understood by those of ordinary skill in the art. In addition, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. Thus, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, unless the context clearly indicates otherwise, the term "a joint" means "one or more joints".

[0019] With respect to the definitions provided herein, unless otherwise stated or implied from the context, the defined terms and phrases include the meanings provided. Unless otherwise expressly stated or obvious from the context, the following terms and phrases do not exclude the meanings known to those skilled in the relevant art. These definitions are provided to aid in the description of specific embodiments and are not intended to limit the claimed invention, as the scope of the present invention is limited solely by the claims.

[0020] Throughout the specification, various aspects and compositions of the present invention may be presented in the format of a range. The format of the range is used for convenience and should not be interpreted as a rigid limitation on the scope of the present invention. Therefore, unless otherwise specified, the description of the range should be deemed to have clearly disclosed all possible sub-ranges and each numerical value within the range. For example, the description of the range 1-5 should be deemed to have specifically disclosed sub-ranges, such as 1-2, 1-3, 1-4, 2-3, 2-4, 2-5, 3-4, etc., as well as single and partial numbers within the range, such as 1, 2, 3, 4 and 5. This has nothing to do with the breadth of the disclosed range. If specific values ​​are required, these will be indicated in the specification.

[0021] The term "acceptable excipient" includes excipients or agents that are physiologically compatible and not harmful to the compounds described in the present invention or their use, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such carriers and agents for preparing compositions of pharmaceutically active substances is well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005).

[0022] The term "acceptable salt" includes, but is not limited to, inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, etc.; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; amino acid salts, such as arginine salts, asparagine salts, glutamate salts, etc.; metal salts, such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metals, such as calcium salts, magnesium salts, etc.; and organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.

[0023] Base salts include, but are not limited to, salts formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed with triethylamine, alkoxyammonium such as salts formed with ethanolamine, and salts formed with ethylenediamine, choline or amino acids such as arginine, lysine or histidine. Conventional information about the types of acceptable salts and their formation is known to those skilled in the art, for example, in the "Handbook of Pharmaceutical Salts" by PHStahl, CGWermuth, 1996. stedition, 2002, Wiley-VCH.

[0024] The terms "administration" and / or "administering" a compound are to be understood as referring to providing a compound of the invention to a subject in need of treatment.

[0025] The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0026] Throughout the specification, the word "comprise" or variations such as "comprising" or "including" will be understood to imply the inclusion of stated elements, integers or steps, or groups of elements, integers or steps, but not the exclusion of any other elements, integers or steps, or groups of elements, integers or steps.

[0027] The present invention relates to the treatment of mammalian subjects. The treatment of a "mammalian" subject may also be referred to as the treatment of a "patient" or "individual." A "mammalian" subject exhibits a particular symptom or clinical manifestation of a symptom indicating that the subject is in need of treatment, is currently receiving treatment for a disease, or has been diagnosed with a disease to be treated.

[0028] Therefore, unless otherwise expressly stated, the present invention should be understood to be applicable to humans and other non-human mammals. Humans can be male or female. Other non-human mammals may be primates, livestock and farm animals (e.g., sheep, horses, cattle, pigs), domestic pets (e.g., cats and dogs), domesticated animals (e.g., racehorses, camels, greyhounds), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), and mammals that are typically found in the wild but may also be found in zoos, safari parks, etc. and may be susceptible to treatment.

[0029] The term "treatment" and its variants used in the present invention refer to clinical interventions designed to change the natural course of a subject during a clinical pathological process. Desirable therapeutic effects include reducing the rate of progression of the disease, improving or alleviating the state of the disease, and alleviating or improving prognosis. For example, if one or more of the above therapeutic results are achieved, the subject can be successfully "treated". As used in the present invention, the term "treatment" and its variants encompass the meaning of "prevention", which should be understood to refer to clinical interventions intended to avoid the development of a clinical pathological process.

[0030] "Effective amount" includes a "therapeutically effective" amount, which refers to at least the minimum concentration or dosage that achieves a detectable improvement in a particular disease (e.g., bone marrow edema). The effective amount of the present invention can vary depending on factors such as the disease state, the age, sex, and weight of the patient, and the ability of PPS to elicit a desired response in the individual. An effective amount is also an amount in which the beneficial effects of PPS treatment outweigh any toxic or deleterious effects. "Effective amount" also includes a "prophylactically effective" amount, which refers to the amount of drug or the rate of drug administration required to produce the desired preventive result. DETAILED DESCRIPTION

[0031] The present disclosure relates to a method for treating postoperative joint pain in a mammal, which comprises the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal.

[0032] Preferably, the postoperative joint pain is in at least one joint. Preferably, the at least one joint is preferably selected from: one or more of an ankle joint, an elbow joint, a finger joint, a hip joint, a knee joint, a shoulder joint and a wrist joint. Preferably, the at least one joint is a knee joint.

[0033] Preferably, the post-operative pain is caused by joint replacement surgery.

[0034] The joint replacement is preferably a total joint replacement. Preferably, the total joint replacement is selected from one or more of: total ankle replacement, total elbow replacement, total finger replacement, total hip replacement, total knee replacement, total shoulder replacement and total wrist replacement. The total joint replacement is preferably a total knee replacement.

[0035] The joint replacement is preferably a partial joint replacement. Preferably, the partial joint replacement is selected from one or more of: partial ankle replacement, partial elbow replacement, partial finger replacement, partial hip replacement, partial knee replacement, partial shoulder replacement and partial wrist replacement. The partial joint replacement is preferably a partial knee replacement.

[0036] Preferably, the postoperative joint pain is selected from one or more of: acute pain; chronic pain; general pain and persistent pain. Preferably, the postoperative joint pain is persistent pain. Preferably, the persistent pain is septic persistent pain. Preferably, the persistent pain is caused by periprosthetic fracture.

[0037] Preferably, the persistent pain is aseptic persistent pain. The aseptic persistent pain is preferably intra-articular aseptic persistent pain. Preferably, the intra-articular aseptic persistent pain is caused by the following conditions, and the conditions are selected from one or more of aseptic prosthesis loosening, prosthesis wear, instability, recurrent hemarthrosis, patellar maltracking, tendon rupture and stiffness. The aseptic persistent pain is preferably extra-articular aseptic persistent pain. Preferably, the extra-articular aseptic persistent pain is caused by extra-articular osteoarthritis or extra-articular ischemic necrosis.

[0038] Preferably, in addition to the postoperative joint pain, the mammal also suffers from another arthritis condition. The other arthritis condition is preferably selected from rheumatoid arthritis or osteoarthritis. Preferably, the other arthritis condition is rheumatoid arthritis. The other arthritis condition is preferably osteoarthritis. Preferably, the osteoarthritis is degenerative osteoarthritis. The other arthritis condition preferably occurs in another joint different from the joint affected by the postoperative pain. Preferably, the other joint is one knee joint, and the joint affected by the postoperative pain is the other knee joint. In a human patient, the other knee joint is preferably the left knee joint, and the joint affected by the postoperative pain is the right knee joint.

[0039] Preferably, the polysulfated polysaccharide is selected from the group consisting of: high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate, chondroitin polysulfate, chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide, sulfated dialdehyde acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin and one or more of small sulfated compounds, including but not limited to inositol hexasulfate.

[0040] Preferably, the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate. Preferably, the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate.

[0041] Preferably, the pentosan polysulfate (PPS) is selected from one or more of sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS) and zinc pentosan polysulfate (ZnPPS).

[0042] Preferably, the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

[0043] In a preferred embodiment, NaPPS is produced by Bene-PharmaChem GmbH & Co KG, Geretsried, Germany, and complies with the regulations of the US FDA and the European Community EMEA.

[0044] Preferably, the treatment is by administering the polysulfated polysaccharide or an acceptable salt thereof to the mammal in an effective amount of about 0.5 to about 2 mg / kg of mammal per dose. The effective amount is preferably about 0.5 to about 1.0 mg / kg, about 1.0 to about 1.5 mg / kg, or about 1.5 to about 2.0 mg / kg of mammal per dose. Preferably, the effective amount is about 0.5 mg / kg, about 1.0 mg / kg, or about 2.0 mg / kg of mammal per dose. The effective amount is preferably about 2.0 mg / kg of mammal per dose.

[0045] Preferably, the treatment is by administering the polysulfated polysaccharide or an acceptable salt thereof to the mammal in an effective amount, wherein the effective amount is a fixed dose in the range of about 25 mg to about 4000 mg. The fixed dose is preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg. Preferably, the fixed dose is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 2000 mg, about 3000 mg or about 4000 mg.

[0046] Those skilled in the art will recognize that PPS and PPS compositions suitable for administration by a variety of routes can be prepared by reference to standard textbooks in the field, such as Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005. These compositions include injections, oral preparations (including tablets and capsules containing gastrointestinal drug absorption extenders and enhancers), intravenous preparations, and the like.

[0047] Preferably, the treatment is: administered by injection; by topical administration; by suppository or orally. Preferably, the treatment is administered by injection. Preferably, the injection is selected from subcutaneous (SC), intramuscular (IM), intravenous (IV), intraarticular (IA) or periarticular. Preferably, the treatment is administered by subcutaneous (SC). Preferably, the subcutaneous (SC) injection is a slow SC injection.

[0048] Preferably, the drug is administered to a human once a day, twice a week or three times a week. Preferably, the drug is administered to a human twice a week. Preferably, the drug is administered to a human twice a week, with a minimum of three days and a maximum of four days between doses. Preferably, the drug is administered to a human twice a week for three consecutive weeks. Preferably, the drug is administered to a human according to a twice a week for six consecutive weeks.

[0049] Preferably, the total dose of polysulfated polysaccharide administered in the treatment regimen is from about 200 to about 4000 mg.

[0050] It will be appreciated that the treatment can be adapted to the individual. For example, for individuals who are heavier or lighter, the dosage will be adjusted accordingly. The treatment regimen can also be adjusted based on the severity of the pain experienced by the subject. In certain cases where the subject experiences high levels of pain, it may be desirable to achieve a therapeutic load of PPS as quickly as possible. This may require, for example, administering about 1.0 mg / kg or more of PPS daily until the pain disappears.

[0051] When administered by injection, it is typically administered by a nurse / physician in a clinical setting. One skilled in the art will appreciate that the key to successful treatment is administering enough PPS to the subject to achieve the optimal therapeutic dose in the vicinity of the tissue lesion. Since PPS is known to accumulate in connective tissue, loading can be achieved over time, for example, at a daily dose of 1 mg PPS / kg over 4-5 days. It is anticipated that for severe, chronic cases, a subject may require more than one course of treatment per year, and may require two or three courses per year.

[0052] From a safety perspective, it is preferred to use a lower dose range (1-2 mg PPS / kg or a fixed dose of approximately 25-50 mg) for a longer period of time and with less frequent dosing. This is because PPS is a known anticoagulant and higher doses (>3 mg PPS / kg or a fixed dose of approximately 150-200 mg) may increase the basal APT, which may promote bleeding from any open wounds.

[0053] Although administration by injection is preferred, oral or topical formulations of PPS may be used in follow-up (maintenance doses) after an initial IM or SC PPS treatment. This will also apply to oral administration. For administration by intravenous infusion, a lower dose of 0.5-1 mg PPS / kg per day is preferred.

[0054] The present disclosure also contemplates the co-administration of other therapeutic agents with polysulfated polysaccharides. When other therapeutic agents are used in combination with the compounds of the present invention, they may be used in amounts indicated, for example, in the Physician's Desk Reference (PDR) or otherwise determined by one of ordinary skill in the art.

[0055] It should be understood that for any particular patient, the specific dosage level and dosing frequency may vary and depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the patient's age, weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the particular disease, and the subject being treated. For example, it should be understood that larger animals require larger doses. For illustration, a large animal such as a horse may require a fixed dose of about 4000 mg.

[0056] The therapeutic properties of the present disclosure may be determined by using imaging techniques. For example, bone marrow edema lesions (BMELs) may be diagnosed in joint conditions, diseases or disorders by MRI.

[0057] Bone marrow edema

[0058] Bone marrow edema lesions (BMELs) are lesions that occur in the subchondral bone and are detected by MRI to characterize the severity of symptoms in patients with, for example, osteoarthritis, including pain (

[19] -

[21] ) and cartilage degeneration (

[22] -

[25] ). BMELs are usually assessed using fat-suppressed proton density or T2-weighted sequences. BMELs appear as high-intensity signals on fat-suppressed T2-weighted and fat-suppressed proton density-weighted sequences

[26] .

[0059] The MRI signal associated with BMELs is thought to be due to increased concentrations of blood and interstitial fluid (including infiltrating macrophages) in the area of ​​trabecular microfracture and to collapse of the bone marrow.

[26] Improved spatial resolution and multiplanar reconstruction offer a potential role for 3D fast spin echo sequences, particularly for imaging cartilage.

[27]

[0060] In this regard, the use of MRI to assess BMELs has attracted great interest in monitoring osteoarthritic diseases such as knee OA.

[0061] BMELS and knee osteoarthritis

[0062] BMELs in patients with knee OA may manifest as areas of increased signal intensity on knee MRI and, in established disease, are associated with knee pain

[20] , disease severity, and disease progression, including radiographic progression of knee OA

[28] and MRI-based cartilage loss(

[23] ,

[29] ). Furthermore, in progressive osteoarthritis, BMELs are more likely to persist and increase in size as cartilage loss increases

[23] . Furthermore, the severity of BMELs has been shown to be associated with the risk of knee replacement

[30] .

[0063] The close association of BMELs with pain and cartilage loss has heightened pharmaceutical interest in targeting this structural lesion to monitor knee OA progression and therapeutic efficacy (

[31] -

[33] ). Therefore, imaging of BMELs by MRI has become a tool not only for diagnosing conditions, diseases, or disorders affecting the joint, but also for measuring clinical outcomes.

[0064] The present disclosure contemplates reducing pain in a mammal and / or improving function in a mammal as a clinical outcome. Clinical outcomes may also be measured using patient-reported outcome measurement instruments. Patient-reported pain and / or functional outcomes may be used. These include the Numerical Rating Scale (NRS) for pain

[34] , the Lysholm Knee Function Score

[35] , and the Knee Injury and Osteoarthritis Outcome Score (KOOS)

[36] , which are used to assess pain, symptoms, function, and quality of life.

[0065] Preferably, the reduced pain in the mammal is determined by a pain scoring method. Preferably, the reduced pain in the post-operative joint is determined by a pain scoring method. Preferably, the reduced pain in the additional joint affected by the additional arthritic condition is determined by a pain scoring method. Preferably, the reduced pain in the post-operative joint and the reduced pain in the additional joint affected by the additional arthritic condition are determined by a pain scoring method.

[0066] Preferably, the pain reduction in the human patient is determined by using a patient reported outcome measurement instrument. The patient reported outcome measurement instrument is preferably a rating scale. Preferably, the rating scale is a numeric rating scale (NRS) as described herein.

[0067] The improved function of the mammal is preferably determined by a function scoring method. Preferably, the improved joint function of the mammal is determined by a function scoring method. The improved knee joint function of the mammal is preferably determined by a function scoring method.

[0068] Preferably, the improvement in knee function in the human patient is determined by using a patient reported outcome measure. The patient reported outcome measure is preferably the Lysholm Knee Score as described herein.

[0069] Preferably, the presence of bone marrow edema lesions is reduced. The presence of bone marrow edema lesions associated with osteoarthritis is preferably reduced. Preferably, the presence of bone marrow edema lesions associated with osteoarthritis in the other joint is reduced. The volume of bone marrow edema lesions is preferably reduced. Preferably, the reduction of bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0070] Preferably, the presence of bone marrow edema lesions is resolved. The presence of bone marrow edema lesions associated with osteoarthritis is preferably resolved. Preferably, the presence of bone marrow edema lesions associated with osteoarthritis in the other joint is resolved. Reduction of bone marrow edema lesions is preferably assessed by magnetic resonance imaging (MRI).

[0071] The present disclosure relates to a composition comprising polysulfated polysaccharide or an acceptable salt thereof, and an acceptable excipient, and the composition is used for treating postoperative joint pain in mammals.

[0072] The present disclosure relates to a composition comprising polysulfated polysaccharide or an acceptable salt thereof, and an acceptable excipient, and the composition is used for treating postoperative joint pain in mammals.

[0073] The present disclosure also contemplates the above composition for treating postoperative joint pain in mammals or the above composition for treating postoperative joint pain in mammals, wherein, preferably, the postoperative joint pain is in at least one joint. Preferably, the at least one joint is preferably selected from: one or more of an ankle joint, an elbow joint, a finger joint, a hip joint, a knee joint, a shoulder joint and a wrist joint. Preferably, the at least one joint is a knee joint.

[0074] Preferably, the post-operative pain is caused by joint replacement surgery.

[0075] The joint replacement is preferably a total joint replacement. Preferably, the total joint replacement is selected from one or more of: total ankle replacement, total elbow replacement, total finger replacement, total hip replacement, total knee replacement, total shoulder replacement and total wrist replacement. The total joint replacement is preferably a total knee replacement.

[0076] The joint replacement is preferably a partial joint replacement. Preferably, the partial joint replacement is selected from one or more of: partial ankle replacement, partial elbow replacement, partial finger replacement, partial hip replacement, partial knee replacement, partial shoulder replacement and partial wrist replacement. The partial joint replacement is preferably a partial knee replacement.

[0077] Preferably, the postoperative joint pain is selected from one or more of: acute pain; chronic pain; general pain and persistent pain. Preferably, the postoperative joint pain is persistent pain. Preferably, the persistent pain is septic persistent pain. Preferably, the persistent pain is caused by periprosthetic fracture.

[0078] Preferably, the persistent pain is aseptic persistent pain. The aseptic persistent pain is preferably intra-articular aseptic persistent pain. Preferably, the intra-articular aseptic persistent pain is caused by the following conditions, and the conditions are selected from one or more of aseptic prosthesis loosening, prosthesis wear, instability, recurrent hemarthrosis, patellar maltracking, tendon rupture and stiffness. The aseptic persistent pain is preferably extra-articular aseptic persistent pain. Preferably, the extra-articular aseptic persistent pain is caused by extra-articular osteoarthritis or extra-articular ischemic necrosis.

[0079] Preferably, in addition to the postoperative joint pain, the mammal also suffers from another arthritis condition. The other arthritis condition is preferably selected from rheumatoid arthritis or osteoarthritis. Preferably, the other arthritis condition is rheumatoid arthritis. The other arthritis condition is preferably osteoarthritis. Preferably, the osteoarthritis is degenerative osteoarthritis. The other arthritis condition preferably occurs in another joint different from the joint affected by the postoperative pain. Preferably, the other joint is one knee joint and the joint affected by the postoperative pain is the other knee joint. In a human patient, the other knee joint is preferably the left knee joint, and the joint affected by the postoperative pain is the right knee joint.

[0080] Preferably, the polysulfated polysaccharide is selected from the group consisting of: high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate, chondroitin polysulfate, chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide, sulfated dialdehyde acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin and one or more of small sulfated compounds, including but not limited to inositol hexasulfate.

[0081] Preferably, the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate.

[0082] Preferably, the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate.

[0083] Preferably, the pentosan polysulfate (PPS) is selected from one or more of sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS) and zinc pentosan polysulfate (ZnPPS).

[0084] Preferably, the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

[0085] In a preferred embodiment, NaPPS is produced by Bene-PharmaChem GmbH & Co KG, Geretsried, Germany, and complies with the regulations of the US FDA and the European Community EMEA.

[0086] Preferably, the treatment is by administering the polysulfated polysaccharide or an acceptable salt thereof to the mammal in an effective amount of about 0.5 to about 2 mg / kg of mammal per dose. The effective amount is preferably about 0.5 to about 1.0 mg / kg, about 1.0 to about 1.5 mg / kg, or about 1.5 to about 2.0 mg / kg of mammal per dose. Preferably, the effective amount is about 0.5 mg / kg, about 1.0 mg / kg, or about 2.0 mg / kg of mammal per dose. The effective amount is preferably about 2.0 mg / kg of mammal per dose.

[0087] Preferably, the treatment is by administering the polysulfated polysaccharide or an acceptable salt thereof to the mammal in an effective amount, wherein the effective amount is a fixed dose in the range of about 25 mg to about 4000 mg. The fixed dose is preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg. Preferably, the fixed dose is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 2000 mg, about 3000 mg or about 4000 mg.

[0088] Preferably, the treatment is: administered by injection; by topical administration; by suppository or orally. Preferably, the treatment is administered by injection. Preferably, the injection is selected from subcutaneous (SC), intramuscular (IM), intravenous (IV), intraarticular (IA) or periarticular. Preferably, the treatment is administered by subcutaneous (SC). Preferably, the subcutaneous (SC) injection is a slow SC injection.

[0089] Preferably, the drug is administered to a human via a daily, twice weekly or three times weekly regimen. Preferably, the drug is administered to a human via a twice weekly regimen. Preferably, the drug is administered to a human via a twice weekly regimen, with a minimum of three days and a maximum of four days between administrations. Preferably, the drug is administered to a human via a twice weekly regimen for three consecutive weeks. Preferably, the drug is administered to a human via a twice weekly regimen for six consecutive weeks.

[0090] Preferably, the total dose of polysulfated polysaccharide administered in the treatment regimen is from about 200 to about 4000 mg.

[0091] Preferably, the reduced pain in the mammal is determined by a pain scoring method. Preferably, the reduced pain in the post-operative joint is determined by a pain scoring method. Preferably, the reduced pain in the additional joint affected by the additional arthritic condition is determined by a pain scoring method. Preferably, the reduced pain in the post-operative joint and the reduced pain in the additional joint affected by the additional arthritic condition are determined by a pain scoring method.

[0092] Preferably, the pain reduction in the human patient is determined by using a patient reported outcome measurement instrument. The patient reported outcome measurement instrument is preferably a rating scale. Preferably, the rating scale is a numeric rating scale (NRS) as described herein.

[0093] The improved function of the mammal is preferably determined by a function scoring method. Preferably, the improved joint function of the mammal is determined by a function scoring method. The improved knee joint function of the mammal is preferably determined by a function scoring method.

[0094] Preferably, the improvement in knee function in the human patient is determined by using a patient reported outcome measure. The patient reported outcome measure is preferably the Lysholm Knee Score as described herein.

[0095] Preferably, the presence of bone marrow edema lesions is reduced. The presence of bone marrow edema lesions associated with osteoarthritis is preferably reduced. Preferably, the presence of bone marrow edema lesions associated with osteoarthritis in the other joint is reduced. The volume of bone marrow edema lesions is preferably reduced. Preferably, the reduction of bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0096] Preferably, the presence of bone marrow edema lesions is resolved. The presence of bone marrow edema lesions associated with osteoarthritis is preferably resolved. Preferably, the presence of bone marrow edema lesions associated with osteoarthritis in the other joint is resolved. Reduction of bone marrow edema lesions is preferably assessed by magnetic resonance imaging (MRI).

[0097] The present disclosure relates to the use of polysulfated polysaccharides or acceptable salts thereof in treating postoperative joint pain in mammals.

[0098] The present disclosure relates to the use of polysulfated polysaccharide or an acceptable salt thereof in preparing a medicament for treating postoperative joint pain in mammals.

[0099] The present disclosure also contemplates the above-mentioned use of polysulfated polysaccharides or their acceptable salts in treating postoperative joint pain in mammals or the above-mentioned use of polysulfated polysaccharides or their acceptable salts in preparing a medicament for treating postoperative joint pain in mammals, wherein, preferably, the postoperative joint pain is in at least one joint. Preferably, the at least one joint is preferably selected from: one or more of an ankle joint, an elbow joint, a finger joint, a hip joint, a knee joint, a shoulder joint and a wrist joint. Preferably, the at least one joint is a knee joint.

[0100] Preferably, the post-operative pain is caused by joint replacement surgery.

[0101] The joint replacement is preferably a total joint replacement. Preferably, the total joint replacement is selected from one or more of: total ankle replacement, total elbow replacement, total finger replacement, total hip replacement, total knee replacement, total shoulder replacement and total wrist replacement. The total joint replacement is preferably a total knee replacement.

[0102] The joint replacement is preferably a partial joint replacement. Preferably, the partial joint replacement is selected from one or more of: partial ankle replacement, partial elbow replacement, partial finger replacement, partial hip replacement, partial knee replacement, partial shoulder replacement and partial wrist replacement. The partial joint replacement is preferably a partial knee replacement.

[0103] Preferably, the postoperative joint pain is selected from one or more of: acute pain; chronic pain; general pain and persistent pain. Preferably, the postoperative joint pain is persistent pain. Preferably, the persistent pain is septic persistent pain. Preferably, the persistent pain is caused by periprosthetic fracture.

[0104] Preferably, the persistent pain is aseptic persistent pain. The aseptic persistent pain is preferably intra-articular aseptic persistent pain. Preferably, the intra-articular aseptic persistent pain is caused by the following conditions, and the conditions are selected from one or more of aseptic prosthesis loosening, prosthesis wear, instability, recurrent hemarthrosis, patellar maltracking, tendon rupture and stiffness. The aseptic persistent pain is preferably extra-articular aseptic persistent pain. Preferably, the extra-articular aseptic persistent pain is caused by extra-articular osteoarthritis or extra-articular ischemic necrosis.

[0105] Preferably, in addition to the postoperative joint pain, the mammal also suffers from another arthritis condition. The other arthritis condition is preferably selected from rheumatoid arthritis or osteoarthritis. Preferably, the other arthritis condition is rheumatoid arthritis. The other arthritis condition is preferably osteoarthritis. Preferably, the osteoarthritis is degenerative osteoarthritis. The other arthritis condition preferably occurs in another joint different from the joint affected by the postoperative pain. Preferably, the other joint is one knee joint and the joint affected by the postoperative pain is the other knee joint. In a human patient, the other knee joint is preferably the left knee joint, and the joint affected by the postoperative pain is the right knee joint.

[0106] Preferably, the polysulfated polysaccharide is selected from the group consisting of: high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate, chondroitin polysulfate, chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide, sulfated dialdehyde acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin and one or more of small sulfated compounds, including but not limited to inositol hexasulfate.

[0107] Preferably, the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate.

[0108] Preferably, the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate.

[0109] Preferably, the pentosan polysulfate (PPS) is selected from one or more of sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS) and zinc pentosan polysulfate (ZnPPS).

[0110] Preferably, the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

[0111] In a preferred embodiment, NaPPS is produced by Bene-PharmaChem GmbH & Co KG, Geretsried, Germany, and complies with the regulations of the US FDA and the European Community EMEA.

[0112] Preferably, the treatment is by administering the polysulfated polysaccharide or an acceptable salt thereof to the mammal in an effective amount of about 0.5 to about 2 mg / kg of mammal per dose. The effective amount is preferably about 0.5 to about 1.0 mg / kg, about 1.0 to about 1.5 mg / kg, or about 1.5 to about 2.0 mg / kg of mammal per dose. Preferably, the effective amount is about 0.5 mg / kg, about 1.0 mg / kg, or about 2.0 mg / kg of mammal per dose. The effective amount is preferably about 2.0 mg / kg of mammal per dose.

[0113] Preferably, the treatment is by administering the polysulfated polysaccharide or an acceptable salt thereof to the mammal in an effective amount, wherein the effective amount is a fixed dose in the range of about 25 mg to about 4000 mg. The fixed dose is preferably about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg. Preferably, the fixed dose is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 2000 mg, about 3000 mg or about 4000 mg.

[0114] Preferably, the treatment is: administered by injection; by topical administration; by suppository or orally. Preferably, the treatment is administered by injection. Preferably, the injection is selected from subcutaneous (SC), intramuscular (IM), intravenous (IV), intraarticular (IA) or periarticular. Preferably, the treatment is administered by subcutaneous (SC). Preferably, the subcutaneous (SC) injection is a slow SC injection.

[0115] Preferably, the drug is administered to a human via a daily, twice weekly or three times weekly regimen. Preferably, the drug is administered to a human via a twice weekly regimen. Preferably, the drug is administered to a human via a twice weekly regimen, with a minimum of three days and a maximum of four days between administrations. Preferably, the drug is administered to a human via a twice weekly regimen for three consecutive weeks. Preferably, the drug is administered to a human via a twice weekly regimen for six consecutive weeks.

[0116] Preferably, the total dose of polysulfated polysaccharide administered in the treatment regimen is from about 200 to about 4000 mg.

[0117] Preferably, the reduced pain in the mammal is determined by a pain scoring method. Preferably, the reduced pain in the post-operative joint is determined by a pain scoring method. Preferably, the reduced pain in the additional joint affected by the additional arthritic condition is determined by a pain scoring method. Preferably, the reduced pain in the post-operative joint and the reduced pain in the additional joint affected by the additional arthritic condition are determined by a pain scoring method.

[0118] Preferably, the pain reduction in the human patient is determined by using a patient reported outcome measurement instrument. The patient reported outcome measurement instrument is preferably a rating scale. Preferably, the rating scale is a numeric rating scale (NRS) as described herein.

[0119] The improved function of the mammal is preferably determined by a function scoring method. Preferably, the improved joint function of the mammal is determined by a function scoring method. The improved knee joint function of the mammal is preferably determined by a function scoring method.

[0120] Preferably, the improvement in knee function in the human patient is determined by using a patient reported outcome measure. The patient reported outcome measure is preferably the Lysholm Knee Score as described herein.

[0121] Preferably, the presence of bone marrow edema lesions is reduced. The presence of bone marrow edema lesions associated with osteoarthritis is preferably reduced. Preferably, the presence of bone marrow edema lesions associated with osteoarthritis in the other joint is alleviated. The volume of bone marrow edema lesions is preferably reduced. Preferably, the reduction of bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0122] Preferably, the presence of bone marrow edema lesions is resolved. The presence of bone marrow edema lesions associated with osteoarthritis is preferably resolved. Preferably, the presence of bone marrow edema lesions associated with osteoarthritis in the other joint is resolved. Reduction of bone marrow edema lesions is preferably assessed by magnetic resonance imaging (MRI).

[0123] Exemplary embodiments

[0124] 1. A method for treating postoperative joint pain in a mammal, comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal.

[0125] 2. The method of exemplary embodiment 1, wherein the postoperative joint pain is in at least one joint.

[0126] 3. A method as described in exemplary embodiment 2, wherein the at least one joint is selected from: one or more of: an ankle joint, an elbow joint, a finger joint, a hip joint, a knee joint, a shoulder joint and a wrist joint.

[0127] 4. A method as described in exemplary embodiment 3, wherein the at least one joint is a knee joint.

[0128] 5. The method according to any one of exemplary embodiments 1 to 4, wherein the postoperative pain is caused by joint replacement.

[0129] 6. A method as described in exemplary embodiment 5, wherein the joint replacement is a total joint replacement.

[0130] 7. A method as described in exemplary embodiment 6, wherein the total joint replacement is selected from: one or more of: total ankle replacement, total elbow replacement, total finger replacement, total hip replacement, total knee replacement, total shoulder replacement and total wrist replacement.

[0131] 8. A method as described in exemplary embodiment 7, wherein the total joint replacement is a total knee replacement.

[0132] 9. The method of Exemplary Embodiment 5, wherein the joint replacement is a partial joint replacement.

[0133] 10. A method as described in exemplary embodiment 9, wherein the partial joint replacement is selected from: one or more of: partial ankle replacement, partial elbow replacement, partial finger replacement, partial hip replacement, partial knee replacement, partial shoulder replacement and partial wrist replacement.

[0134] 11. The method of exemplary embodiment 10, wherein the partial joint replacement is a partial knee replacement.

[0135] 12. The method according to any one of exemplary embodiments 1 to 11, wherein the postoperative joint pain is selected from one or more of: acute pain; chronic pain; general pain and persistent pain.

[0136] 13. The method of exemplary embodiment 12, wherein the postoperative joint pain is persistent pain.

[0137] 14. The method according to exemplary embodiment 13, wherein the persistent pain is septic persistent pain.

[0138] 15. The method of exemplary embodiment 13, wherein the persistent pain is caused by periprosthetic fracture.

[0139] 16. The method of exemplary embodiment 13, wherein the persistent pain is sterile persistent pain.

[0140] 17. The method according to exemplary embodiment 16, wherein the sterile persistent pain is intra-articular sterile persistent pain.

[0141] 18. A method as described in exemplary embodiment 17, wherein the sterile persistent pain in the joint is caused by the following conditions, and the conditions are selected from one or more of sterile prosthesis loosening, prosthesis wear, instability, recurrent joint effusion, patellar maltracking, tendon rupture and stiffness.

[0142] 19. The method according to exemplary embodiment 16, wherein the sterile persistent pain is extra-articular sterile persistent pain.

[0143] 20. The method according to exemplary embodiment 19, wherein the extra-articular sterile persistent pain is caused by extra-articular osteoarthritis or extra-articular avascular necrosis.

[0144] 21. The method of any preceding exemplary embodiment, wherein said mammal suffers from an additional arthritic condition in addition to said post-operative joint pain.

[0145] 22. The method of exemplary embodiment 21, wherein the additional arthritic condition is selected from rheumatoid arthritis or osteoarthritis.

[0146] 23. The method of exemplary embodiment 22, wherein the additional arthritic condition is rheumatoid arthritis.

[0147] 24. The method of Exemplary Embodiment 22, wherein the additional arthritic condition is osteoarthritis.

[0148] 25. The method according to exemplary embodiment 24, wherein the osteoarthritis is degenerative osteoarthritis.

[0149] 26. The method of any of exemplary embodiments 21-25, wherein the additional arthritic condition occurs in an additional joint different from the joint affected by the postoperative pain.

[0150] 27. A method as described in exemplary embodiment 26, wherein the additional joint is a knee joint and the joint affected by the postoperative pain is another knee joint.

[0151] 28. A method as described in exemplary embodiment 27, wherein, in a human patient, the additional knee joint is a left knee joint and the joint affected by the postoperative pain is a right knee joint.

[0152] 29. A method as described in any of exemplary embodiments 1 to 28, wherein the polysulfated polysaccharide is selected from the group consisting of: high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate, chondroitin polysulfate, chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide, sulfated bisaldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin and one or more of small sulfated compounds, including but not limited to inositol hexasulfate.

[0153] 30. The method of example embodiment 29, wherein the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate (PPS), chondroitin polysulfate, and chitosan polysulfate.

[0154] 31. A method as described in exemplary embodiment 30, wherein the pentosan polysulfate (PPS) is selected from one or more of: sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS) and zinc pentosan polysulfate (ZnPPS).

[0155] 32. The method according to exemplary embodiment 31, wherein the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

[0156] 33. The method of any one of exemplary embodiments 1-32, wherein the treatment is by administering to the mammal the polysulfated polysaccharide or an acceptable salt thereof in an effective amount of about 0.5 to about 2 mg / kg of the mammal per dose.

[0157] 34. The method of exemplary embodiment 33, wherein the effective amount is about 0.5 to about 1.0 mg / kg, about 1.0 to about 1.5 mg / kg, or about 1.5 to about 2.0 mg / kg of the mammal per dose.

[0158] 35. The method of exemplary embodiment 33, wherein the effective amount is about 0.5 mg / kg, about 1.0 mg / kg, or about 2.0 mg / kg of the mammal per dose.

[0159] 36. The method of exemplary embodiment 33, wherein the effective amount is about 2.0 mg / kg of mammal per dose.

[0160] 37. A method as described in any of exemplary embodiments 1-32, wherein the treatment is by administering to the mammal an effective amount of the polysulfated polysaccharide or an acceptable salt thereof, wherein the effective amount is a fixed dose in the range of about 25 mg to about 4000 mg.

[0161] 38. The method of exemplary embodiment 37, wherein the fixed dose is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0162] 39. The method of exemplary embodiment 37, wherein the fixed dose is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 2000 mg, about 3000 mg, or about 4000 mg.

[0163] 40. The method of any one of exemplary embodiments 1-39, wherein the treatment is: administered by injection; administered topically; administered by suppository or orally.

[0164] 41. The method of exemplary embodiment 40, wherein the treatment is administered by injection.

[0165] 42. The method of exemplary embodiment 41, wherein the injection is selected from subcutaneous (SC) injection, intramuscular (IM) injection, intravenous (IV) injection, intra-articular (IA) injection, or peri-articular injection.

[0166] 43. The method of exemplary embodiment 42, wherein the treatment is administered by subcutaneous (SC) injection or by slow subcutaneous (SC) injection.

[0167] 44. The method of any one of exemplary embodiments 40-43, wherein the administration to a human is by a treatment regimen of once a day, twice a week, or three times a week.

[0168] 45. The method of exemplary embodiment 44, wherein the administration to the human is via a twice weekly treatment regimen.

[0169] 46. ​​The method of exemplary embodiment 45, wherein the administration to a human is via a twice-weekly treatment regimen with a minimum of three days and a maximum of four days between two administrations.

[0170] 47. The method of exemplary embodiment 46, wherein the administration to a human is via a twice weekly treatment regimen for three consecutive weeks.

[0171] 48. The method of exemplary embodiment 47, wherein the total dose of polysulfated polysaccharide administered in the treatment regimen is from about 200 to about 4000 mg.

[0172] 49. The method of any one of exemplary embodiments 1-48, wherein the reduction in pain in the mammal is determined by a pain scoring method.

[0173] 50. The method of exemplary embodiment 49, wherein the reduction in postoperative joint pain is determined by a pain scoring method.

[0174] 51. The method of Exemplary Embodiment 49, wherein the reduction in pain in the additional joint affected by the additional arthritic condition is determined by a pain scoring method.

[0175] 52. The method of Exemplary Embodiment 49, wherein said postoperative joint pain and said reduction in pain in said additional joint affected by said additional arthritic condition is determined by a pain scoring method.

[0176] 53. The method of any of exemplary embodiments 49-52, wherein the reduction in pain in the human patient is determined by using a patient-reported outcome measurement instrument.

[0177] 54. A method as described in exemplary embodiment 53, wherein the patient-reported outcome measurement instrument is a rating scale.

[0178] 55. A method as described in exemplary embodiment 54, wherein the rating scale is a numerical rating scale (NRS) described herein.

[0179] 56. A method as described in any of exemplary embodiments 1-55, wherein the improved function of the mammal is determined by a functional scoring method.

[0180] 57. The method of exemplary embodiment 56, wherein the improved joint function of the mammal is determined by a functional scoring method.

[0181] 58. A method as described in exemplary embodiment 57, wherein the improvement in knee joint function of the mammal is determined by a functional scoring method.

[0182] 59. A method as described in exemplary embodiment 58, wherein the improvement in knee function in the human patient is determined by using a patient-reported outcome measurement instrument.

[0183] 60. The method of exemplary embodiment 59, wherein the patient-reported outcome measure is the Lysholm Knee Score described herein.

[0184] 61. The method of any one of exemplary embodiments 1-60, wherein the presence of bone marrow edema lesions is reduced.

[0185] 62. The method of exemplary embodiment 61, wherein the presence of bone marrow edema lesions associated with osteoarthritis is reduced.

[0186] 63. The method of exemplary embodiment 62, wherein the presence of bone marrow edema lesions associated with osteoarthritis in the additional joint is reduced.

[0187] 64. The method of any of exemplary embodiments 61-63, wherein the volume of bone marrow edema lesions is reduced.

[0188] 65. The method of exemplary embodiment 64, wherein the reduction in bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0189] 66. The method of any one of exemplary embodiments 1-60, wherein the presence of bone marrow edema lesions is resolved.

[0190] 67. The method of exemplary embodiment 66, wherein the presence of bone marrow edema lesions associated with osteoarthritis is resolved.

[0191] 68. The method of exemplary embodiment 67, wherein the presence of bone marrow edema lesions associated with osteoarthritis in the additional joint is resolved.

[0192] 69. The method of any of exemplary embodiments 66-68, wherein regression of bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0193] 70. A composition comprising a polysulfated polysaccharide or an acceptable salt thereof, and an acceptable excipient, for treating postoperative joint pain in a mammal.

[0194] 71. A composition comprising a polysulfated polysaccharide or an acceptable salt thereof, and an acceptable excipient, wherein the composition is used for treating postoperative joint pain in a mammal.

[0195] 72. Use of a polysulfated polysaccharide or an acceptable salt thereof for treating postoperative joint pain in a mammal.

[0196] 73. Use of polysulfated polysaccharide or an acceptable salt thereof in the preparation of a medicament for treating postoperative joint pain in mammals.

[0197] 74. The composition of Exemplary Embodiment 70 or Exemplary Embodiment 71 or the use of Exemplary Embodiment 72 or Exemplary Embodiment 73, wherein the postoperative joint pain is in at least one joint.

[0198] 75. The composition or use of exemplary embodiment 74, wherein the at least one joint is selected from one or more of an ankle joint, an elbow joint, a finger joint, a hip joint, a knee joint, a shoulder joint and a wrist joint.

[0199] 76. The composition or use of example embodiment 75, wherein the at least one joint is a knee joint.

[0200] 77. The composition or use of any one of exemplary embodiments 70-76, wherein the postoperative pain is caused by joint replacement surgery.

[0201] 78. The composition or use of example embodiment 77, wherein the joint replacement is a total joint replacement.

[0202] 79. The composition or use of exemplary embodiment 78, wherein the total joint replacement is selected from one or more of total ankle replacement, total elbow replacement, total finger replacement, total hip replacement, total knee replacement, total shoulder replacement, and total wrist replacement.

[0203] 80. The composition or use of example embodiment 79, wherein the total joint replacement is a total knee replacement.

[0204] 81. The composition or use of example embodiment 77, wherein the joint replacement is a partial joint replacement.

[0205] 82. The composition or use of exemplary embodiment 81, wherein the partial joint replacement is selected from one or more of partial ankle replacement, partial elbow replacement, partial finger replacement, partial hip replacement, partial knee replacement, partial shoulder replacement, and partial wrist replacement.

[0206] 83. The composition or use of example embodiment 82, wherein the partial joint replacement is a partial knee replacement.

[0207] 84. The composition or use of any one of exemplary embodiments 70-83, wherein the postoperative joint pain is selected from one or more of: acute pain; chronic pain; general pain and persistent pain.

[0208] 85. The composition or use of exemplary embodiment 84, wherein the postoperative joint pain is persistent pain.

[0209] 86. The composition or use of exemplary embodiment 85, wherein the persistent pain is septic persistent pain.

[0210] 87. The composition or use of example embodiment 85, wherein the persistent pain is caused by a periprosthetic fracture.

[0211] 88. The composition or use of exemplary embodiment 85, wherein the persistent pain is sterile persistent pain.

[0212] 89. The composition or use of exemplary embodiment 88, wherein the sterile persistent pain is intra-articular sterile persistent pain.

[0213] 90. The composition or use of exemplary embodiment 89, wherein the intra-articular aseptic persistent pain is caused by one or more of aseptic prosthesis loosening, prosthesis wear, instability, recurrent hemarthrosis, patellar maltracking, tendon rupture and stiffness.

[0214] 91. The composition or use of exemplary embodiment 90, wherein the sterile persistent pain is extra-articular sterile persistent pain.

[0215] 92. The composition or use of exemplary embodiment 91, wherein the extra-articular sterile persistent pain is caused by extra-articular osteoarthritis or extra-articular avascular necrosis.

[0216] 93. The composition or use of any of the above exemplary embodiments, wherein in addition to the post-operative joint pain, the mammal suffers from another arthritic condition.

[0217] 94. The composition or use of exemplary embodiment 93, wherein the additional arthritic condition is selected from rheumatoid arthritis or osteoarthritis.

[0218] 95. The composition or use of exemplary embodiment 94, wherein the additional arthritic condition is rheumatoid arthritis.

[0219] 96. The composition or use of exemplary embodiment 94, wherein the additional arthritic condition is osteoarthritis.

[0220] 97. The composition or use of example embodiment 96, wherein the osteoarthritis is degenerative osteoarthritis.

[0221] 98. The composition or use of any one of exemplary embodiments 93-97, wherein the additional arthritic condition occurs in a joint other than the joint affected by the post-operative pain.

[0222] 99. The composition or use of example embodiment 98, wherein the additional joint is a knee joint and the joint affected by the postoperative pain is another knee joint.

[0223] 100. The composition or use of exemplary embodiment 99, wherein, in a human patient, the additional knee joint is the left knee joint and the joint affected by the postoperative pain is the right knee joint.

[0224] 101. The composition of any of exemplary embodiments 70-100 or the use of any of exemplary embodiments 72-100, wherein the polysulfated polysaccharide is selected from the group consisting of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate, chondroitin polysulfate, chitosan polysulfate, dermatan polysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide, sulfated bisaldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin and one or more of small sulfated compounds, including but not limited to inositol hexasulfate.

[0225] 102. The composition or use of exemplary embodiment 101, wherein the polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate (PPS), chondroitin polysulfate, and chitosan polysulfate.

[0226] 103. A composition or use as described in exemplary embodiment 102, wherein the pentosan polysulfate (PPS) is selected from one or more of: sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS) and zinc pentosan polysulfate (ZnPPS).

[0227] 104. The composition or use of exemplary embodiment 103, wherein the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

[0228] 105. The composition of any of exemplary embodiments 70-104 or the use of any of exemplary embodiments 72-104, wherein the treatment is by administering to the mammal the polysulfated polysaccharide or an acceptable salt thereof in an effective amount of about 0.5 to about 2 mg / kg of the mammal per dose.

[0229] 106. The composition or use of exemplary embodiment 105, wherein the effective amount is about 0.5 to about 1.0 mg / kg, about 1.0 to about 1.5 mg / kg, or about 1.5 to about 2.0 mg / kg of the mammal per dose.

[0230] 107. The composition or use of exemplary embodiment 105, wherein the effective amount is about 0.5 mg / kg, about 1.0 mg / kg, or about 2.0 mg / kg of the mammal per dose.

[0231] 108. The composition or use of exemplary embodiment 105, wherein the effective amount is about 2.0 mg / kg mammal per dose.

[0232] 109. The composition of any of exemplary embodiments 70-104 or the use of any of exemplary embodiments 72-104, wherein the treatment is by administering to the mammal an effective amount of the polysulfated polysaccharide or an acceptable salt thereof, wherein the effective amount is a fixed dose in the range of about 25 mg to about 4000 mg.

[0233] 110. The composition or use of exemplary embodiment 109, wherein the fixed dose is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0234] 111. The composition or use of exemplary embodiment 109, wherein the fixed dose is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 2000 mg, about 3000 mg or about 4000 mg.

[0235] 112. The composition of any of exemplary embodiments 70-111 or the use of any of exemplary embodiments 74-111, wherein the treatment is: administered by injection; by topical administration; by suppository or orally.

[0236] 113. The composition or use of exemplary embodiment 112, wherein the treatment is administered by injection.

[0237] 114. The composition or use of exemplary embodiment 113, wherein the injection is selected from subcutaneous (SC) injection, intramuscular (IM) injection, intravenous (IV) injection, intra-articular (IA) injection or peri-articular injection.

[0238] 115. The composition or use of exemplary embodiment 114, wherein the treatment is administered by subcutaneous (SC) injection or by slow subcutaneous (SC) injection.

[0239] 116. The composition or use of any one of exemplary embodiments 112-115, wherein the administration to a human is by a treatment regimen of once a day, twice a week, or three times a week.

[0240] 117. The composition or use of exemplary embodiment 116, wherein the administration to a human is by a twice weekly treatment regimen.

[0241] 118. The composition or use according to exemplary embodiment 117, wherein the composition or use is administered to a human via a twice-weekly treatment regimen with a minimum of three days and a maximum of four days between administrations.

[0242] 119. The composition or use of exemplary embodiment 118, wherein the administration to a human is by a twice-weekly, three-week treatment regimen.

[0243] 120. The composition or use of exemplary embodiment 119, wherein the total dose of polysulfated polysaccharide administered in the treatment regimen is from about 200 to about 4000 mg.

[0244] 121. The composition of any one of exemplary embodiments 70-120 or the use of any one of exemplary embodiments 72-120, wherein the reduction in pain in the mammal is determined by a pain scoring method.

[0245] 122. The composition or use of exemplary embodiment 121, wherein the reduction in postoperative joint pain is determined by a pain scoring method.

[0246] 123. The composition or use of exemplary embodiment 121, wherein the reduction in pain in the additional joint affected by the additional arthritic condition is determined by a pain scoring method.

[0247] 124. The composition or use of exemplary embodiment 121, wherein said postoperative joint pain and said reduction in pain in said additional joint affected by said additional arthritic condition are determined by a pain scoring method.

[0248] 125. The composition or use of any of exemplary embodiments 121-124, wherein the reduction in pain in the human patient is determined using a patient-reported outcome measurement instrument.

[0249] 126. The composition or use of example embodiment 125, wherein the patient reported outcome measurement instrument is a rating scale.

[0250] 127. The composition or use of exemplary embodiment 126, wherein the rating scale is a numerical rating scale (NRS) as described herein.

[0251] 128. The composition of any one of exemplary embodiments 70-127 or the use of any one of exemplary embodiments 72-127, wherein the improved function of the mammal is determined by a functional scoring method.

[0252] 129. The composition or use of exemplary embodiment 128, wherein the improved joint function of the mammal is determined by a functional scoring method.

[0253] 130. The composition or use of example embodiment 129, wherein the mammal's knee function is improved as determined by a functional scoring method.

[0254] 131. The composition or use of exemplary embodiment 130, wherein the improvement in knee function in the human patient is determined using a patient reported outcome measurement instrument.

[0255] 132. The composition or use of exemplary embodiment 131, wherein the patient reported outcome measure is the Lysholm Knee Score described herein.

[0256] 133. The composition of any of exemplary embodiments 70-132 or the use of any of exemplary embodiments 72-132, wherein the presence of bone marrow edema lesions is reduced.

[0257] 134. The composition or use of exemplary embodiment 133, wherein the presence of osteoarthritis-associated bone marrow edema lesions is reduced.

[0258] 135. The composition or use of exemplary embodiment 134, wherein the presence of bone marrow edema lesions associated with osteoarthritis in the additional joint is reduced.

[0259] 136. The composition or use of any one of exemplary embodiments 133-135, wherein the volume of bone marrow edema lesions is reduced.

[0260] 137. The composition or use of exemplary embodiment 136, wherein the reduction in bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0261] 138. The composition of any of exemplary embodiments 70-132 or the use of any of exemplary embodiments 72-132, wherein the presence of bone marrow edema lesions is resolved.

[0262] 139. The composition or use of exemplary embodiment 138, wherein the presence of bone marrow edema lesions associated with osteoarthritis is resolved.

[0263] 140. The composition or use of exemplary embodiment 139, wherein the presence of bone marrow edema lesions associated with osteoarthritis in the additional joint is resolved.

[0264] 141. The composition or use of any one of exemplary embodiments 139-140, wherein regression of bone marrow edema lesions is assessed by magnetic resonance imaging (MRI).

[0265] Example

[0266] Example 1 - Effect of PPS on pain in a patient with left knee osteoarthritis and persistent pain after total right knee replacement Impact on clinical outcomes of pain and function

[0267] Example 1 is a study evaluating the safety, tolerability, and outcomes of PPS treatment in patients with degenerative osteoarthritis of the left knee with bone marrow edema lesions (BMEL) and persistent pain after total right knee replacement by magnetic resonance imaging (MRI).

[0268] The patient was treated with PPS under the TGA Special Access Scheme (B). (As injectable PPS is not a registered product in Australia, approval to treat the patient with PPS was obtained from the Australian Government Department of Health - Therapeutic Goods Administration under the Special Access Scheme (SAS).

[0269] The patient is a female in her 60s with advanced osteoarthritis (OA) in her right knee. She underwent a total knee replacement (TKR) in her right knee and developed sterile, persistent pain following this arthroplasty. She also had pain in her left knee (degenerative OA) and a TKR was recommended in that joint.

[0270] She was treated with PPS. The treatment regimen consisted of administering PPS at a preferred dose of 2 mg / kg body weight twice a week for three weeks by subcutaneous injection (six injections total).

[0271] Her left (native) joint pain score on the Numeric Rating Scale (NRS) improved from 8 / 10 to 0 / 10, the Lysholm knee function score improved from 58 / 100 (fair) to 99 / 100 (excellent), and there was a reduction in the size of bone marrow edema lesions as assessed by magnetic resonance imaging (MRI). Pre-treatment MRI (at baseline): showed bone marrow edema stage up to two-thirds; moderate bone marrow edema lesions were less than 20 mm in size. Post-treatment MRI (after PPS administration): showed negligible bone marrow edema stage; minimal bone marrow edema lesions were less than 5 mm in size.

[0272] Following this single systemic treatment for left knee osteoarthritis, the sterile, persistent pain in the right artificial joint also subsided / ceased and decreased to zero. The improvement in the right knee pain response occurred simultaneously with and was directly related to the improvement in the left knee. It was further observed that the improvement in the right knee pain response was not due to the improvement in the left knee, nor was it related to the rehabilitation or compensation of the left knee.

[0273] In summary, the patients in the study had the following characteristics:

[0274] High NRS pain score

[0275] Normal joint function as determined by the Lysholm knee score

[0276] MRI evidence of bone marrow edema

[0277] The solution has the following features:

[0278] Treatment: Subcutaneous injection of PPS (recommended dose 2 mg / kg) twice a week for 3 weeks (6 injections in total)

[0279] Table 1 shows the clinical outcomes including BMEL assessment, pain, and functional outcome scores.

[0280] Table 1. Clinical results

[0281]

[0282] Table 1 Description

[0283] The Numerical Rating Scale (NRS)

[34] is an 11-point system (0–10), with 0 being pain-free and 10 being the most severe pain.

[0284] The Lysholm knee score

[35] is a total score ranging from 0 to 100 calculated from the results of the eight functional components of the Lysholm knee scoring scale: limp (5 points), brace (5 points), locking (15 points), instability (25 points), pain (25 points), swelling (10 points), stair climbing (10 points), and squatting (5 points). The total score is divided into the following levels: 95–100 indicates excellent function, 84–94 indicates good function, 65–83 indicates fair function, and <65 indicates poor function.

[0285] In conclusion, no adverse effects were reported when PPS was used under TGA-SAS (B) in patients with left knee pain associated with degenerative osteoarthritis and sterile persistent pain in the right knee after TKR.

[0286] Subcutaneous injection of PPS (recommended dose is 2 mg / kg) twice a week for 3 weeks (6 injections in total) can significantly reduce BMEL and improve pain and activity scores of the left knee joint as assessed by magnetic resonance imaging.

[0287] Surprisingly, the post-operative sterile, persistent pain in the right artificial knee also subsided / ceased and dropped to zero. The surprising improvement in the right knee pain response was not caused by, nor related to, the improvement in the left knee joint.

[0288] Those skilled in the art will appreciate that, without departing from the broad overall scope of the present disclosure, various changes and / or modifications may be made to the above-described embodiments. Therefore, the present embodiments should be considered in all aspects as illustrative rather than restrictive.

[0289] References

[0290] 1.Lim HA,Song EK,Seon JK,Park KS,Shin YJ,Yang HY,Causes of AsepticPersistent Pain after Total Knee Arthroplasty.Clinics in OrthopedicSurgery.2017;9(1):50-56.

[0291] 2.Mayerhoefer ME,Krmaer J,Breitenseher MJ,Norden C,Vakil-Adli A,Hofmann S etal.Short-term outcome of painful bone marrow oedema of the kneefollowing oral treatment with iloprost or tramadol:results of an exploratoryphase II study of 41patients.Rheumatology.2007;46(9):1460-5.

[0292] 3.Batemen D,Kennedy J.Non-steroidal anti-inflammatory drugs andelderly patients.British Medical Journal.1995;310:817-8.

[0293] 4.Brandt KD.Should nonsteroidal anti-inflammatory drugs be used totreat osteoarthritis?Rheumatic diseases clinics of North America.1993;19(1):29-44.

[0294] 5.O'Mahony D.Prevention of corticosteroid-induced osteoporosis andfractures.Journalof Clinical Pharmacy and Therapeutics.1999;24(2):83-5.

[0295] 6.Miyata N,Kumagai K,Osaki M,Murata M,Tomita M,Hozumi A,etal.Pentosanreduces osteonecrosis of femoral head in SHRSP.Clinical andexperimental hypertension(NewYork,NY:1993).2010;32(8):511-6.

[0296] 7.Scully MF,Weerasinghe KM,Ellis V,Djazaeri B,Kakkar VV.Anticoagulantandantiheparin activities of a pentosan polysulphate.Thrombosis Research1983;31(1):87-97.

[0297] 8.Krupinski K,Breddin HK,Casu B.Anticoagulant and antithromboticeffects ofchemically modified heparins and pentosan polysulfate.Haemostasis1990;20(2):81-92.

[0298] 9.Shanmugam M,Mody KH.Heparinoid-active sulphated polysaccharidesfrom marinealgae as potential blood anticoagulant agents.Current Science2000;79(12):1672-1683.

[0299] 10.Vongchan P,Sajomsang W,Kasinrerk W,Subyen D,KongrawelertP.Anticoagulantactivities of the chitosan polysulfate synthesized from marinecrab shell by semi-heterogeneousconditions.Science Asia 2003;29:115-120.

[0300] 11.Vinazzer H.Prevention of recurrence of cerebrovascularthromboses.A randomizedcomparative study acetylsalicylic acid and sodiumpentosan polysulfate.Fortschr Med 1987;105(5):79-85.

[0301] 12.Losonczy H,David M,Nagy I.Effect of pentosan polysulfate onactivated partialthromboplastin time,thrombin time,euglobulin clot lysis andtissue-type plasminogen activatorand plasminogen activator inhibitoractivities in patients with thromboembolic disease.SeminThromb Hemost 1991;17(4):394-8.

[0302] 13.Anderson VR,Perry CM.Pentosan polysulfate:a review of its use inthe relief ofbladder pain or discomfort in interstitial cystitis.Drugs 2006;66(6):821-35.

[0303] 14.Dimitrakov J,Kroenke K,Steers WD,Berde C,Zurakowski D,Freeman MR,JacksonJL.Pharmacologic management of painful bladder syndrome / interstitialcystitis:asystematic review.Arch Intern Med 2007;167(18):1922-9.

[0304] 15.Davis EL,El Khoudary SR,Talbott EO,Davis J,Regan LR.Safety andefficacy ofthe use of intravesical and oral pentosan polysulfate sodium forinterstitial cystitis:arandomized double-blind clinical trial.J Urol 2008;179(1):177-85.

[0305] 16.WO 2008 / 144836.Sulphated xylans for treatment or prophylaxis ofrespiratorydiseases.

[0306] 17.WO 2002 / 41901.Treatment of osteoporosis.

[0307] 18.WO 2012 / 103588.Treatment of bone marrow(oedema)withpolysulfatedpolysaccharides.

[0308] 19.Davies-Tuck ML,Wluka AE,Wang Y,English DR,Giles GG,Cicuttini F.Thenaturalhistory of bone marrow lesions in community-based adults with noclinical knee osteoarthritis.Annals of the Rheumatic Diseases.2009;68(6):904-8.

[0309] 20.Felson DT,Chaisson CE,Hill CL,Totterman SM,Gale ME,Skinner KM,etal.Theassociation of bone marrow lesions with pain in kneeosteoarthritis.Annals of internal medicine.2001;134(7):541-9.

[0310] 21.Zhai G,Blizzard L,Srikanth V,Ding C,Cooley H,Cicuttini F,etal.Correlates of kneepain in older adults:Tasmanian Older Adult CohortStudy.Arthritis and rheumatism.2006;55(2):264-71.

[0311] 22.Roemer FW,Guermazi A,Javaid MK,Lynch JA,Niu J,Zhang Y,et al.Changein MRI-detected subchondral bone marrow lesions is associated with cartilageloss:the MOST Study.Alongitudinal multicentre study of kneeosteoarthritis.Ann Rheum Dis.2009;68(9):1461-5.

[0312] 23.Hunter DJ,Zhang Y,Niu J,Goggins J,Amin S,LaValley MP,etal.Increase in bonemarrow lesions associated with cartilage loss:alongitudinal magnetic resonance imaging studyof knee osteoarthritis.Arthritisand rheumatism.2006;54(5):1529-35.

[0313] 24.Wluka AE,Wang Y,Davies-Tuck M,English DR,Giles GG,CicuttiniFM.Bonemarrow lesions predict progression of cartilage defects and loss ofcartilage volume in healthymiddle-aged adults without knee pain over 2yrs.Rheumatology(Oxford,England).2008:47(9):1392-6.

[0314] 25.Wluka AE,Hanna F,Davies-Tuck M,Wang Y,Bell RJ,Davis SR,et al.Bone marrow lesions predict increase in knee cartilage defects and loss ofcartilage volume in middle-aged women without knee pain over 2 years.Ann RheumDis.2009:68(6):850-5.

[0315] 26.Starr AM,Wessely MA,Albastaki U,Pierre-Jerome C,Kettner NW.Bone marrowdema:pathophysiology,differential diagnosis,and imaging.Actaradiologica(Stockholm,Sweden:1987).2008:49(7):771-86.

[0316] 27.Altahawi FF,Blount KJ,Morley NP,Raithel E,Omar IM.Comparing anaccelerated3D fast spin-echo sequence(CS-SPACE)for knee 3-T magneticresonance imaging withtraditional 3D fast spin-echo(SPACE)and routine 2Dsequences.Skeletal radiology.2017;46(1):7-15.

[0317] 28.Felson DT,McLaughlin S,Goggins J,LaValley MP,Gale ME,Totterman S,et al.Bonemarrow edema and its relation to progression of kneeosteoarthritis.Annals of internal medicine.2003;139(5 Pt 1):330-6.

[0318] 29.Raynauld JP,Martel-Pelletier J,Berthiaume MJ,Abram F,Choquette D,Haraoui B,etal.Correlation between bone lesion changes and cartilage volumeloss in patients withosteoarthritis of the knee as assessed by quantitativemagnetic resonance imaging over a 24-month period.Ann Rheum Dis.2008;67(5):683-8.

[0319] 30.Tanamas SK,Wluka AE,Pelletier JP,Pelletier JM,Abram F,Berry PA,etal.Bonemarrow lesions in people with knee osteoarthritis predict progressionof disease and jointreplacement:a longitudinal study.Rheumatology(Oxford,England).2010;49(12):2413-9.

[0320] 31.Lowitz T,Museyko O,Bousson V,Laouisset L,Kalender WA,Laredo JD,etal.Bonemarrow lesions identified by MRI in knee osteoarthritis are associatedwith locally increasedbone mineral density measured by QCT.Osteoarthritis andcartilage.2013;21(7):957-64.

[0321] 32.Laslett LL,Dore DA,Quinn SJ,Boon P,Ryan E,Winzenberg TM,etal.Zoledronic acidreduces knee pain and bone marrow lesions over 1 year:arandomised controlled trial.AnnRheum Dis.2012;71(8):1322-8.

[0322] 33.Varenna M,Zucchi F,Failoni S,Becciolini A,Berruto M.Intravenousneridronate inthe treatment of acute painful knee osteoarthritis:a randomizedcontrolled study.Rheumatology(Oxford,England).2015;54(10):1826-32.

[0323] 34.Hjermstad MJ,Fayers PM,Haugen DF,Caraceni A,Hanks GW,Loge JH,etal.Studiescomparing Numerical Rating Scales,Verbal Rating Scales,and VisualAnalogue Scales forassessment of pain intensity in adults:a systematicliterature review.Journal of pain andsymptom management.2011;41(6):1073-93.

[0324] 35.Briggs KK,Kocher MS,Rodkey WG,Steadman JR.Reliability,validity,andresponsiveness of the Lysholm knee score and Tegner activity scale forpatients with meniscalinjury of the knee.The Journal of bone and jointsurgery American volume.2006;88(4):698-705.

[0325] 36.Roos EM,Lohmander LS.Knee injury and Osteoarthritis Outcome Score(KOOS):from joint injury to osteoarthritis.Health Qual Life Outcomes 2003;1:64.

Claims

1. A method for treating postoperative joint pain in a mammal, comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal.

2. Use of polysulfated polysaccharide or an acceptable salt thereof in treating postoperative joint pain in mammals.

3. Use of polysulfated polysaccharide or its acceptable salt in the preparation of a medicament for treating postoperative joint pain in mammals.

4. The method according to claim 1 or the use according to claim 2 or 3, wherein The postoperative joint pain is in at least one joint, and the at least one joint is selected from: one or more of an ankle joint, an elbow joint, a finger joint, a hip joint, a knee joint, a shoulder joint and a wrist joint.

5. The method or use according to claim 4, wherein The at least one joint is a knee joint.

6. The method or use according to any one of claims 1 to 5, wherein: The postoperative pain was caused by joint replacement surgery.

7. The method or use according to claim 6, wherein The joint replacement is a total joint replacement or a partial joint replacement, which is selected from: total ankle replacement, total elbow replacement, total finger replacement, total hip replacement, total knee replacement, total shoulder replacement, total wrist replacement, partial ankle replacement, partial elbow replacement, partial finger replacement, partial hip replacement, partial knee replacement, partial shoulder replacement and partial wrist replacement. One or more.

8. The method or use according to claim 7, wherein The joint replacement is total knee replacement or partial knee replacement.

9. The method or use according to any one of claims 1 to 8, wherein The postoperative joint pain is selected from one or more of: acute pain; chronic pain; general pain and persistent pain.

10. The method or use according to claim 9, wherein The persistent pain is selected from one or more of septic persistent pain, persistent pain caused by periprosthetic fracture and aseptic persistent pain.

11. A method or use as claimed in any preceding claim, wherein In addition to the post-operative joint pain, the mammal suffers from another arthritic condition, wherein the other arthritic condition is rheumatoid arthritis, osteoarthritis or degenerative osteoarthritis.

12. The method or use according to claim 11, wherein The additional arthritic condition is degenerative osteoarthritis.

13. The method or use according to claim 11 or 12, wherein The additional arthritic condition occurs in a joint other than the joint affected by the post-operative pain.

14. The method or use according to claim 13, wherein The additional joint is a knee joint, and the joint affected by the postoperative pain is another knee joint.

15. The method or use according to claim 14, wherein In human patients, the additional knee joint is the left knee joint and the joint affected by the post-operative pain is the right knee joint.

16. A method or use as claimed in any preceding claim, wherein The polysulfated polysaccharide is selected from one or more of high molecular weight heparin, low molecular weight heparin, heparan sulfate, pentosan polysulfate (PPS), chondroitin polysulfate and chitosan polysulfate.

17. The method or use according to claim 16, wherein The pentosan polysulfate (PPS) is selected from one or more of sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS) and zinc pentosan polysulfate (ZnPPS).

18. The method or use of claim 17, wherein The pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

19. A method or use as claimed in any preceding claim, wherein The treatment is by administering to the mammal the polysulfated polysaccharide or an acceptable salt thereof in an effective amount of about 0.5 to about 2 mg / kg, about 0.5 to about 1.0 mg / kg, about 1.0 to about 1.5 mg / kg or about 1.5 to about 2.0 mg / kg of the mammal per dose, or wherein the effective amount is a fixed dose in the range of about 25 mg to about 4000 mg.

20. The method or use of claim 19, wherein The effective amount is about 0.5 mg / kg, about 1.0 mg / kg, or about 2.0 mg / kg of the mammal per dose.

21. The method or use of claim 20, wherein: The effective amount is about 2.0 mg / kg of mammal per dose.

22. The method or use of claim 19, wherein: The fixed dose is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 2000 mg, about 3000 mg or about 4000 mg.

23. A method or use as claimed in any preceding claim, wherein The treatment is: administered by subcutaneous (SC), intramuscular (IM), intravenous (IV), intraarticular (IA) or periarticular injection; by topical administration; by suppository or orally.

24. The method or use of claim 23, wherein The treatment was administered by subcutaneous (SC) injection.

25. The method or use of claim 24, wherein The subcutaneous (SC) injection was a slow SC injection.

26. The method or use according to any one of claims 23 to 25, wherein: Administration to humans is by a once daily, twice weekly or three times weekly treatment regimen.

27. The method or use of claim 26, wherein It is administered to humans via a twice-weekly treatment regimen.

28. The method or use of claim 27, wherein It is administered to humans via a twice-weekly treatment regimen with a minimum of three days and a maximum of four days between doses.

29. The method or use of claim 28, wherein It is administered to humans via a twice-weekly treatment regimen for three consecutive weeks.

30. The method or use of claim 28, wherein: It is administered to humans via a twice-weekly treatment regimen for six weeks.

31. The method or use of claim 29 or 30, wherein: The total dose of polysulfated polysaccharide administered in the treatment regimen is from about 200 to about 4000 mg.

32. A method or use as claimed in any preceding claim, wherein: Pain relief in human patients was determined using the Numerical Rating Scale (NRS) described herein.

33. A method or use as claimed in any preceding claim, wherein: Improved knee function in human patients is determined by the Lysholm knee score as described herein.

34. A method or use as claimed in any preceding claim, wherein The presence of bone marrow edema lesions was reduced.

35. The method or use according to any one of claims 13 to 31, wherein: The presence of bone marrow edema lesions associated with osteoarthritis in the additional joints is reduced.

36. The method or use of claim 34 or 35, wherein The reduction in the volume of bone marrow edema lesions was assessed by magnetic resonance imaging (MRI).

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