Method of treating lower back pain with hyaluronic acid

Abstract

The present invention provides methods for treating lower back, hip, and / or sacral region pain in a subject, the methods comprising administering to the subject by one or more injections a composition comprising hyaluronic acid (HA) and a pharmaceutically acceptable carrier. The injections are made at the subject's iliac crest, posterior superior iliac spine, and / or soft tissue attachment points of the sacrum or in close proximity thereto.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 594,020, filed October 29, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Chronic lower back pain is a common problem, affecting a significant proportion of the population. Most cases of chronic lower back pain are believed to have no known cause. 1 However, specific anatomical structures (including the lumbar facet joints, intervertebral discs, and sacroiliac joints) are often considered the source of pain in individuals with specific areas of chronic lower back pain. Other sources of lower back pain include myofascial pain caused by muscles or their fascial coverings (which needs to be distinguished from tendinopathy or enthesopathy); rare spondyloarthritis (including ankylosing spondylitis and psoriatic arthritis) characterized by enthesitis (inflammation at the site where tendons / ligaments attach to bone); and compression of the superior or middle gluteal cutaneous nerve as it passes through the iliac crest, which is associated with paresthesia (a hallmark of neuropathic pain). 2-4 .

[0003] It is often difficult to treat effectively; existing treatments either work only in a limited proportion of individuals, are only moderately effective, or have considerable potential side effects (including the risk of drug addiction). Nonsteroidal anti-inflammatory drugs (NSAIDs) (including naproxen, meloxicam, celecoxib, etc.) are commonly used, but these drugs have shown only moderate effectiveness in clinical practice and controlled clinical trials. Muscle relaxants (such as baclofen, cyclobenzaline, calcipodox, etc.) may be useful in narrative cases of lower back pain, but their benefits in controlled trials are less clear. 5 Opioid analgesics are also widely used to treat chronic lower back pain, but clinical evidence is limited by short-term studies and their effectiveness is moderate. 5 Furthermore, these types of drugs carry the well-known risks of addiction and abuse. Therefore, there is a need for new methods of treating lower back pain that demonstrate therapeutic efficacy and reduce the likelihood of harmful side effects. Summary of the Invention

[0004] In one aspect, the present invention provides methods for treating lower back, hip, and / or sacral pain in a subject. These methods include administering a composition comprising a therapeutically effective amount of hyaluronic acid (HA) and a pharmaceutically acceptable carrier to the subject via one or more injections. The injection is performed at the soft tissue attachment points of the iliac crest, posterior superior iliac spine, and / or sacrum, or in an area immediately adjacent to them. The pain may be nociceptive, and these methods may further include palpating the iliac crest, posterior superior iliac spine, and / or sacrum and selecting areas of pain / tenderness for injection. Attached Figure Description

[0005] Figure 1 This is a diagram showing the location of the sacrum

[100] relative to recognized surface landmarks, and specifically marking locations on the sacrum where tenderness testing and optional hyaluronic acid injections are required, marked with an "X" to indicate these locations relative to the subject's left side. The sites for tenderness testing and optional hyaluronic acid injections are located immediately adjacent to the lateral aspect of the median sacral crest

[101] and along the lateral edge / lateral border of the sacrum

[102] . Four sites for tenderness testing and optional hyaluronic acid injections are marked at each location.

[0006] Figure 2 This is a diagram showing the origin of the gluteus maximus

[201] along the lateral edge / lateral border of the sacrum

[102] and the lateral edge / lateral border of the posterior superior iliac spine

[202] , where “X” marks the sites for palpation and optional injection. The origin of the gluteus medius

[203] along the lower border of the iliac crest

[204] (another site for palpation and hyaluronic acid injection, as shown) is also depicted. Four sites for palpation and optional hyaluronic acid injection are marked with reference to the location along the lateral edge / lateral border of the sacrum

[102] . Two sites for palpation and optional hyaluronic acid injection are marked with reference to the location along the lateral border of the posterior superior iliac spine

[202] . Four sites for palpation and optional hyaluronic acid injection are marked with reference to the location along the lower border of the iliac crest

[204] .

[0007] Figure 3 This is a diagram showing the medial and superior border of the posterior superior iliac spine

[303] and the superior border of the iliac crest

[302] , to which the thoracolumbar fascia, particularly the interwoven thoracolumbar composite

[301] , is attached. The sites marked with “X” are examined for tenderness and, optionally, injected with hyaluronic acid. Referring to the location along the medial and superior border of the posterior superior iliac spine

[303] , two sites for palpation and, optionally, hyaluronic acid injection are marked. Referring to the location along the superior border of the iliac crest

[302] , four sites for palpation and, optionally, hyaluronic acid injection are marked.

[0008] Figure 4 This is a diagram illustrating the complex basic ligamentous anatomy of the sacrum, including the posterior sacroiliac ligament

[401] and the sacrotuberous ligament

[402] . The sacral ligaments are located deep within the muscle layer, making it difficult to distinguish pain originating from tendon, aponeurosis, fascia, or ligament attachment points. Therefore, the pain treated by this invention can originate from ligaments, tendons, aponeurosis, or myofascia, or it can be caused by periostitis of the iliac crest or sacrum. Detailed Implementation

[0009] Several studies have identified the soft attachment points of the iliac crest as a potential source of chronic back pain. For example, there are reports describing (1) the treatment of “iliac crest pain syndrome” (the so-called pain source) by local anesthetic injection in approximately 40% of individuals with undifferentiated chronic lower back pain. 6-7,18 (2) "Iliolumbar syndrome", characterized by lower back pain caused by the attachment of the iliolumbar ligament to the iliac crest. 8-9 (3) Thickening of the tendon end of the erector spinae muscle in lower back pain 10 (4) In patients with persistent back pain and persistent lower back pain following lumbar spine surgery, treatment of presumed iliac crest tendinopathy by injection of local anesthetic or proliferative therapy. 11 However, no pathological studies (including biopsy evaluations) have explored the contribution of tissue damage at the soft tissue attachment points of the iliac crest or sacrum in patients with common chronic lower back or hip pain.

[0010] Hyaluronic acid (HA) is a large, naturally occurring polymer that is a major component of synovial fluid, tendons, ligaments, and the extracellular matrix, and is involved in lubricating joint movement. In addition to its lubricating properties, HA also exhibits anti-inflammatory properties, the effects of which depend on concentration and molecular weight. 12 .

[0011] HA has been approved by the FDA as an injectable treatment for knee osteoarthritis, where its therapeutic effect is believed to be primarily mediated by its lubricating properties. Furthermore, the use of HA in other types of arthritis has been extensively explored. While HA has shown some success in treating several tendon disorders, including supraspinatus tendinopathy, lateral epicondylitis, and patellar tendinopathy, there is no evidence of its efficacy in treating ligamentous tendinopathy. 13 Several attempts to use HA to treat lower back pain have been reported. 14-16 However, the results of these studies were mixed and limited to exploring the effects of HA on pain associated with: (1) the fascial plane of the thoracolumbar fascia, (2) nerve-related origins (e.g., lumbar radiculopathy), (3) degenerative disc disease, or (4) facet joint arthritis.

[0012] As demonstrated in the examples, the inventors have found that injecting HA into the soft tissue attachment points of the iliac crest, posterior superior iliac spine, and / or sacrum is effective in treating patients suffering from lower back, sacral, and / or hip pain. Therefore, the present invention provides methods for treating pain, including administering one or more HA injections.

[0013] Lower back, hip and / or sacral pain In one aspect, the present invention provides a method for treating pain in a subject who is experiencing pain in the lower back, hip, and / or sacral region. “Subject” or “patient” means any organism requiring and / or undergoing treatment, such as a farm animal, domestic animal, or human. In some embodiments, the subject is a human. As used herein, “lower back” refers to the lumbar region between the last thoracic vertebra (T12) and the first sacral vertebra (S1) and extending laterally to include the iliac crest; “sacral region” refers to the area at the base of the spine containing the sacrum; and “hip” refers to the region below the lower back, including all soft tissues and bones extending to the gluteal cleft on each side.

[0014] In one aspect, these methods involve administering to a subject a composition containing a therapeutically effective amount of HA. HA is D-glucuronic acid and N Polymers of acetyl-D-glucosamine, naturally occurring in various sizes with molecular weights ranging from 5 to 20,000 kilodaltons (kDa). The method of the present invention can use HA having any suitable molecular weight. In some embodiments, the composition comprises HA with a molecular weight of about 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, 10000, 15000, or 20000 kDa, or a molecular weight within the range defined by any of the foregoing values. In some embodiments, the HA has a molecular weight of at least 500 kDa. In some embodiments, the HA has a molecular weight of about 500 kDa to about 730 kDa, or between about 450 kDa and 800 kDa, or between 400 kDa and 1000 kDa. HA can be present in the composition at any suitable concentration. In some embodiments, HA is present in the composition at a concentration of about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, or 25 mg / mL, or at a concentration within the range defined by any of the foregoing values. In some embodiments, HA is present in the composition at a concentration of about 10 mg / mL. The concentration of HA in the composition may be between 9-11 mg / mL, between 8-12 mg / mL, or between 5-15 mg / mL.

[0015] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known in the art and include, but are not limited to, diluents (e.g., Tris-HCl, acetates, phosphates), preservatives (e.g., thimerosal, benzyl alcohol, parabens), solubilizers (e.g., glycerol, polyethylene glycol), emulsifiers, liposomes, and nanoparticles. Pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include isotonic solutions, alcohol / water solutions, emulsions, or suspensions, including saline and buffer media. The composition may further comprise additives (such as albumin or gelatin to prevent absorption onto the surface), surfactants (e.g., Tween 20, Tween 80, Pluronic F68, bile salts), antioxidants (e.g., ascorbic acid, sodium metabisulfite), fillers, or tension modifiers (e.g., lactose, mannitol). Components of the composition may be covalently attached to polymers (e.g., polyethylene glycol), complexed with metal ions, or incorporated into or added to particulate formulations of polymeric compounds (e.g., polylactic acid, polyglycolic acid, hydrogels, etc.), or incorporated into liposomes, microemulsions, micelles, monocompartmental or multicompartmental liposomes, erythrocyte smears, or protoplasts. The composition may also be formulated in lipophilic reservoirs (e.g., fatty acids, waxes, oils) for controlled or sustained release.

[0016] In some embodiments, pharmaceutically acceptable carriers comprise sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and water. HA is FDA approved and is commercially available as an injectable treatment for knee osteoarthritis in several brands with different molecular weights (including, but not limited to, Hyalgan, Synvisc™, Monovisc™, Orthovisc™, and Durolane™). Therefore, in some embodiments, these methods include administration of a commercially available formulation.

[0017] As used herein, the term "therapeutic effective amount" refers to an amount of HA sufficient to treat the pain of a subject receiving the composition. Methods for assessing pain treatment are known in the art and include, but are not limited to, assessments based on pain severity (mean and / or maximum) and duration of pain. In some embodiments, pain severity is assessed using a visual analog numeral rating scale ranging from 0 (no pain) to 10 (possibly the most severe pain). Mean and maximum pain severity may be assessed daily, weekly, or monthly. In some embodiments, administration of the HA composition reduces the patient's mean and / or maximum pain severity. In some embodiments, administration of the HA composition reduces the total number of hours a patient experiences pain per day. In some embodiments, administration of the HA composition increases the number of pain-free days per week and / or per month.

[0018] The HA composition can be administered to patients experiencing acute or chronic pain. As used herein, “chronic pain” refers to pain lasting for at least 3 months, while “acute pain” refers to sudden, transient pain that typically subsides within less than 3 months. The HA composition can be administered to patients experiencing pain of any severity. In some embodiments, the HA composition is administered to patients experiencing chronic lower back, hip, and / or sacral pain with a maximum daily pain severity of at least 7 / 10 on the Visual Analogue Scale (VAS).

[0019] In some embodiments, the pain is nociceptive pain. As used herein, “nociceptive pain” means pain caused by / arising from damage to one or more body tissues. Nociceptive pain differs from neuropathic pain caused by damage to the nervous system. In some embodiments, nociceptive pain is caused by soft tissues immediately adjacent to the iliac crest, posterior superior iliac spine, and / or sacrum. As used herein, “soft tissue” means supporting body tissues and / or connective body tissues, including muscles, tendons, ligaments, and aponeurosis. In some embodiments, the source of pain in the soft tissues is tendinopathy affecting the attachment points of ligaments, tendons, and aponeurosis in the lower back and hip area to the iliac crest, posterior superior iliac spine, and / or posterolateral region of the sacrum. The source of pain in the soft tissues may also be myofascial (originating from muscles or their fascial coverings) or may be caused by periostitis of the iliac crest or sacrum (inflammation of the periosteum surrounding the bone).

[0020] In some embodiments, the subject has lower back, hip, and / or sacral pain with one or more co-existing etiologies, such as degenerative disc disease, facet joint arthritis, sacroiliitis, osteoporotic vertebral compression fracture, lumbar radiculopathy, or spinal stenosis. A skilled technician will readily understand the available methods for correctly diagnosing these other conditions. In other embodiments, the composition is administered to a subject without any additional co-existing conditions causing the pain. These individual sources of lower back pain can be ruled out through appropriate medical history, examination, and diagnostic studies. For example, to rule out peripheral neurogenic sources of pain in these areas (such as from gluteal neuralgia or neuropathy), there should be no associated sensory abnormalities or loss of sensation.

[0021] In one aspect, the composition is administered via one or more injections. The composition can be administered via 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 injections, or via a number of injections within the range defined by any of the foregoing values. Injections can be repeated indefinitely every 4-8 weeks, or administered indefinitely as needed. In some embodiments, the composition is administered via 2-10 injections. Injections can be made using any suitable needle (including, but not limited to, a 30 ½-inch needle), and any suitable amount of HA can be delivered. In some embodiments, each injection delivers approximately 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, or 10 mL of the composition, or a volume of the composition within the range defined by any of the foregoing values. In some embodiments, each injection delivers approximately 0.5 mL to 1 mL of the composition. In some embodiments, each injection delivers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 mg of HA, or an amount of HA within the range defined by any of the foregoing values. In some embodiments, each injection delivers 5 mg or more of HA. In some embodiments, each injection delivers 5 mg to 10 mg of HA. The amount of HA delivered can be selected independently for each injection.

[0022] In some embodiments, injection is performed at or immediately adjacent to the soft tissue attachments of the iliac crest, posterior superior iliac spine, and / or sacrum of the subject. Injection may be performed within approximately ½ to 1 inch from the iliac crest, posterior superior iliac spine, and / or sacrum. Injection may be acceptable in the soft tissue at the bony attachments of tendons or ligaments immediately adjacent to the palpable location, provided the volume of injected hyaluronic acid is sufficient to diffuse to these attachments. Larger injection volumes and doses may allow injection at greater distances from these locations, but these methods do not consider injection into or immediately adjacent to distal structures such as the spinal canal, neural foramina, intervertebral discs, intrafascial planes, or facet joints. Within the designated locations and distances for injection, a thoracolumbar complex is formed, which is an interwoven layer of the fascial layers of the previously separated thoracolumbar fascia, making it impossible to inject hyaluronic acid between the fascial layers at these designated locations. 17 .

[0023] In some embodiments, the composition is administered by two or more injections spaced apart. The two or more injections may be spaced at intervals of about ¼ inch, ½ inch, ¾ inch, 1 inch, 1 ¼ inch, 1 ½ inch, 1 ¾ inch, 2 inches, 3 inches, or 4 inches, or at intervals within the range defined by any of the foregoing values. In some embodiments, the two or more injections are spaced at intervals of about ½ inch to about 1 inch.

[0024] In some embodiments, these methods further include identifying one or more injection sites for one or more injections, including palpating the iliac crest, posterior superior iliac spine, and / or sacrum. As used herein, “palpating” or “palpate” refers to a manual examination designed to assess one or more of the size, shape, hardness, location, smoothness, texture, and / or tenderness of a body part by touch / sensation. Palpating can be used to detect focal tenderness on or along one or more of the following tendon attachments (tendon ends): erector spinae, multifidus, gluteus maximus, gluteus medius, quadratus lumborum, and / or external and internal oblique muscles. Focal tenderness can be identified when a subject responds to pain by emitting a painful audible sound, withdrawing, or moving their body in response to pain evoked by forceful palpation, and can reveal pain originating from tendon attachments, ligament attachments, or periosteum.

[0025] Any suitable palpation technique can be used. For example, palpation can be performed as follows: (1) Starting along the lower sacrum, palpate the lateral edge of the sacrum from the bottom (away from the head) to the top (towards the head), with palpation sites spaced approximately 1 / 2 inch to 1 inch apart (see [link to palpation technique]). Figure 1

[102] ), (2) Palpate the area immediately adjacent to the median crest on the same side of the sacrum from bottom to top, with palpation sites spaced approximately 1 inch to 1 inch apart (see

[102] ). Figure 1

[101] ), (3) Repeat the palpation described in (1)-(2) on the contralateral side of the sacrum; (4) Palpate the medial and lateral borders of the posterior superior iliac spine on each side from bottom to top, with palpation sites spaced approximately 1 inch to 1 inch apart (see

[101] ). Figure 3

[303] Figure 2

[202] ); and (5) palpate the upper and lower borders of the posterior iliac crest on each side, down to the lateral aspect of the iliac crest or the anterior superior iliac spine, with palpation sites spaced approximately 1 inch to 1 inch apart (see

[202] ). Figure 3

[302] Figure 2

[204] ). Exemplary sites for palpation on the left side of the subject are... Figures 1-3 The iliac crests are shown in the diagram and marked with an "X" in each figure. The order in which these sites are palpated can be any suitable order. For example, palpating from the anterior superior iliac spine down to the lower sacrum can help identify the iliac crest in obese patients.

[0026] In some embodiments, areas of focal pain and / or tenderness identified by palpation are selected as injection sites, and the HA composition is injected into the soft tissue attachment points of these sites or their immediate vicinity. Palpation may identify 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 injection sites, or the number of injection sites within any of the foregoing values. In some embodiments, one or more injections are performed at 2-10 identified injection sites in a single treatment.

[0027] The composition can be administered using any suitable dosing regimen. For example, the composition can be administered once daily, or once every 1, 2, 4, 6, 8, 10, 12, 24, or 36 weeks, or once within any of the foregoing values. In some embodiments, the composition is administered once weekly. In other embodiments, the composition is administered once every 4 to 8 weeks. In still other embodiments, the composition is administered once weekly during the initial treatment period, and once every 4 to 8 weeks after the initial treatment period. In some embodiments, the initial treatment period comprises two separate injection cycles spaced one week apart. The palpation method described herein can be repeated before each administration to identify the injection site.

[0028] This disclosure is not limited to the specific details of the construction, component arrangement, or method steps set forth herein. The compositions and methods disclosed herein can be prepared, practiced, used, performed, and / or formed in a variety of ways that are obvious to those skilled in the art based on the following disclosure. The wording and terminology used herein are for descriptive purposes only and should not be construed as limiting the scope of the claims. As used in the specification and claims, sequence indicators (such as first, second, and third) refer to various structures or method steps and are not intended to indicate any particular structure or step, or any particular order or configuration of such structures or steps. Unless otherwise indicated herein or otherwise clearly contradicted by the context, all methods described herein can be performed in any suitable order. Unless otherwise claimed, the use of any and all instances or exemplary language (e.g., “such”) provided herein is intended only to benefit this disclosure and does not imply any limitation on the scope of this disclosure. No language in the specification or any structure shown in the drawings should be construed as indicating that any unclaimed element is essential for the practice of the disclosed subject matter. The terms “comprising,” “including,” or “having,” as used herein, and variations thereof, are intended to cover the elements listed thereafter and their equivalents, as well as additional elements. Embodiments described as “comprising,” “including,” or “having” specific elements are also considered to “consist substantially of those specific elements” and “comprise those specific elements.”

[0029] Unless otherwise stated herein, the description of ranges of values ​​herein is intended only as a shorthand for individually referring to each individual value falling within that range, and each individual value is incorporated into the specification as if it were described individually herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values ​​such as 2% to 40%, 10% to 30%, or 1% to 3% be explicitly enumerated in this specification. These are merely examples of the specific intended content, and all possible combinations of values ​​between and including the enumerated minimum and maximum values ​​are considered to be explicitly stated in this disclosure. The use of the word “about” to describe a particular stated quantity or range of a quantity is intended to indicate that values ​​very close to the stated quantity are included in that quantity, such as values ​​that might or would naturally be considered due to manufacturing tolerances, instrument errors, and human errors in the measurement. Unless otherwise stated, all percentages of quantities are by weight.

[0030] No reference (including any non-patent or patent documents cited in this specification) is acknowledged to constitute prior art. In particular, it should be understood that, unless otherwise stated, citation of any document herein does not imply an admission that any of such documents constitutes part of common general knowledge in the art in the U.S. or any other country. Any discussion of references represents the claims of their authors, and the applicant reserves the right to question the accuracy and relevance of any document cited herein. Unless otherwise expressly stated, all references cited herein are incorporated by way of full reference. In the event of any discrepancies between any definitions and / or descriptions found in the cited references, this disclosure shall prevail.

[0031] The following examples are intended to be illustrative only and are not intended to limit the scope of the invention or the appended claims.

[0032] Example The following examples demonstrate that injecting HA into the soft tissue attachments of the iliac crest, posterior superior iliac spine, and / or sacrum, or their immediate vicinity, can be effective in treating patients with lower back, sacral, and / or hip pain. In these examples, unless otherwise specified, a visual analogue number scale ranging from 0 (no pain) to 10 (potentially most severe pain) was used to assess pain severity, and hyaluronic acid (HA) injection solution (Hyalgan TM ; 10 mg / mL, MW: 500,000 to 730,000 Daltons, 2 mL pre-filled syringe) Administered using a 30 1 / 2-inch needle.

[0033] Example 1 In July 2023, a 51-year-old female patient reported stabbing pain in both feet accompanied by sacral pain radiating to both buttocks and down to her right thigh. The pain had been persistent since 2020 (significantly worsening in the months prior to presentation), worsening when sitting or standing and relieved when lying down. The patient had previously undergone vertebroplasty in 2017 for an L1 compression fracture, after which the pain had subsided. Physical examination revealed focal tenderness along the iliac crest (significantly along both posterior superior iliac spines). Pain recurred in her sacral region upon pressure on the anterior iliac bone while supine.

[0034] Prior to her initial visit, her lumbar MRI showed (1) degenerative changes in the lumbar spine, with the worst condition at L5-S1, where there was similar mild lateral recess stenosis that could contact the descending S1 nerve root, but without significant spinal canal or foramen stenosis; (2) no significant spinal canal or foramen stenosis at other levels; and (4) chronic superior endplate compression deformity of the L1 vertebral body, suggesting a previous vertebroplasty.

[0035] The patient was prescribed Norco for persistent back pain and had been receiving epidural steroid injections since 2020 without benefit. Previous EMG (electromyography) and NCS (neural conduction studies) showed mild axonal sensorimotor polyneuropathy, but no evidence of lumbar or sacral motor radiculopathy.

[0036] A pelvic CT scan performed between the two visits showed (1) no acute pelvic protrusion, (2) spondylolisthesis with grade I posterior slippage of L5 relative to S1, and (3) mild to moderate facet joint disease. Nuclear medicine skeletal examination showed changes consistent with an L1 compression fracture, but no other significant abnormalities.

[0037] On September 21, 2023, the patient reported recurrent lower back pain, typically of severity 7 / 10 (severe to very severe). Palpation revealed focal tenderness along her bilateral posterior superior iliac spines. For the reported back / sacral pain, a total of 4 mL (40 mg) of HA was administered as follows: 1 mL along the lower part of her left PSIS, 1 mL along the upper part of her left PSIS, and 1 mL each along the lower and upper parts of her right PSIS.

[0038] On September 28, 2023, the patient reported a significant improvement in pain severity, with pain levels now typically around 3 / 10 (mild to moderate) when walking. The second round of HA injections was administered to the soft tissues of the lower back as follows: 1 mL along the lower portion of the right PSIS; 1 mL along the upper portion of the right PSIS; 2 mL along the posteromedial aspect of the right iliac crest, just lateral to the PSIS; 1 mL along the lower portion of the left PSIS; 1 mL along the upper portion of the left PSIS; and 2 mL along the posteromedial aspect of the left iliac crest, just lateral to the left PSIS. A total of 8 mL (80 mg) of HA was injected.

[0039] On October 24, 2023, the patient reported that her lower back pain had largely disappeared while walking, but she still experienced mild pain when lying down and extending her hips forward.

[0040] On November 30, 2023, the patient reported a gradual improvement in lower back pain, reaching a severity of 6 / 10 (mean) and 9 / 10 (maximum) on the right side and 6 / 10 (mean and maximum) on the left side. Palpation was used to determine the location of the right PSIS and to identify focal tenderness along the medial and lateral borders of the right PSIS. 4 mL (40 mg) of HA was injected near the right PSIS as follows: 1 mL was injected into the soft tissue immediately adjacent to the inferior medial border of the PSIS, and 1 mL was injected approximately 1 inch above the superior medial border of the PSIS; 1 mL was injected into the soft tissue immediately adjacent to the inferior lateral border of the right PSIS, and 1 mL was injected approximately 1 inch above the superior lateral border of the PSIS. Proceeding approximately 2 to 3 inches laterally along the posterior iliac crest from the previous injection site, inject 2 mL (20 mg) of HA into the fibrous bone attachment points of the lateral erector spinae or quadratus lumborum muscles to the iliac crest as follows: 1 mL into the soft tissue immediately adjacent to the superior border of the iliac crest, and 1 mL approximately 1 inch lateral to the superior border of the iliac crest. Inject 2 mL (20 mg) of HA into the fibrous bone attachment points of the gluteus maximus and / or gluteus medius muscles to the inferior border of the iliac crest: 1 mL at each of the two injection sites at the inferior border of the iliac crest (the same lateral locations as the injection along the superior border).

[0041] On January 4, 2024, the patient reported a pain-free period of 3-4 weeks after the previous injection, similar to the pain-free period after the first two injection cycles (September 21, 2023 and September 28, 2023). However, the lower back pain recurred during the visit, with an average severity of 2 / 10 (mild) and a maximum severity of 4 / 10 (moderate).

[0042] Example 2 On October 5, 2023, a 55-year-old female patient reported chronic bilateral lower back pain, recently developing foot pain that slowly radiated down the calves but was primarily located on the plantar surface of the foot. The lower back pain severity was 7 / 10 (between severe and very severe) at rest and as high as 9 / 10 (between very severe and potentially more severe) after a full day of standing. The patient had intact lower extremity strength and bilateral focal tenderness along the posterior superior iliac spine, extending several inches laterally from the posterior superior iliac spine along the posterior iliac crest.

[0043] An MRI performed on October 10, 2023, showed: a slight wedge-shaped change in L1, which appeared to be chronic; 2 mm posterior slippage of L2 and L3 with 2 mm disc bulging; 1 mm posterior slippage of L3 relative to L4 with 1.5 mm disc bulging; 4 mm anterior slippage of L4 relative to L5; facet joint disease, which contributed to mild left foraminal stenosis; mild multifactorial spinal stenosis, including 4 mm anterior slippage of L5 relative to S1; and mild left foraminal stenosis (greater than right foraminal stenosis).

[0044] On October 5, 2023, after signing an informed consent form, she was treated with hyaluronic acid (HA) injections for her chronic lower back pain as follows: four injections (0.5 mL each) along the left sacral attachment point of the erector spinae muscle; four injections (0.5 mL each) along the right sacral attachment point of the erector spinae muscle; four injections (two each above and below the posterior superior iliac spine [PSIS]), mainly along the medial side of the PSIS (0.5 mL each); and four injections (two each above and below the PSIS), mainly along the medial side of the PSIS (0.5 mL each) along the right posteromedial iliac crest. The injection sites are as follows. Figure 1 The result of focal tenderness at the palpation site shown is determined.

[0045] On October 12, 2023, the patient reported a maximum lower back pain severity of 5-6 / 10 (severe). HA was repeatedly injected into her lower back as follows: four injections (0.5 mL each) along the left sacral attachment of the erector spinae muscle; four injections (0.5 mL each) along the right sacral attachment of the erector spinae muscle; two injections along the left posteromedial iliac crest along the PSIS (one above and one below the PSIS) (1 mL each); and two injections along the right posteromedial iliac crest along the PSIS (one above and one below the PSIS) (1 mL each). These injection sites were also as described above. Figure 1 The result of focal tenderness at the palpation site shown is determined.

[0046] On November 9, 2023, the patient reported an average lower back pain of 2-3 / 10 (mild to moderate) for most of the day, but in the preceding days, the severity of the pain had increased to about 7 / 10 (severe to very severe) as her shift was nearing its end.

[0047] On December 7, 2023, the patient reported that lower back pain had been relatively stable since the last visit, with a typical severity of 2-3 / 10 in the morning / afternoon, reaching 6-7 / 10 towards the end of the evening shift. Prior to the first HA injection, the pain would begin at 5-6 / 10 in the morning (moderate to severe) and gradually worsen throughout the day.

[0048] On January 8, 2024, the patient reported a recurrence of pain starting during the Christmas week, typically with a severity level of 3 / 10 in the morning, 5 / 10 at the start of work, 7 / 10 at noon, and 8-9 / 10 at the end of work and in the evening. HA injection was administered as follows: two injections (1 mL each) along the upper medial aspect of the left PSIS; two injections (1 mL each) along the lower lateral aspect of the left PSIS; two injections (1 mL each) along the upper medial aspect of the right PSIS; and two injections (1 mL each) along the lower lateral aspect of the right PSIS. These injection sites were also as described above. Figure 1The result of focal tenderness at the palpation site shown is determined.

[0049] Starting October 2, 2023, the patient received treatment for peripheral neuropathy, with bilateral application of lidocaine / prilocaine 2.5% cream to both feet. This topical treatment was ineffective. It wasn't until November 9, 2023, after confirming the effectiveness of HA injections for back pain, that pregabalin at a dose of 75 mg (twice daily) was prescribed. This helped with foot pain but did not prevent the recurrence of lower back pain reported on January 8, 2024.

[0050] On February 6, 2024, the patient reported significant improvement in lower back pain following a previous HA injection, with pain severity ranging from approximately 2 / 10 at the start of the morning, 5 / 10 at noon, and 7 / 10 towards the end of the day and in the evening.

[0051] On March 5, 2024, the patient reported a recurrence of lower back pain, which had been exacerbated by a recent fall. HA injection was administered as follows: two injections (1 mL each) along the upper medial aspect of the left PSIS; two injections (1 mL each) along the lower lateral aspect of the left PSIS; two injections (1 mL each) along the upper medial aspect of the right PSIS; and two injections (1 mL each) along the lower lateral aspect of the right PSIS. These injection sites were as follows. Figure 1 The result of focal tenderness at the palpation site shown is determined.

[0052] On May 7, 2024, the patient reported no recurrence of lower back pain, with the current severity being approximately 2 / 10 in the morning and for most of the day. No further injections were administered, and by August 15, 2024, the pain remained mild, with an average severity of 2 / 10 for most of the day and evening.

[0053] Example 3 On October 17, 2023, a 59-year-old female patient reported chronic lower back pain in the bilateral lower lumbar region, with no pain in the hip, thigh, leg, or foot. The back pain began approximately 10 years prior and gradually worsened over time, currently reaching a maximum daily severity of 7 / 10 (severe to very severe). Examination revealed focal tenderness along her bilateral posterior iliac crests, extending more medially to the left iliac crest. An MRI of her lumbar spine performed on April 13, 2023, showed mild lumbar spondylosis, no high-grade spinal stenosis, and mild foraminal stenosis at L4-5.

[0054] The patient reported that previous chiropractic treatments exacerbated her pain, and previous treatments with NSAIDs, muscle relaxants, and Norco (hydrocodone / acetaminophen combination) provided no benefit, while continued treatment with tramadol and cyclobenzaprine offered only slight relief. She had previously tried NSAIDs, muscle relaxants, and Norco (hydrocodone / acetaminophen combination) without success.

[0055] In early 2023, an interventional pain management specialist reported the following findings: tenderness in the left and right lumbar gluteal regions, no tenderness in the left or right greater trochanter, tenderness in the left and right sacroiliac joints, positive Faber tests on both sides, and a left straight leg raise radiating to the left and a right straight leg raise radiating to the right. Further comments on the physical examination included positive facet joint provocation tests on the lumbar spine and tenderness above the sacroiliac joints. The patient was treated with interventional pain management involving medial branch blocks at L4, L5, and bilateral sacral alae guided by fluoroscopy, but did not benefit from these injections. Subsequently, the patient was treated with lumbar epidural steroid injections at the L5-S1 intervertebral space guided by fluoroscopy, with only two days of relief reported after this treatment. The patient refused further lumbar epidural steroid injections.

[0056] On October 17, 2023, the patient was diagnosed with lower back pain with tendinopathy and was given hyaluronic acid (HA) injections as follows: two injections along the left posterior iliac crest (1 mL each at two sites); two injections along the left posteromedial iliac crest (PSIS; 1 mL each at two sites); and four injections along the right posterior iliac crest (1 mL each at four sites). These injection sites were determined as follows: Figure 1 The result of focal tenderness at the palpation site shown is determined.

[0057] On October 24, 2023, the patient reported a reduction in pain, with the maximum daily severity score in the previous days ranging from 4 to 6 out of 10. On October 26, 2023, the patient reported a maximum pain severity score of 0 to 1 out of 10 during the most severe period of the past 24 hours. HA injection was administered as follows: 8 injections (0.5 mL each) along the left posterior iliac crest, with 4 sites along the upper margin and 4 sites along the lower margin extending to the PSIS; and 8 injections (0.5 mL each) along the right posterior iliac crest, with 4 sites along the upper margin and 4 sites along the lower margin extending to the PSIS.

[0058] On November 27, 2023, the patient reported a pain-free period of approximately one week following a previous HA injection. Although pain has begun to recur (with a maximum severity of 5-6 / 10 over several hours each day), the patient is pain-free for most of the day. The patient reported similar symptoms on January 2, 2024. In contrast, the pain was persistent prior to the HA injection.

[0059] On January 15, 2024, the patient reported a gradual recurrence of pain over the past 7 days, with a severity of 5-6 / 10 for most of the day and a maximum severity of 8-9 / 10. HA injections were administered using palpation instructions as follows: 8 injections (0.4 mL each) along the posterior iliac crest, with 4 sites along the superior margin and 4 sites along the inferior margin extending to the PSIS; and 8 injections (0.5 mL each) along the right posterior iliac crest, with these sites along the superior and inferior margins extending to the PSIS.

[0060] On March 15, 2024, the patient reported that the back pain had improved from persistent to pain-free for most of the day, but still present with pain lasting for several hours each day. HA injections were administered as follows: eight injections (0.5 mL each) along the left posterior iliac crest, four along the upper edge and four along the lower edge – extending to the PSIS; and eight injections (0.5 mL each) along the right posterior iliac crest, four along the upper edge and four along the lower edge – extending to the PSIS.

[0061] On May 15, 2024, the patient reported overall improvement following the previous injections, with back pain lasting only about an hour and a half a day and no pain for many days. Over the past few days, the severity of lower back pain has begun to increase, but it remains much less intense than before HA treatment. On May 21, 2024, HA injections were administered as follows: eight injections (0.5 mL each) along the left posterior iliac crest, four along the upper edge and four along the lower edge – extending to the PSIS; and eight injections (0.5 mL each) along the right posterior iliac crest, four along the upper edge and four along the lower edge – extending to the PSIS.

[0062] Example 4 A 47-year-old male reported chronic lower back pain that had persisted for the past year following a fall. Lumbar spine X-rays and MRI showed no signs of fracture. The pain was localized to his left lower back (in a focal area along the upper border of his gluteus maximus muscle). In the months prior to the appointment, the average daily pain level was 7 / 10, reaching a maximum severity of approximately 9 / 10. The patient had not experienced any leg pain or tingling, and previous treatment with cyclobenzaprine and ibuprofen had not been beneficial. Examination revealed focal, significant tenderness at the gluteus maximus attachment along the lateral border of his left posterior superior iliac spine (PSIS). Hyaluronic acid injection in hyalgan form (20 mg / ml) was administered along the lateral border of the left PSIS (two injections; 1 mL each). At a reassessment eleven days later, the patient reported an average pain severity of 2 / 10 or lower, with a maximum severity of 2 / 10 (including work and exercise). Examination revealed only mild tenderness along the lateral border of his left PSIS (at the gluteus maximus attachment). During this visit, he received the following follow-up injections: two more injections (1 mL each) along the lateral edge of his left PSIS. Thirty days later, he underwent a reassessment and reported that his pain was well controlled, except for a few days of moderate pain due to a work-related back strain, with an average pain severity of 1-2 / 10.

[0063] Example 5 (Pre-example) A 64-year-old male patient reported focal pain in the hip and sacral region, without radiating to the lower leg, which had persisted since a motor vehicle accident more than three months prior. On examination, his lower extremity strength and reflexes were intact. Palpation of his left greater trochanter or iliac crest revealed no tenderness, but focal tenderness was present along the left lateral border of his sacrum. His hip X-ray was within the normal range, with no evidence of hip arthritis, sacroiliitis, or other pathological changes identifiable by X-ray. Significant tenderness was present on palpation along the left lateral border of his sacrum. Hyaluronic acid was administered to him at a concentration of 10 mg / ml, in 0.5 mL doses, at four separate sites along the lateral border of his sacrum. This procedure was repeated one week later, and significant pain improvement was observed within two months.

[0064] References 1. Hartvigsen et al., What low back pain is and why we need to pay attention , Lancet 2018 Jun 9; 391(10137):2356-2367. 2. Karl HW et al., S Superior and middle cluneal nerve entrapment: a cause of low back and radicular pain, Pain Physician 2022; 25:E503-521. 3.Morimote et al., Surgical treatment of superior cluneal nerve entrapment neuropathy , Journal of Neurosurgery Spine 2013; 19:71-75. 4.Hansson P. Neuropathic pain: clinical characteristics and diagnostic workup , European Journal of Pain, 2002; 6 Supplement A:47-50. 5. Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline 6.Collee G. et al., Iliac crest pain syndrome in low back pain: frequency and features , Journal of Rheumatology 1991; 18(7): 1064-7. 7.Njoo K. et al., Interobserver agreement on the iliac crest pain syndrome in general practice , Journal of Rheumatology 1995; 22(8): 1532-5;Collee G. et al., Iliac crest pain syndrome in low back pain. A double blind, randomized study of local injection therapy , Journal of Rheumatology 1991; 18(7): 1060-3. 8.Naim F. et al., Treatment of the chronic iliolumbar syndrome by infiltration of the iliolumbar ligament , Western Journal of Medicine 1982;136(4): 372-4. 9.Nayak B. et al., Recovering from nonspecific low back pain despair: Ultrasound-guided intervention in iliolumbar syndrome , The Indian journal ofradiology&imaging 2020; 30(4): 448-52). 10.Liu I. et al., Ultrasonographic diagnosis and guided treatment of erector spinae aponeurosis enthesopathy , Medical ultrasonography 2022; 24(1):120-21. 11.Wilkinson H, 用于引起轴向脊柱疼痛的附着点病和“失败的背部综合征”的注射疗法:一项单盲、随机和交叉研究 用于引起轴向脊柱疼痛的附着点病和“失败的背部综合征”的注射疗法:一项单盲、随机和交叉研究 交叉研究 Pain Physician 2005; 8: 167-173 12.Neumann et al., 高分子量透明质酸抑制晚期糖基化终产物诱导的NF-κB激活和细胞因子 表达 FEBS Letters 1 999; 453:283-87. 13.Agostini F et al., 透明质酸注射对肌腱病患者疼痛和功能的影响:一项叙述性综述 透明质酸注射对肌腱病患者疼痛和功能的影响:一项叙述性综述 ,Journal of Back and Musculoskeletal Rehabilitation, 2022; 35:949-961. 14. Nesporova K. et al., 在胸腰筋膜中注射透明质酸:一项模型研究 在胸腰筋膜中注射透明质酸:一项模型研究 , International Journal of Biological Macromolecules,2023; 253(Pt 3): 126879. 15. Campa JA, 交联透明质酸用于治疗神经性盆腔疼痛,实用疼痛管理 交联透明质酸用于治疗神经性盆腔疼痛,实用疼痛管理 , 2018; 18(5) 16. Amirdelfan K. et al., 同种异体间充质前体细胞 治疗与退行性椎间盘疾病相关的慢性下腰痛:一项前瞻性随机、安慰剂对照的36个月安全性和有效性研究 治疗与退行性椎间盘疾病相关的慢性下腰痛:一项前瞻性随机、安慰剂对照的36个月安全性和有效性研究 安全性和有效性 , The Spine Journal, 2021; 21(2): 212-230. 17. Willard FH et al., 胸腰筋膜:解剖学、功能和临床考虑因素 胸腰筋膜:解剖学、功能和临床考虑因素 , J Anat. 2012 Dec;221(6):507-36). 18.Collee G. et al., 下腰痛中的髂嵴疼痛综合征。局部注射疗法的双盲、随机研究 下腰痛中的髂嵴疼痛综合征。局部注射疗法的双盲、随机研究 , Journal of Rheumatology 1991; 18(7): 1060-3. Example 1. A method for treating pain in a subject, the method comprising administering to the subject a composition comprising (a) a therapeutically effective amount of hyaluronic acid and (b) a pharmaceutically acceptable carrier, wherein the subject is experiencing pain in the lower back, hip, and / or sacral region, and wherein the composition is administered by one or more injections.

[0065] 2. The method as described in Example 1, wherein the pain is nociceptive pain.

[0066] 3. The method as described in Example 1 or 2, wherein the one or more injections are performed at the soft tissue attachment points of the iliac crest, posterior superior iliac spine and / or sacrum of the subject or in their immediate vicinity.

[0067] 4. The method as described in any one of Examples 1-3, wherein the one or more injections are performed at a soft tissue attachment point approximately 1 inch to 1 inch from the iliac crest, posterior superior iliac spine and / or sacrum.

[0068] 5. The method of any one of Examples 1-4, wherein the composition is administered by two or more injections along the iliac crest, posterior superior iliac spine and / or sacrum of the subject, and wherein the two or more injections are spaced apart at intervals of about ¼ inch to about 4 inches.

[0069] 6. The method as described in Example 5, wherein the two or more injections are spaced apart by an interval of about 1 inch to about 1 inch.

[0070] 7. The method of any one of Examples 1-6, further comprising identifying one or more injection sites for the one or more injections, wherein the identification comprises palpating the iliac crest, posterior superior iliac spine and / or sacrum and selecting areas that are painful or tender upon palpation for injection.

[0071] 8. The method as described in Example 6 or 7, wherein the single or multiple injections are performed at 2-30 injection sites.

[0072] 9. The method as described in Example 8, wherein the single or multiple injections are performed at 2-10 injection sites.

[0073] 10. The method as described in any one of Examples 1-9, wherein the hyaluronic acid has a molecular weight of at least 500 kilodaltons (kDa).

[0074] 11. The method as described in Example 10, wherein the hyaluronic acid has a molecular weight of about 500 kDa to about 730 kDa.

[0075] 12. The method as described in any one of Examples 1-11, wherein the hyaluronic acid is present in the composition at a concentration of 5 mg / mL to 20 mg / mL.

[0076] 13. The method as described in Example 12, wherein the hyaluronic acid is present in the composition at a concentration of about 10 mg / mL.

[0077] 14. The method as described in any one of Examples 1-13, wherein each injection in the single or multiple injections delivers 5 mg or more of the hyaluronic acid.

[0078] 15. The method as described in Example 14, wherein each injection in the single or multiple injections delivers 5 mg to 10 mg of the hyaluronic acid.

[0079] 16. The method as described in any one of Examples 1-15, wherein the composition is applied once a week.

[0080] 17. The method as described in any one of Examples 1-15, wherein the composition is applied once every four to eight weeks.

[0081] 18. The method of any one of Examples 1-15, wherein the composition is (a) applied weekly during the initial treatment period and (b) applied every four to eight weeks after the completion of the initial treatment period.

[0082] 19. The method as described in Example 18, wherein the initial treatment period comprises two separate injection sessions, which are approximately one week apart.

[0083] 20. The method as described in any one of Examples 1-19, wherein the one or more injections are performed in the manner described in Examples 1-19. Figures 1 - 3 Performed at one or more of the locations shown

[101] ,

[102] ,

[202] ,

[204] ,

[302] , and / or

[303] .

Claims

1. A method for treating pain in a subject, the method comprising administering to the subject a composition comprising (a) a therapeutically effective amount of hyaluronic acid and (b) a pharmaceutically acceptable carrier, wherein the subject is experiencing pain in the lower back, hip, and / or sacral region, and wherein the composition is administered by one or more injections at the soft tissue attachment points of the subject's iliac crest, posterior superior iliac spine, and / or sacrum, or in areas immediately adjacent to them.

2. The method of claim 1, wherein the pain is nociceptive pain.

3. The method of claim 1, wherein the one or more injections are performed at a soft tissue attachment point approximately 1 inch to 1 inch from the iliac crest, posterior superior iliac spine, and / or sacrum.

4. The method of claim 1, wherein the composition is administered by two or more injections along the iliac crest, posterior superior iliac spine and / or sacrum of the subject, and wherein the two or more injections are spaced apart at intervals of about ¼ inch to about 4 inches.

5. The method of claim 4, wherein the two or more injections are spaced apart at intervals of about ½ inch to about 1 inch.

6. The method of claim 1, further comprising identifying one or more injection sites for the single or multiple injections, wherein the identification includes palpating the iliac crest, posterior superior iliac spine, and / or sacrum and selecting areas that are painful or tender upon palpation for injection.

7. The method of claim 6, wherein the single or multiple injections are performed at 2-30 injection sites.

8. The method of claim 7, wherein the single or multiple injections are performed at 2-10 injection sites.

9. The method of claim 1, wherein the hyaluronic acid has a molecular weight of at least 500 kilodaltons (kDa).

10. The method of claim 9, wherein the hyaluronic acid has a molecular weight of 500 kDa to 730 kDa.

11. The method of claim 1, wherein the hyaluronic acid is present in the composition at a concentration of 5 mg / mL to 20 mg / mL.

12. The method of claim 11, wherein the hyaluronic acid is present in the composition at a concentration of about 10 mg / mL.

13. The method of claim 1, wherein each injection in the single or multiple injections delivers 5 mg or more of the hyaluronic acid.

14. The method of claim 13, wherein each injection in the single or multiple injections delivers 5 mg to 10 mg of the hyaluronic acid.

15. The method of claim 1, wherein the composition is applied once a week.

16. The method of claim 1, wherein the composition is applied once every four to eight weeks.

17. The method of claim 1, wherein the composition is (a) applied weekly during the initial treatment period and (b) applied every four to eight weeks after the completion of the initial treatment period.

18. The method of claim 17, wherein the initial treatment period comprises two separate injection sessions, which are spaced approximately one week apart.

19. The method of claim 1, wherein the one or more injections are performed at one or more sites at positions [101], [102], [202], [204], [302], and / or [303] as shown in Figures 1-3.

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