Methods of treating spinal or paraspinal pain with hyaluronic acid

Abstract

The present invention provides methods of treating spinal and / or paraspinal pain in a subject, 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 into soft tissue of the spinal and / or paraspinal region. The pain may be cervical, lumbar, and / or thoracic.

Description

[0001] METHODS OF TREATING SPINAL OR PARASPINAL PAIN WITH HYALURONIC ACID

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to US Provisional Application No. 63 / 630,414, filed February 2, 2024, the contents of which are herein incorporated by reference in its entirety.

[0004] FIELD

[0005] This invention relates to the therapeutic treatment of neck or back pain. In particular, this invention relates to methods of treating or preventing spinal and / or paraspinal pain with hyaluronic acid injections.

[0006] BACKGROUND

[0007] Chronic neck pain or back pain frequently manifest in the spinal or paraspinal region. Pain in this location is often nonspecific in origin, and refractory to currently available treatments, causing a significant degree of disability. Current treatments with limited benefits for chronic nonspecific neck or back pain include physical therapy, muscle relaxants, non-steroidal antiinflammatory medications, opioid medications, and a select fraction of patients may benefit from interventional pain management procedures such as radiofrequency neurotomy. More effective treatments, with fewer side effects or complications, useful for a wider population of patients, are desperately needed.

[0008] SUMMARY

[0009] In an aspect, the present invention provides methods of treating spinal and / or paraspinal pain in a subject. The methods comprise administering to the subject, by one or more injections, a composition comprising hyaluronic acid (HA) and a pharmaceutically acceptable carrier. The injections are made into soft tissue of the spinal and / or paraspinal region. The injections may be made between adjacent spinal processes, along a lateral aspect of a vertebral spinous process, posterior to a vertebral lamina, posterior to a transverse process, and / or into the paraspinal musculature lateral to the spinal vertebrae.

[0010] The pain may be present in the cervical spinal and / or paraspinal region, the lumbar spinal and / or paraspinal region, or the thoracic spinal and / or paraspinal region, and the methods may further comprise identifying one or more injection sites for the one or more injections, the identifying comprising (a) palpating the subject’s (i) cervical, lumbar, or thoracic interspinous ligament regions and / or (ii) cervical, lumbar, or thoracic paraspinal musculature, and (b) selecting areas of pain or tenderness on palpating for injection.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG I is a drawing illustrating the nuchal [6] and interspinous

[0010] ligaments, showing the midline ligamentous structures of the cervical spine. The interspinous ligament attaches to the superior and inferior aspects of the cervical spinous processes

[0012] (the spinous process of the C7 vertebra is depicted on the figure). Other anatomical landmarks depicted in the figure include external occipital protuberance [2], the atlas (Cl) vertebra

[0016] , the axis (C2) vertebra

[0018] , the posterior atlanto-occipital membrane [4], the ligamenta flava [8], the supraspinous ligament

[0014] , the atlas (Cl) vertebra

[0016] , the axis (C2) veterbra

[0018] , a vertebral transverse process

[0020] , the articular capsules of zygapophy seal joints

[0022] , and the anterior longitudinal ligament

[0024] , In embodiments, injections of hyaluronic acid are made into the region of the interspinous ligament. Sites marked with an “X” are palpated and optionally injected. Seven sites for palpation and optional hyaluronic acid injection are marked.

[0013] FIG. 2 is a drawing illustrating deep muscles of the posterior cervical spine, including the rotatores brevis

[0028] and longus

[0026] , which originate on the transverse processes

[0020] and attach on the vertebral lamina, the multifidus

[0030] , which originate on the transverse processes and insert on the cervical spinous processes

[0012] , and the semispinalis cervicis

[0034] , which is superficial to the multifidus, originates on the transverse processes, and inserts on the spinous processes. Injections of hyaluronic acid are made into the interspinous region or along the lateral margins of the spinous processes, delivering hyaluronic acid into or immediately adjacent to these muscles and / or their vertebral attachments.

[0014] FIG. 3 is a drawing illustrating the origin of the splenius capitis

[0036] muscle from the posterior and lateral margins of the cervical spinous processes. This muscle is superficial to the rotatores, multifidus, and semispinalis cervicis, and its vertebral attachments may be injected directly or injections made in their immediate vicinity.

[0015] FIG. 4 is a drawing illustrating example sites of injection along the lateral margin of the cervical spinous processes. The figure shows a cross section through one of the cervical vertebrae and its surrounding musculature. As can be seen from the illustration, injections along the lateral margin of the cervical spinous processes may be made into the multifidus

[0030] , semispinalis cervicis

[0050] , splenius capitis

[0036] , or their respective vertebral attachments (shown on the right side of the subject). Sites marked with an “X” are palpated and optionally injected with hyaluronic acid. Four sites for palpation and optional hyaluronic acid injection are marked. In addition, more lateral musculature, including the levator scapulae

[0046] , posterior scalene

[0042] , middle scalene

[0040] , splenius cervicis

[0048] , and longissimus capitis

[0044] (shown on the left of the subject), and trapezius

[0052] (shown on the right of the subject), may suitably be injected.

[0016] FIG. 5 is a drawing illustrating a posterior view of the course of the vertebral artery

[0054] in the cervical spine. Other anatomical landmarks depicted in the figure include the the atlas (Cl) vertebra

[0016] , the axis (C2) vertebra

[0018] , and the C3 vertebra

[0056] , Injections of hyaluronic acid are preferably made between or along the cervical spinous processes, and along the most medial aspect of the vertebral lamina, with great caution being made to avoid injecting anywhere near the vertebral artery, which is positioned more laterally.

[0017] FIG. 6 is a drawing illustrating a lateral view of the lumbar spine. The figure shows the lumbar vertebrae and associated spinous processes

[0060] , as well as the lumbar interspinous ligament

[0064] , which attaches to the superior and inferior margins of the lumbar spinous processes, and lumbar supraspinous ligament

[0066] , Other anatomical landmarks depicted in the figure include the body of the LI vertebra

[0068] , the anterior longitudinal ligament

[0024] , and intervertebral discs

[0070] , Sites marked with an “X” are palpated and optionally injected. Five sites for palpation and optional hyaluronic acid injection are marked.

[0018] FIG. 7 is a drawing illustrating the lumbar multifidus muscle

[0030] on the left, which runs deep to the muscles illustrated on the right, and which inserts on the inferior margins of the spinous processes

[0060] , The aponeurotic / fascial extensions of the erector spinae group of muscles, including the longissimus dorsi

[0076] and iliocostalis lumborum

[0078] , also attach to the spinous processes via the thoracolumbar fascia. Also depicted on the left is the quadratus lumborum

[0072] , Each of these muscles or their attachments may be directly injected with hyaluronic acid or into their immediate vicinity. Sites marked with an “X” are palpated and optionally injected. Four sites for palpation and optional hyaluronic acid injection are marked.

[0019] FIG. 8 is a drawing illustrating a cross section of a lumbar vertebrae with its surrounding muscles (including the psoas

[0082] , erector spinae

[0084] , and multifidus

[0030] , shown on the right) and intervertebral disc

[0070] , Injections may optionally be made along the lateral margins of the spinous process, along the posterior lamina, or into the multifidus muscle. Sites marked with an “X” are palpated and optionally injected. Six sites for palpation and optional hyaluronic acid injection are marked.

[0020] DETAILED DESCRIPTION

[0021] Hyaluronic acid (HA) is a large, naturally occurring polymer that is a major constituent of synovial fluid, tendon, ligament and extracellular matrix and is involved in lubricating joint movements, amidst other biological functions. As used herein, “hyaluronic acid” or “HA” encompasses, HA, its conjugate base (hyaluronate), and derivatives thereof.

[0022] HA exists in a large range of molecular weights, depending on the length of the polymer. Distinct pharmacological differences are observed between lower molecular weight HA (<100 kDa) and higher molecular weight HA (>500 kDa). The anti-inflammatory effects of hyaluronic acid are more readily apparent with the higher molecular weights of hyaluronic acid. For example, Low MW HA (average MW of 230,000 Daltons) has no impact on microglial activation due to lipopolysaccharide (LPS) exposure, whereas high MW HA (average MW of 1,700,000 Daltons) inhibited microglial activation due to LPS.1Additionally, HA inhibition of NF-kB activation is dose and molecular weight dependent, with qualitative differences appearing with HA molecular weights below 500 kDa.2Further, an RT-PCR analysis of gene expression of LPS stimulated macrophages showed that at lower molecular weights of HA (-100 kDa), inflammatory gene expression increased, at 500 kDa, there were mixed anti-inflammatory and pro-inflammatory responses, and at 1,500 kDa effects were primarily anti-inflammatory.3

[0023] HA is FDA-approved as an injection treatment for osteoarthritis of the knee, where the therapeutic effect has been believed to be mediated primarily by its lubricant properties. In addition, HA has been investigated extensively for its use in other arthritic joints. While HA has been used with some degree of success in several tendinous disorders, including supraspinatus tendinosis, lateral epicondylitis, and patellar tendinopathy, no evidence has demonstrated the efficacy of HA in treating ligamentous enthesopathies.4Several attempts at using HA to treat lower back pain have been reported.5'7However, these studies have produced mixed results, and have been limited to investigating the effect of HA on pain associated with (1) the fascial planes of the thoracolumbar fascia (this has only been done in animals), (2) neuropathic origin (e.g., lumbar radiculopathy), (3) degenerative disc disease, or (4) vertebral facet joint arthritis.

[0024] As demonstrated in the Examples, the present inventor discovered that injections of higher molecular weight hyaluronic acid (>500,000 kDa) into the paraspinal muscles and / or the soft tissue attachments of the spinal vertebrae, was effective in reducing spinal / paraspinal pain. Thus, provided herein are methods of treating spinal and paraspinal pain comprising administering one or more HA injections.

[0025] In an aspect, the present invention provides methods of treating spinal and / or paraspinal pain in a subject. As used herein, the “spinal and paraspinal region” includes all the spinal vertebrae, the soft tissue attachments to the spinal vertebrae, any tendon, ligament, fascia, or aponeurosis that attaches to the spinal vertebrae, any muscle that connects to the spinal vertebrae via any tendon, fascia or aponeurosis, and the erector spinae musculature. As used herein, the spinal and paraspinal region does not include intervertebral discs. A “subject” or “patient” refers to any organism in need of and / or subjected to a treatment, such as a farm animal, domestic animal, or human. In some embodiments, the subject is a human.

[0026] In an aspect, the methods comprise administering to the subject a composition comprising a therapeutically effective amount of HA. HA is a polymer of D-glucuronic acid and A'-acetyl-D- glucosamine that occurs naturally at varied sizes, with molecular weights ranging from 5 to 20,000 kilodaltons (kDa). The present methods may use HA having any suitable molecular weight. In some embodiments, the composition comprises HA having 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 a range bounded by any of the forgoing. 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. The methods may suitably use linear HA or cross-linked HA. Suitable polymer cross-linking agents are known in the art and include, without limitation, cross-linking proteins / peptides, 1,4-Butanediol diglycidyl ether, and divinyl sulfone.

[0027] In some embodiments, the composition comprises a pharmaceutically acceptable salt of HA. As used herein, a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) 7 Pharm. Sci. 66: 1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like. In some embodiments, the composition comprises a HA sodium salt.

[0028] The HA may be present in the composition at any suitable concentration. In some embodiments, the 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 a range bounded by any of the foregoing. In some embodiments, the 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.

[0029] In an aspect, 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, acetate, phosphate), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), solubilizing agents (e.g., glycerol, polyethylene glycerol), emulsifiers, liposomes, and nanoparticles. Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of nonaqueous 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, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. The composition may further comprise additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), bulking substances or tonicity modifiers (e.g., lactose, mannitol). Components of the compositions may be covalently attached to polymers (e.g., polyethylene glycol), complexed with metal ions, or incorporated into or onto particulate preparations of polymeric compounds (e.g., polylactic acid, polyglycolic acid, hydrogels, etc.) or onto liposomes, microemulsions, micelles, unilamellar, bilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. The compositions may also be formulated in lipophilic depots (e g., fatty acids, waxes, oils) for controlled or sustained release.

[0030] In some embodiments, the pharmaceutically acceptable carrier comprises sodium chloride, monobasic sodium phosphate, dibasic sodium phosphate, and water. HA is FDA-approved and commercially available as an injection treatment for osteoarthritis of the knee in several brands of differing molecular weights (including, without limitation, Hyalgan®, Synvisc®, Monovisc®, Orthovisc®, Durolane®). Thus, in some embodiments, the methods comprise administering a commercially available formulation.

[0031] As used herein, the term “therapeutically effective amount” refers to an amount of HA sufficient to treat a disease or disorder in a subject receiving the composition. Treating spinal and / or paraspinal pain includes reducing or alleviating the duration and / or severity of pain symptoms. Treating spinal and / or paraspinal pain also includes reducing the frequency of pain symptom occurrence in the subject. Methods for assessing pain treatment are known in the art and include, without limitation, assessments based on pain severity (average and / or maximum) and pain duration. In some embodiments, pain severity is assessed using a visual analog numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible). Average and maximum pain severity may be assessed on a daily, weekly, or monthly basis. In some embodiments, the patient’s average pain severity and / or maximum pain severity is reduced following administration of the HA composition. In some embodiments, the total number of hours per day during which the patient experiences pain is reduced following administration of the HA composition. In some embodiments, the number of pain-free days per week and / or month is increased following administration of the HA composition.

[0032] The composition is administered by one or more injections. The composition may be administered by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 injections, or by a number of injections within a range bounded by any of the foregoing. In some embodiments, the composition is administered by 2-10 injections in a single treatment. The injections may be made using any suitable needle, including, without limitation, a 30 gauge, ’A” needle, and may deliver any suitable amount of HA. In some embodiments, each injection delivers about 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 a range bounded by any of the foregoing. In some embodiments, each injection delivers about 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 a range bounded by any of the foregoing. In some embodiments, each injection delivers 1 mg or more of HA. In some embodiments, each injection delivers 1 mg to 20 mg of HA. The amount of HA delivered may be independently selected for each injection. In some embodiments, the HA is administered by microneedling, which may comprise at least 10, at least 50, at least 100, at least 500, or at least 1000 injections, or any number of injections within a range bounded by any of the forgoing, and which may deliver (a) a total volume of the composition of about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, or 10 mL, or a total volume of the composition within a range bounded by any of the foregoing, and / or (b) a total amount of HA of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 mg of HA, or a total amount of HA within a range bounded by any of the foregoing.

[0033] In an aspect, the injections are made into the soft tissues of the spinal and / or paraspinal region. As used herein, “soft tissues” refer to supportive and / or connective body tissues, including, without limitation, muscles, tendons, ligaments, and aponeuroses. The injections may suitably be made into any soft tissues of the paraspinal region, or their attachments to the spinal vertebrae, including muscles, tendon, ligament, or aponeurosis and their respective entheses on the spinal vertebrae. Such injections may also affect the underlying periosteum of the spinal vertebrae. However, injections are not made into the intervertebral discs. As used herein, a “soft tissue attachment” refers to a point at which a tendon, ligament, fascia, or aponeurosis attaches to bone. In some embodiments, the injections are made into, or immediately adjacent to, the soft tissue attachments of the spinal vertebrae, which may comprise injecting the composition within 'A” to 1” of these soft tissue attachments. Vertebral sites having soft tissue attachments include, without limitation, the vertebral spinous processes, vertebral lamina, and transverse processes. Thus, in some embodiments, the injections are made along the lateral aspect of the vertebral spinous processes, posterior vertebral lamina, or posterior transverse process. In some embodiments, the injections are made into the space between adjacent vertebral spinal processes.

[0034] In some embodiments, the composition is administered by two or more injections, spaced at an interval. The two or more injections may be spaced at an interval of about 14”, %”, 1”, 1 ’A”, 1 A”, 1 %”, 2”, 3”, or 4”, or by an interval within a range bounded by any of the foregoing. In some embodiments, the two or more injections are spaced at an interval of about A” to about 1”.

[0035] In some embodiments, the methods further comprise identifying one or more injection sites for the one or more injections, comprising palpating the spinal / paraspinal region and selecting areas of pain or tenderness on palpating for injection. As used herein, “palpating” or “palpate” refers to a manual examination designed to assess by touch / feel one or more of the size, shape, firmness, location, consistency, texture, and / or tenderness of a body part. The palpation may be used to detect focal tenderness at or near any of the anatomical locations described herein. The focal tenderness may be identified when the subject vocalizes pain, winces, or moves their body in response to the pain elicited by firm palpation, and may reveal pain arising from muscle, tendon, ligament, fascia, aponeurosis, their respective bony attachments or the underlying periosteum. 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 or immediately adjacent to the soft tissues at these sites. The palpation may identify 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 injection sites, or a number of injection sites within a range bounded by any of the foregoing. In some embodiments, the one or more injections are made into 2-10 identified injection sites in a single treatment.

[0036] The composition may be administered using any suitable dosing scheme. For example, the composition may be administered daily, or once every 1, 2, 4, 6, 8, 10, 12, 24, or 36 weeks, or within a range bounded by any of the foregoing. In some embodiments, the composition is administered once per week. In other embodiments, the composition is administered once every 4 to 8 weeks, and the administration may be repeated every 4-8 weeks indefinitely, or may be administered on an as needed basis indefinitely. In some embodiments, the composition is administered during two or more treatment periods, each treatment period comprising administration once per week for 3 to 5 weeks, with the treatment periods separated by about 6 months. In further embodiments, the composition is administered once per week during an initial treatment period and once every 4 to 8 weeks following completion of the initial treatment period. In some embodiments, the initial treatment period comprises 2 or 3 separate injection sessions, one week apart from each other. Prior to each administration, the palpation methods described herein may be repeated to identify sites for injection.

[0037] The HA composition may be suitably administered to any patient experiencing acute or chronic spinal and / or paraspinal pain. As used herein, “chronic pain” refers to pain that has persisted for a duration of at least 3 months, while “acute pain” refers to sudden, temporary pain that typically resolves in less than 3 months. The HA composition may be administered to a patient experiencing pain of any severity. In some embodiments, the HA composition is administered to a patient experiencing cervical, thoracic and / or lumbar spinal and / or paraspinal pain.

[0038] Cervical Spinal or Paraspinal Pain

[0039] In some embodiments, the composition is administered to a subject experiencing pain in the cervical spinal and / or paraspinal region. As used herein, the “cervical spinal and paraspinal region” refers to a region bounded superiorly (toward the head) by the Cl vertebra, inferiorly (away from the head) by the spinous process of the T1 vertebra, laterally (away from the midline) by the posterior border of the sternocleidomastoid muscle, and anteriorly (toward the front) by the anterior border of the longus colli muscle. In some embodiments, the pain is chronic pain. In some embodiments, the pain originates from the soft tissues, or their vertebral attachments, of the cervical spinal and paraspinal region. In some embodiments, the pain is present in the midline of the posterior cervical region. In some embodiments, the pain is present in more lateral locations of this space. In some embodiments, the composition is administered to the subject following exclusion of other well-known sources of neck pain, including, without limitation, marrow metastasis, cervical dystonia, and cervical radiculopathy. Methods for the diagnosis and treatment of these conditions are well known in the art. Diagnostic imaging is not mandatory for the methods disclosed herein, although it may be helpful to exclude other pathologies.

[0040] In some embodiments, subjects that have palpable tenderness to firm palpation of one or more of the cervical interspinous ligament

[0010] regions, the adjacent muscles that course just posterior to the lamina and transverse processes

[0020] of the cervical vertebrae, including the multifidus

[0030] , semispinalis cervicis

[0050] , and splenius capitis

[0036] , or more laterally, including the trapezius

[0052] , splenius cervicis

[0048] , levator scapulae

[0046] , longissimus capitis

[0045] , posterior scalene

[0042] , and / or middle scalene

[0040] muscles are selected for treatment. Any suitable method of palpation may be used to identify palpable tenderness at these locations. In some embodiments, palpation is performed as follows: patients with chronic midline posterior region neck pain are palpated at each interspinous ligament region, beginning at the vertebra prominens, the C7 vertebra, which has the most prominent spinous process

[0012] in the cervicothoracic region, and proceeding superiorly to each individual interspinous ligament region, as well as inferiorly to the C7-T1 interspace region. In some embodiments, the musculature along the lateral margins of the cervical spinous processes are then palpated on each side and from inferior to superior or superior to inferior. Exemplary sites for palpation and optional HA injection are illustrated in FIGS. 1 and 4, and are shown on the figure as marked with an “X.” Sites having palpable tenderness may be selected for HA injection as described herein.

[0041] For more lateral injections, toward the transverse processes and the foramen transversarium, through which the vertebral artery

[0054] passes, a !4" needle or smaller may be used to maintain a distance that does not risk arterial puncture. Injection of hyaluronic acid into the vertebral artery may cause stroke due to the viscous nature of hyaluronic acid solutions. In some embodiments, injections are made with a 30 gauge, ! ” needle. This needle depth is shorter than the length of the cervical spinous processes, and so safely avoids injection into the cervical epidural space, the thecal sac or into the spinal cord, yet can penetrate deeply enough to deliver hyaluronic acid into the interspinous region and adjacent soft tissue attachments of the spinous processes and lamina in patient of normal body habitus.

[0042] The treatment of cervical spinal and / or paraspinal pain may suitably comprise administration of any disclosed composition, by any disclosed number of injections / inj ection sites, spaced at any disclosed interval, using any disclosed injection volume to deliver any disclosed quantity of HA, by any disclosed dosing scheme as described above. In some embodiments, the HA composition comprises 10 mg / mL of HA having a molecular weight of 500 to 730 kDa, and 0.25 - 1 m of the composition is injected into each palpably tender interspinous region, along each palpably tender lateral margin of a spinous process, and each palpably tender cervical muscle in the cervical paraspinal region. In some embodiments, the one or more injections are made into 2-10 identified injection sites in a single treatment.

[0043] Lumbar Spinal and / or Paraspinal Pain

[0044] In some embodiments, the composition is administered to a subject experiencing pain in the lumbar spinal and / or paraspinal region. As used herein, the “lumbar spinal and paraspinal region” refers to the lumbar vertebrae themselves, the soft tissue attachments to the vertebrae, including tendon, ligamentous, aponeurotic and / or fascial attachments, the tendons, muscles or ligaments that arise from these attachments, including muscles that indirectly attach to the lumbar spinal vertebrae via the thoracolumbar fascia. As used herein, the lumbar spinal and paraspinal region is bounded superiorly by the T12 spinous process, laterally by the lateral border of the iliocostalis muscle, and inferiorly by the top of the sacrum medially, the inferior margin extending upward on each side at least 1” superior to the iliac crest. Tn some embodiments, the pain arises from the spinal or paraspinal soft tissues, or their attachments to the lumbar vertebrae. In some embodiments, the pain is present in the midline region of the subject’s lower back, or elsewhere in the lumbar paraspinal region. The pain may be chronic. In some embodiments, the composition is administered to the subject following exclusion of other well-known sources of back pain, including, without limitation, vertebral compression fracture, bone metastases, and lumbar radiculopathy. Methods for diagnosing and treating these sources of back pain are known in the art. In some embodiments, less well recognized, yet likely common sources of back pain such as the “iliac crest pain syndrome” or “iliolumbar syndrome” or iliac crest and / or sacral enthesopathies or periostitis, have been excluded through deep palpation of the iliac crests, posterior superior iliac spines, and lateral sacrum.

[0045] To date, no imaging modality (MRI, CT, Ultrasound) has proven reliably effective for identifying the origin of nonspecific pain in the lumbar spinal and paraspinal region. In some embodiments, subjects having palpable tenderness to palpation of one or more of the lumbar interspinous ligament

[0064] regions, along the lateral margins of the lumbar spinous processes

[0060] , deeper palpation of the muscles that course along the posterior margins of the vertebral transverse processes and / or vertebral lamina, including the multifidus

[0030] or more laterally along the region of the longissimus dorsi

[0076] , quadratus lumborum

[0072] , and iliocostalis lumborum

[0078] muscles are selected for treatment. Any suitable method of palpation may be used to identify palpable tenderness at these locations. In some embodiments, palpation is performed as follows: (1) the spinous process of the L4 lumbar vertebrae is palpated using the level of the iliac crests as a horizontal landmark, (2) moving just inferior reaches the L4-5 interspinous ligament regions, and palpating just superior reaches the L3-4 interspinous ligament region, and (3) subsequent lumbar vertebral levels are then identified by palpating the separate spinous processes. Exemplary sites for palpation and optional HA injection are illustrated in FIGS. 6-8, and are shown on the figure as marked with an “X.” Sites having palpable tenderness may be selected for HA injection as described herein. In some embodiments, the composition is injected into, or immediately adjacent to, the soft tissue attachments of the lumbar vertebrae, which may entail injecting within ’A” to 1” of these soft tissue attachments. In some embodiments, the composition is injected more laterally into the iliocostalis or longissimus dorsi muscular regions. Injections are not made between the fascial planes of the superficial and deep layers of the deep thoracolumbar fascia, into the facet joints, or into the intervertebral disc.

[0046] The treatment of lumbar spinal and / or paraspinal pain may suitably comprise administration of any disclosed composition, by any disclosed number of injections / injection sites, spaced at any disclosed interval, using any disclosed injection volume to deliver any disclosed quantity of HA, by any disclosed dosing scheme as described above. In some embodiments, the HA composition comprises 10 mg / mL of HA having a molecular weight of 500 to 730 kDa, and 0.5 - 1 mL of the composition is injected into each palpably tender site identified as described above. In some embodiments, the one or more injections are made into 2-10 identified injection sites in a single treatment.

[0047] Thoracic Spinal and / or Paraspinal Pain

[0048] In some embodiments, the composition is administered to a subject experiencing pain in the thoracic spinal and / or paraspinal region. As used herein, the “thoracic spinal and paraspinal region” refers to the region bounded superiorly by the T1 spinous process and inferiorly by the T12 spinous process and the soft tissues that attach to or originate from the thoracic vertebrae. In some embodiments, the pain arises from the spinal or paraspinal soft tissues, or their attachments to of the thoracic vertebrae. In some embodiments, subjects having palpable tenderness to palpation of one or more of the thoracic interspinous regions, the rhomboid muscles, and / or trapezius are selected for treatment. Any suitable method of palpation may be used. In some embodiments, the palpation comprises palpating the musculature between the scapulae and thoracic spine, the thoracic interspinous ligament regions, and the musculature immediately posterior to the thoracic vertebral laminae and transverse processes. Sites having palpable tenderness may be selected for HA injection as described herein. The injections may suitably be made into the interspinous region, the musculature immediately lateral to the thoracic spinous processes, the rhomboid muscles, or the trapezius, exercising considerable caution to avoid risk of penetrating the intercostal muscles and lung.

[0049] The treatment of thoracic spinal and / or paraspinal pain may suitably comprise administration of any disclosed composition, by any disclosed number of injections / injection sites, spaced at any disclosed interval, using any disclosed injection volume to deliver any disclosed quantity of HA, by any disclosed dosing scheme as described above. In some embodiments, the HA composition comprises 10 mg / mL of HA having a molecular weight of 500 to 730 kDa, and 0.5 - 1 mL of the composition is injected into each palpably tender site identified as described above. In some embodiments, the one or more injections are made into 2-10 identified injection sites in a single treatment.

[0050] The present disclosure is not limited to the specific details of construction, arrangement of components, or method steps set forth herein. The compositions and methods disclosed herein are capable of being made, practiced, used, carried out and / or formed in various ways that will be apparent to one of skill in the art in light of the disclosure that follows. The phraseology and terminology used herein is for the purpose of description only and should not be regarded as limiting to the scope of the claims. Ordinal indicators, such as first, second, and third, as used in the description and the claims to refer to various structures or method steps, are not meant to be construed to indicate any specific structures or steps, or any particular order or configuration to such structures or steps. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to facilitate the disclosure and does not imply any limitation on the scope of the disclosure unless otherwise claimed. No language in the specification, and no structures shown in the drawings, should be construed as indicating that any non-claimed element is essential to the practice of the disclosed subject matter. The use herein of the terms “including,” “comprising,” or “having,” and variations thereof, is meant to encompass the elements listed thereafter and equivalents thereof, as well as additional elements. Embodiments recited as “including,” “comprising,” or “having” certain elements are also contemplated as “consisting essentially of’ and “consisting of’ those certain elements.

[0051] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited 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%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure. Use of the word “about” to describe a particular recited amount or range of amounts is meant to indicate that values very near to the recited amount are included in that amount, such as values that could or naturally would be accounted for due to manufacturing tolerances, instrument, and human error in forming measurements, and the like. All percentages referring to amounts are by weight unless indicated otherwise.

[0052] No admission is made that any reference, including any non-patent or patent document cited in this specification, constitutes prior art. In particular, it will be understood that, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in the United States or in any other country. Any discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinence of any of the documents cited herein. All references cited herein are fully incorporated by reference, unless explicitly indicated otherwise. The present disclosure shall control in the event there are any disparities between any definitions and / or description found in the cited references.

[0053] The following examples are meant only to be illustrative and are not meant as limitations on the scope of the invention or of the appended claims.

[0054] EXEMPLARY EMBODIMENTS

[0055] Embodiment 1. A method of treating spinal and / or paraspinal pain in a subject, comprising administering to the subject by one or more injections a composition comprising (a) a therapeutically effective amount of hyaluronic acid and (b) a pharmaceutically acceptable carrier, wherein the one or more injections are made into soft tissue of the spinal and / or paraspinal region.

[0056] Embodiment 2. The method of embodiment 1, wherein the one or more injections are made between adjacent vertebral spinous processes.

[0057] Embodiment 3. The method of embodiment 1 or 2, wherein the one or more injections are made along a lateral aspect of a vertebral spinous process, posterior to a vertebral lamina, or posterior to a transverse process. Embodiment 4. The method of any one of the preceding embodiments, wherein the pain is present in the cervical spinal and / or paraspinal region.

[0058] Embodiment 5. The method of embodiment 4, further comprising identifying one or more injection sites for the one or more injections, wherein the identifying comprises:

[0059] (a) palpating the subject’s:

[0060] (i) cervical interspinous ligament regions,

[0061] (ii) cervical paraspinal musculature lateral to a spinous process, posterior to a vertebral lamina, and / or posterior to a transverse process, and / or

[0062] (iii) cervical paraspinal musculature lateral to a vertebra, the cervical paraspinal musculature comprising the levator scapulae, middle scalene, posterior scalene, splenius cervicis and / or longissimus capitis; and

[0063] (b) selecting areas of pain or tenderness on palpating for injection.

[0064] Embodiment 6. The method of embodiment 4 or 5, wherein the one or more injections are made into one or more sites as shown in FIGS. 1 and 4.

[0065] Embodiment 7. The method of any one of embodiments 1-3, wherein the pain is present in the lumbar spinal and / or paraspinal region.

[0066] Embodiment 8. The method of embodiment 7, further comprising identifying one or more injection sites for the one or more injections, wherein the identifying comprises:

[0067] (a) palpating the subject’s:

[0068] (i) lumbar interspinous ligament regions,

[0069] (ii) lumbar paraspinal musculature posterior to a vertebral lamina and / or a transverse process, and / or

[0070] (iii) lumbar paraspinal musculature lateral to the lumbar vertebrae, wherein the lumbar paraspinal musculature comprises the iliocostalis lumborum and / or longissimus dorsi; and

[0071] (b) selecting areas of pain or tenderness on palpating for injection. Embodiment 9. The method of embodiment 7 or 8, wherein the one or more injections are made into one or more sites as shown in FIGS. 6-8.

[0072] Embodiment 10. The method of embodiment 1, wherein the pain is present in the thoracic spinal and / or paraspinal region.

[0073] Embodiment 11. The method of embodiment 10, further comprising identifying one or more injection sites for the one or more injections wherein the identifying comprises:

[0074] (a) palpating the subject’s:

[0075] (i) thoracic interspinous ligament regions,

[0076] (ii) thoracic paraspinal musculature posterior to a vertebral lamina and / or a transverse process, and / or

[0077] (iii) rhomboid and / or trapezius muscle; and

[0078] (b) selecting areas of pain or tenderness on palpating for injection.

[0079] Embodiment 12. The method of any one of the preceding embodiments, wherein the one or more injections are made into 2-10 injection sites.

[0080] Embodiment 13. The method of any one of the preceding embodiments, wherein:

[0081] (i) the hyaluronic acid has a molecular weight of at least 500 kDa;

[0082] (ii) the hyaluronic acid is present in the composition at a concentration of 1 mg / mL to 20 mg / mL; and / or

[0083] (iii) each injection of the one or more injections delivers 1 mg or more of the hyaluronic acid.

[0084] Embodiment 14. The method of any one of the preceding embodiments, wherein:

[0085] (i) the hyaluronic acid has a molecular weight of 500 kDa to 730 kDa;

[0086] (ii) the hyaluronic acid is present in the composition at a concentration of about 10 mg / mL; and / or

[0087] (iii) each injection of the one or more injections delivers 1 mg to 20 mg of the hyaluronic acid. Embodiment 15. The method of any one of the preceding embodiments, wherein the composition is administered:

[0088] (i) once every 4 to 12 weeks;

[0089] (ii) during two or more treatment periods, wherein the composition is administered once per week for 3 to 5 weeks during each treatment period, and wherein the treatment periods are separated by about 6 months;

[0090] (iii) once per week during an initial treatment period and once every 4 to 8 weeks following completion of the initial treatment period, wherein the initial treatment period comprises 2 or 3 separate injection sessions separated by about one week; or

[0091] (iv) once every 6 months.

[0092] Embodiment 16. The method of any one of the preceding embodiments, wherein the pain is chronic pain.

[0093] Embodiment 17. The method of any one of the preceding embodiments, wherein the one or more injections are made into the paraspinal musculature lateral to the spinal vertebrae.

[0094] EXAMPLES

[0095] Example 1 (cervical spinal / paraspinal pain)

[0096] A 56 year old female reported chronic neck pain in her lower posterior neck, with a maximum pain severity of 7 out of 10 on a visual analog scale. Examination revealed focal tenderness to her interspinous ligament region between C7-T1 as well as some paraspinal muscle spasm. Baclofen had not been helpful, while diclofenac gel applied liberally around the C7 / T1 spinous processes was partially helpful, but the maximum pain severity still reached 7 out of 10. The pain was exacerbated after a fall. She was seen several months later, with persistent pain, unresponsive to physical therapy, and was treated with hyaluronic acid (Hyalgan; 20 mg / ml; Lot#: G37030) injection into the interspinous ligament between C7 and T1 (total of 1.0 mL injected).

[0097] Three months later, she stated the neck pain was significantly improved for two months, but it had gradually recurred to its baseline level, and examination revealed distinct tenderness between the C6 and C7 spinous processes, and between the C7 and T1 spinous processes. She was injected with hyaluronic acid again as follows:

[0098] Interspinous ligament between C6 and C7, total of 1.0 mL

[0099] Interspinous ligament between C7 and Tl, total of 1.0 mL

[0100] She was examined 2 months later and stated the neck pain was markedly improved. She estimated that prior to the most recent injection her average pain was approximately 8 out of 10 on the visual analog scale, but at this time averaged 3 out of 10 on the visual analog scale, ranging from 2, to occasionally 4 out of 10, and was worse in the mornings. However, the pain began recurring a few weeks later.

[0101] Example 2 (cervical spinal / paraspinal pain)

[0102] A 40 year old female reported chronic neck pain that had been present for at least 1 year, was rated as a constant 4-5 out of 10 in severity, though it increased to 8-9 out of 10 in severity with certain head movements, significantly limiting her physical activities. Examination revealed distinct focal tenderness at her interspinous locations between C5-6, C6-7 and C7-T1. She had prior x-rays and MRIs of her cervical spine. Diclofenac gel was only partially helpful. Hyaluronic acid (Hyalgan 20 mg / ml; Lot#: G37480) injections were administered as follows:

[0103] C5-6 interspace: ~ 0.6 mL

[0104] C6-7 interspace: - 0.7 mL

[0105] C7-T1 interspace: - 0.7 mL

[0106] Two months later, the patient stated the average pain had decreased to approximately 4 out of 10 on average, with a maximum severity of only 5 out of 10, as comparted to a maximum severity of 8-9 out 10 prior to the hyaluronic acid injections. The patient further reported that the reduction in pain had remained for the past two months and did not significantly limit her activities anymore.

[0107] Example 3 (cervical spinal / paraspinal pain)

[0108] A 44 year old female reporty persistent severe neck pain, mostly located in posterior midline. She had undergone cervical spine surgery two years prior. The neck pain had been present for at least 8 to 9 months, severity of the pain was 7 out of 10 on average, reaching a maximum severity up to 8-9 out of 10. Examination revealed distinct tenderness between her C3- 4 C4-5 C5-6 C6-7 and C7-T1 interspaces. Hyaluronic acid (Hyalgan 20 mg / ml; Lot#: G37480) injections were administered as follows:

[0109] C3-4, C4-5, C5-6, C6-7, and C7-T1 interspaces between spinous processes: approximately 0.7 mL in each interspace.

[0110] She stated that the injection reduced the pain to around 4 out of 10 on average for approximately a week, but which then recurred to its baseline severity.

[0111] Example 4 (cervical spinal / paraspinal pain)

[0112] A 47 year old female reported chronic neck pain of more than several months duration. She stated this pain averaged approximately 7-8 out of 10 in severity, and at its worst was 10 out of 10. Examination revealed distinct tenderness in her cervical interspinous ligament region between C3 / 4, C4 / 5, C5 / 6 and C6 / 7. She was treated with hyaluronic acid (Hyalgan 20 mg / 2ml; Lot#: H12050) injections as follows:

[0113] Cervical interspinous ligament at C3 / 4 - 0.5 mL

[0114] Cervical interspinous ligament at C4 / 5 - 0.5 mL

[0115] Cervical interspinous ligament at C5 / 6 - 0.5 mL

[0116] Cervical interspinous ligament at C6 / 7 - 0.5 mL

[0117] Two months later, the patient reported the average pain for the past two months had been approximately 3 out of 10, with a maximum severity of 5 out of 10, and stated she was overall quite pleased with the results. However, she noted in the past few days that the pain had begun to recur to some extent, and requested repeat injection at her next visit.

[0118] Example 5 (cervical spinal / paraspinal pain)

[0119] A 62 year old male reported chronic neck pain, with an average severity of 9 out of 10. Examination revealed distinct tenderness along the superior region of his lateral cervical paraspinal musculature, in the region of the levator scapulae muscle, as well as palpable muscular spasm. He was injected with 2 mL of hyaluronic acid (Hyalgan 20 mg / 2ml, total of 2cc Lot#: H12050 Exp Date: 03-04-2027) as three separate injections of 0.6 to 0.7 mL each, into his levator scapulae region, where there was palpable muscular spasm, spaced approximately ’A" apart. He stated that after the injection the pain was significantly improved for approximately 3 weeks, with an average severity of 3-4 out of 10 on average and maximum severity of 5 out of 10. However, 4 weeks after the initial injections, the pain had begun to worsen to 7-8 out 10 on average and 9 at maximum. Hyaluronic acid injections were administered again as described above, and two weeks later pain was further improved, averaging 2-3 / 10 in severity and 4-5 / 10 at maximum.

[0120] Example 6 (lumbar spinal / paraspinal pain)

[0121] A 54 year old female reported chronic lower back pain for the past 2 years, which was helped only partially by physical therapy, and was in her midline lumbar region. The pain was approximately 6 out of 10 in the morning, not as bothersome in the afternoons, but reaching 8-9 out of 10 after walking for approximately an hour. Examination revealed focal tenderness along her lumbar interspinous region at several levels, but most notable at L4 / 5. An MRI of her lumbar spine revealed a grade 1 anterolisthesis at L4 / L5, some mild disc bulges, but no significant spinal canal or neuroforaminal stenosis. She was treated with hyaluronic acid (Hyalgan 20 mg / ml; Lot#: G34780) as follows:

[0122] L4 / 5 interspace between spinous processes - 2 mL total injected

[0123] She stated that her low back pain was substantially improved for 2 weeks after the hyaluronic acid injection, but gradually recurred over two months, but was not as intense as prior to the injections. Prior to the injections, the maximum pain severity 8-9 out of 10, and two months after injection was 7 out of 10 at its worst, and reaching this intensity less frequently. The average pain was approximately 5 out of 10 two months after the injections. Repeat injections of hyaluronic acid (Hyalgan 20 mg / ml; Lot#: Hl 2050) were administered as follows:

[0124] L3-4 interspinous ligament: 0.5 mL

[0125] L4-5 interspinous ligament 0.5 mL

[0126] L5-S1 interspinous ligament 1.0 mL

[0127] Approximately 8 weeks later, after receiving the second round of injections, she had 3 to 5 days a week without low back pain, although with increased activities she will notice some back pain, for example walking long distance, and carrying or moving heavy objects and this pain may get up to 7 out of 10 in severity. However, the pain was well controlled with only light activities.

[0128] Example 7 (lumbar spinal / paraspinal pain)

[0129] A 61 year old male reported lower back pain, which had been present for approximately 10 years. The pain was midline in his lower back, with an average severity of approximately 5 out of 10 and maximum severity of 7-8 out of 10. He had minimal pain in his lateral lower back regions, and minimal leg pain. Examination revealed focal tenderness to his interspinous ligament regions between L4-5, more distinct at L5-S1, and some at Sl-2. He stated that epidural steroids were helpful for only a few days. He was treated with hyaluronic acid (Hyalgan 20 mg / mL; Lot#: G37480) injections as follows:

[0130] L4-5 interspace: 0.5 mL

[0131] L5-S1 interspace: 1 mL

[0132] S1-S2 interspace: 0.5 mL

[0133] 11 days later, he stated the pain reduced to 4 out of 10 on average and 5 out of 10 at maximum, and was feeling moderately improved. He still had tenderness in the same interspinous regions. Repeat hyaluronic acid (Hyalgan 20 mg / mL; Lot#: G37480) injections were administered as follows:

[0134] L4-5 interspace: 0.5 mL

[0135] L5-S1 interspace: 1 mL

[0136] S1-S2 interspace: 0.5 mL

[0137] 2 months later, the patient reported that the pain was further improved, stating it would only get up to 4 out of 10 at maximum. However, the average pain at this time was approximately 4 out of 10 also.

[0138] Example 8 (lumbar spinal / paraspinal pain)

[0139] A 61 year old male reported chronic low back pain for the past six months. He stated that this was not present when he was sitting, but increased significantly with movement, getting up to 10 out of 10 in severity with movement. Examination revealed focal tenderness at his L3-4 interspinous interspace and L4-5 interspinous interspace, but he was not distinctly tender along the lateral musculature around the same spinous processes. He was treated with hyaluronic acid (Hyalgan 20 mg / mL; Lot#: H12040) injections as follows:

[0140] L3-4 interspinous ligament: 1 mL

[0141] L4-5 interspinous ligament: 1 mL

[0142] He stated the hyaluronic acid was effective for approximately 1 to 2 weeks, pain was approximately 5 out of 10 at maximum during this time, but after four weeks stated it had recurred to its baseline average severity, though with a maximum severity of 8-10 out of 10, as compared to a maximum severity of 10 out of 10 prior to the hyaluronic acid injections.

[0143] Example 9 (lumbar spinal / paraspinal pain)

[0144] A 24 year old female reported lumbar spinal and paraspinal pain which had started in her 20s, and became much more severe after giving birth, approximately year and a half prior to her visit. On average, the pain severity was 6-7 out of 10, with a maximum severity of 8-9 out of 10. Examination revealed distinct tenderness to her bilateral iliac crest and greater trochanteric regions, as well as some lumbar interspinous ligament regions. She received dexamethasone injections along her iliac crest for a presumed iliac crest enthesopathy and for greater trochanteric pain syndrome, and the pain in her thighs and lateral lower back improved significantly. However, she continued to have midline lower back pain. MRI of her lumbar spine did not identify a source of her pain. On exam she had distinct tenderness at the interspinous ligament region of L2-3, L3- 4, L4-5, and L5-S1. She stated at the time that the midline low back pain averaged 8-9 out 10 in severity, and the most severe pain she experienced was approximately a 10. She was treated with hyaluronic acid (Hyalgan 20 mg / mL; Lot#: H12050) injections as follows:

[0145] L2 / 3 interspinous location - 1.0 mL

[0146] L3 / 4 interspinous location - 1.0 mL

[0147] L4 / 5 interspinous location - 1.0 mL

[0148] L5 / S1 interspinous location - 1.0 mL

[0149] She stated the pain was significantly improved after the hyaluronic acid injections for approximately 2 weeks, with an average pain level approximately 5 out of 10 during this time. However, the pain had recurred over time, and by approximately 4 weeks since the injection, the midline lower back pain averaged 6-7 out of 10 in severity.

[0150] Example 10 (lumbar spinal / paraspinal pain)

[0151] A 74-year-old male reported lower back pain for a number of years, with associated hip and thigh pain radiating to his knees for approximately the past year, but no pain in his lower legs. The lower back pain was midline, and on exam there was some focal tenderness to his interspinous ligament at the L4-5 interspace. There was no iliac crest tenderness, or greater trochanteric tenderness. He had severe underlying hip osteoarthritis bilaterally. He stated he received no benefit from epidural steroid injections or gabapentin, oxycodone was helpful for the pain while he was sitting, but not standing. He received hyaluronic acid (Hyalgan 20 mg / mL; Lot#: G37030) injection for presumed lumbar interspinous ligament sprain as follows: 1 mL of hyaluronic acid was injected between the L4 and L5 spinous processes. He stated it took a few days for pain relief to occur after the injections, then he had significant pain relief for 7 to 10 days, was able to ambulate much easier, but then the pain gradually recurred back to its baseline when evaluated four weeks later. A subsequent injection was minimally effective.

[0152] REFERENCES

[0153] 1. Austin J.W., Gilchrist C., Fehlings M.G. High molecular weight hyaluronan reduces lipopolysaccharide mediated microglial activation. J. Neurochem. 2012;122:344-355.

[0154] 2. Neumann A, Schinzel R, Palm D, Riederer P, Munch G. High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett. 1999 Jun 25;453(3):283-7.

[0155] 3. Lee BM, Park SJ, Noh I, Kim CH. Biomater Res. 2021 Aug 30;25( 1) : 27.

[0156] 4. Agostini F et al., Effects of hyaluronic acid injections on pain and functioning in patients affected by tendinopathies: A narrative review, Journal of Back and Musculoskeletal Rehabilitation, 2022; 35:949-961.

[0157] 5. Nesporova K. et al., Injecting hyaluronan in the thoracolumbar fascia: A model study, International Journal of Biological Macromolecules, 2023; 253(Pt 3): 126879.

[0158] 6. Campa JA, Cross-Linked Hyaluronic Acid for the Management of Neuropathic Pelvic Pain, Practical Pain Management, 2018; 18(5)

[0159] 7. Amirdelfan K. et al., Allogeneic mesenchymal precursor cells treatment for chronic low back pain associated with degenerative disc disease: a prospective randomized, placebo-controlled 36-month study of safety and efficacy, The Spine Journal, 2021; 21(2): 212-230.

Claims

CLAIMSWhat is claimed:

1. A method of treating spinal and / or paraspinal pain in a subject, comprising administering to the subject by one or more injections a composition comprising (a) a therapeutically effective amount of hyaluronic acid and (b) a pharmaceutically acceptable carrier, wherein the one or more injections are made into soft tissue of the spinal and / or paraspinal region.

2. The method of claim 1, wherein the one or more injections are made between adjacent vertebral spinous processes.

3. The method of claim 1, wherein the one or more injections are made along a lateral aspect of a vertebral spinous process, posterior to a vertebral lamina and / or, posterior to a transverse process.

4. The method of claim 1, wherein the pain is present in the cervical spinal and / or paraspinal region.

5. The method of claim 4, further comprising identifying one or more injection sites for the one or more injections, wherein the identifying comprises:(a) palpating the subject’s:(i) cervical interspinous ligament regions,(ii) cervical paraspinal musculature lateral to a spinous process, posterior to a vertebral lamina, and / or posterior to a transverse process, and / or(iii) cervical paraspinal musculature lateral to the a vertebra, the cervical paraspinal musculature comprising the levator scapulae, middle scalene, posterior scalene, splenius cervicis and / or longissimus capitis; and(b) selecting areas of pain or tenderness on palpating for injection.

6. The method of claim 5, wherein the one or more injections are made into 2-10 injection sites.

7. The method of claim 4, wherein:(i) the hyaluronic acid has a molecular weight of at least 500 kDa;(ii) the hyaluronic acid is present in the composition at a concentration of 1 mg / mL to 20 mg / mL; and / or(iii) each injection of the one or more injections delivers 1 mg or more of the hyaluronic acid.

8. The method of claim 4, wherein:(i) the hyaluronic acid has a molecular weight of 500 kDa to 730 kDa;(ii) the hyaluronic acid is present in the composition at a concentration of about 10 mg / mL; and / or(iii) each injection of the one or more injections delivers 1 mg to 20 mg of the hyaluronic acid.

9. The method of claim 4, wherein the composition is administered:(i) once every 4 to 12 weeks;(ii) during two or more treatment periods, wherein the composition is administered once per week for 3 to 5 weeks during each treatment period, and wherein the treatment periods are separated by about 6 months;(iii) once per week during an initial treatment period and once every 4 to 8 weeks following completion of the initial treatment period, wherein the initial treatment period comprises 2 or 3 separate injection sessions separated by about one week; or(iv) once every 6 months.

10. The method of claim 4, wherein the one or more injections are made into one or more sites as shown in FIGS. 1 and 4.

11. The method of claim 1, wherein the pain is present in the lumbar spinal and / or paraspinal region.

12. The method of claim 11, further comprising identifying one or more injection sites for theone or more injections, wherein the identifying comprises:(a) palpating the subject’s:(i) lumbar interspinous ligament regions,(ii) lumbar paraspinal musculature posterior to a vertebral lamina and / or a transverse process, and / or(iii) lumbar paraspinal musculature lateral to the lumbar vertebrae, wherein the lumbar paraspinal musculature comprises the iliocostalis lumborum and / or longissimus dorsi.(b) selecting areas of pain or tenderness on palpating for injection.

13. The method of claim 12, wherein the one or more injections are made into 2-10 injection sites.

14. The method of claim 11, wherein:(i) the hyaluronic acid has a molecular weight of at least 500 kDa;(ii) the hyaluronic acid is present in the composition at a concentration of 1 mg / mL to 20 mg / mL; and / or(iii) each injection of the one or more injections delivers 1 mg or more of the hyaluronic acid.

15. The method of claim 11, wherein:(i) the hyaluronic acid has a molecular weight of 500 kDa to 730 kDa;(ii) the hyaluronic acid is present in the composition at a concentration of about 10 mg / mL; and / or(iii) each injection of the one or more injections delivers 1 mg to 20 mg of the hyaluronic acid.

16. The method of claim 11, wherein the composition is administered:(i) once every 4 to 12 weeks;(ii) during two or more treatment periods, wherein the composition is administered once per week for 3 to 5 weeks during each treatment period, and wherein the treatment periods are separated by about 6 months;(iii) once per week during an initial treatment period and once every 4 to 8 weeks following completion of the initial treatment period, wherein the initial treatment period comprises 2 or 3 separate injection sessions separated by about one week; or(iv) once every 6 months.

17. The method of claim 11, wherein the one or more injections are made into one or more sites as shown in FIGS. 6-8.

18. The method of claim 1, wherein the pain is present in the thoracic spinal and / or paraspinal region.

19. The method of claim 18, further comprising identifying one or more injection sites for the one or more injections wherein the identifying comprises:(a) palpating the subject’s:(i) thoracic interspinous ligament regions,(ii) thoracic paraspinal musculature posterior to a vertebral lamina and / or a transverse process, and / or(iii) rhomboid and / or trapezius muscle; and(b) selecting areas of pain or tenderness on palpating for injection.

20. The method of claim 19, wherein the one or more injections are made into 2-10 injection sites.

21. The method of claim 18, wherein:(i) the hyaluronic acid has a molecular weight of at least 500 kDa;(ii) the hyaluronic acid is present in the composition at a concentration of 1 mg / mL to 20 mg / mL; and / or(iii) each injection of the one or more injections delivers 1 mg or more of the hyaluronic acid.

22. The method of claim 18, wherein:(i) the hyaluronic acid has a molecular weight of 500 kDa to 730 kDa;(ii) the hyaluronic acid is present in the composition at a concentration of about 10 mg / mL; and / or(iii) each injection of the one or more injections delivers 1 mg to 20 mg of the hyaluronic acid.

23. The method of claim 18, wherein the composition is administered:(i) once every 4 to 12 weeks;(ii) during two or more treatment periods, wherein the composition is administered once per week for 3 to 5 weeks during each treatment period, and wherein the treatment periods are separated by about 6 months;(iii) once per week during an initial treatment period and once every 4 to 8 weeks following completion of the initial treatment period, wherein the initial treatment period comprises 2 or 3 separate injection sessions separated by about one week; or(iv) once every 6 months.

24. The method of claim 1, wherein the pain is chronic pain.

25. The method of claim 1, wherein the one or more injections are made into the paraspinal musculature lateral to the spinal vertebrae.

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