Regenerative Injection Therapy - Springer Link

Regenerative Injection Therapy

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Felix S. Linetsky, Andrea M. Trescot, and Matthias H. Wiederholz

Abbreviations

History

DMN DPG FDA NSAIDs PRP PSIS RIT TRPV

• Since fifth century BC, practitioners have been using regenerative therapy to treat medical conditions. Hippocrates practiced one of the earliest forms of regenerative therapy by cauterizing ligaments to induce thermomodulation of collagen with scar formation and joint stabilization. – Hypothesis is that it induced inflammation which leads to tissue self-repair [1, 2] • 1939—J. H. Kellgren, MD injected small doses of hypertonic saline into the interspinous ligaments and mapped out the pain patterns of distal referral, mimicking radiculopathy (Fig. 48.1) [3]. • 1954—Feinstein et al. [4] repeated the study by Kellgren done 15 years earlier, again using hypertonic saline injections into the interspinous ligament – They confirmed the radicular referral patterns of the interspinous ligament from C1–S3 (Fig. 48.2a, b). – Also showed that the pattern of pain was independent of the sympathetic system and could refer to an anesthetized area. – Stimulation of the trunk interspinous ligament could result in visceral-like pain. – In addition, they were able to reproduce “numbness” and “heaviness” in the affected limb with these noxious injections. • 1956—George Hackett, MD coined the term Prolotherapy at the Fibro-Osseous Junction [5] • 1963—Gustav Hemwall, MD – Transitioned to hypertonic dextrose as the main proliferant solution [6]

Dorsal median nerves Dextrose/phenol/glycerin Food and Drug Administration Nonsteroidal anti-inflammatory drugs Platelet-rich plasma injections Posterior superior iliac spine Regenerative injection therapy Transient receptor potential vanilloid

Introduction Among many interventional techniques in current use, Regenerative Injection therapy (RIT), also known as prolotherapy or sclerotherapy, is a viable procedure to treat chronic musculoskeletal pain of connective tissues origin. It was originally employed for the treatment of painful peripheral joint hypermobilities secondary to ligament laxity or enthesopathies but fairly quickly evolved to include the treatment of axial joints pain as well. A common feature found in patients with chronic musculoskeletal pain is tenderness on palpation at certain sites, particularly where ligaments, tendons, or aponeuroses attach to bone.

F.S. Linetsky, M.D. (*) Department of Osteopathic Principles and Practice, Nova Southeastern University of Osteopathic Medicine, Clearwater, FL, USA e-mail: [email protected]; [email protected] A.M. Trescot, M.D. Trescot Pain Fellowship, Pain and Headache Center, Wasilla, AK, USA e-mail: [email protected]

Physiologic Tissue Repair

M.H. Wiederholz, M.D. Performance Spine and Sports Medicine, Lawrenceville, NJ, USA e-mail: [email protected]

• Ligament and tendon structure – Ligaments (attach bone to bone) and tendons (attach muscles to bone)

K.A. Sackheim, Pain Management and Palliative Care: A Comprehensive Guide, DOI 10.1007/978-1-4939-2462-2_48, © Springer Science+Business Media New York 2015

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Fig. 48.1 Pain patterns referred from the interspinous ligament after injection of hypertonic saline in normal volunteers. Adapted from Kellgren JH. On the distribution of pain arising from deep somatic structures with charts of segmental pain areas. Somatic Pain. 1939: 35–46) [3, 6]

Fig. 48.2 (a) Pain patterns from hypertonic saline stimulation by injection of hypertonic saline into the interspinous ligaments of C1 to C5. (b) Pain patterns from hypertonic saline stimulation by injection of hypertonic

saline into the interspinous ligaments of L5 to S1Adapted from Feinstein B, Langton JN, Jameson RM, Schiller F. Experiments on pain referred from deep somatic tissues. J Bone Joint Surg 1954;36:981–996) [4, 7]

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Ligaments are parallel bundles of fibers of primarily Type I collagen covered by a more vascular “epiligament” at the bone attachments ◆ Collagen ⇒ tropocollagen ⇒ microfibrils ⇒ fascicles ⇒ endoligament ⇒ ligament ⇒ epiligament [7] ◆ These fibers unfold during initial collagen loading. ◆ After elongation beyond 4 % of the original length, ligaments and tendons lose their elasticity and recoil capability, becoming permanently lax, which leads to joint hypermobility with instability [8]. Tendons have a similar structure but are more like woven cable • Healing response—three phases [9] – Hemorrhage with inflammation Increase in neovascularization and neoneurogenesis (Fig. 48.3) ◆ Integral components of both the regenerative/ reparative and degenerative processes. ◆ Nerve and vascular tissue in-growth have been well documented in degenerated intervertebral discs, posterior spinal ligaments, facet joint capsules, and sacroiliac ligaments. Matrix and cellular proliferation ◆ Hypertrophic fibroblasts create a dense, disorganized collagenous connective tissue matrix Remodeling and maturation ◆ Alignment of the fibers along the long access of the structure

Fig. 48.3 Ultrasound image of the neovascular blood flow at the enthesopathy at C7 after a flexion-extension injury (Image courtesy of Felix Linetsky, MD)

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Cross-linking of the fibers Absorption of the neovascularization – Deleteriously affected by Denervation, inactivity, direct corticosteroid injections, NSAIDs Repetitive trauma or microtrauma with insufficient time for recovery, tissue hypoxia, metabolic and hormonal abnormalities, nicotine • Enthesopathy—refers to a disorder of the enthesis (attachments of ligaments and tendons to bone) [10] – In acute cases of sprains and torn ligaments, healing takes place by proliferation of fibrous tissue. – When the tissues do not heal properly, it results in ligament laxity-induced proliferation of bone and fibrous tissue strengthens the fibro-osseous junction, stabilizing the joint. ◆ ◆

Types of Regenerative Injection Therapy 1. Chemical injectates • Utilizes an inflammatory concentration of lidocaine and dextrose (12.5–25 %) – Creates a fibroblastic response, increasing the tensile strength and bony attachment by 50 % (Fig. 48.4) • Injection is given into and around the painful area, typically the enthesis (the fibro-osseous junction)

Fig. 48.4 Comparison of rabbit tendons untreated versus injected with D50W proliferant, showing 50 % increase in size, tensile strength, and bone attachment (Modified from Hackett GS. Ligament & Tendon Relaxation (Skeletal Disability)—Treated by Prolotherapy (Fibroosseous Proliferation). 3rd ed. Springfield, IL: Charles C. Thomas; 1958)(9) Image courtesy of Felix Linetsky, MD

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• Emphasis is on treating all painful areas and resolving joint instability by treating ligaments and other joint stabilizing structures • Most treatments are given 4–6 weeks apart to allow for new connective tissue formation – Most patients require 3–6 treatments Subcutaneous neural therapy (Neurofascial or neural therapy) • Involves “mini-injections” of 5 % dextrose in subcutaneous tissue at the level of the peptidergic nerves, which contain transient receptor potential vanilloid receptors (TRPV1 nerves) – These nerves are sensitized with trauma, injury, or constriction and represent sites of neurogenic inflammation n These nerves maintain the health and renewal of ligaments and tendons – Injections are done weekly for 5–10 visits Prolozone • Utilizes ozone gas and other therapeutic substances to stimulate healing and eliminate pain in injured soft tissues and joints – Concentration of ozone is 1–3 % – Treatments are done weekly for 3–12 treatments Platelet-Rich Plasma injections (PRP) • Introduced in 1987 [11] as an autologous transfusion component after an open heart operation to avoid homologous blood product transfusion – In the late 1990s, PRP began to be used in many fields (such as orthopedics, dentistry, wound care) to promote tissue healing [11] • Clinical indications—similar to RIT • Side effects and contraindications—similar to RIT • Technique – Consists of autologous blood collection, plasma separation (centrifuge), injection of the concentrated platelets – Injection releases growth factors (see below) to stimulate recovery in nonhealing soft tissues. n Typically given every 1–2 months for 1–6 visits Stem Cell injection • Clinical indications—similar to RIT • Side effects and contraindications—similar to RIT with addition of pain at harvest site and possible carcinogenesis • Technique – Involves utilization of autologous adult pluripotent mesenchymal stem cells harvested from an individual’s bone marrow or adipose tissue for RIT purpose. – Typically done for more advanced cases of joint degeneration, including osteochondral defects, or in cases where RIT with dextrose or PRP have not resolved the problem. – Usually combined with PRP, which is believed to enhance the healing capabilities and cellular repair.


Injection Solutions 1. Neurolytic/chemical irritants—Induce inflammation by altering the surface proteins of cells which causes damage, rendering them susceptible to the immune system • Phenol • Sarapin 2. Chemotactic agents—Directly attract immune cells to the area • Sodium morrhuate 5 % −30 mL sodium salts of cod liver oil (on back order for past two years) • Sylnasol (5 % solution of sodium salts from psyllium seed oil with 2 % benzyl alcohol) [6]—discontinued after 1962 • Sodium tetradecyl sulfate (S.T.D. or Sotradecol®)— 1 % 2 mL and 3 % 2 mL. No longer produced in multidose vials (very expensive $20 for 2 mL. vial.) • Polidocanol (Asclera®)—Polyethylene glycol dodecyl ether (FDA approved for vein sclerosis) 3. Osmotic agents—Induce inflammation by altering the surface proteins of cells, which causes damage, rendering them susceptible to the immune system • Local anesthetic like 1 % lidocaine diluted with 50 % dextrose provides the following the so-called proliferating concentrations and osmolarities: – 4:1 proportion = 10 % dextrose = 555 mOsm/L – 3:1 proportion = 12.5 % dextrose = 694 mOsm/L – 1:2 proportion = 16.5 % dextrose = 916 mOsm/L • Neurolytic concentrations: – 3:2 proportion = 20 % dextrose =1,110 mOsm/L – 1:1 proportion = 25 % dextrose =1,388 mOsm/L – 1 % lidocaine diluted with dextrose/phenol/glycerin (DPG): – 25 % dextrose, 25 % glycerin, 2.5 % phenol • All dilutions are neurolytic: – 3:1 proportion = 1,026 mOsm/L; phenol 0.62 % – 2:1 proportion = 1,368 mOsm/L; phenol 0.83 % – 3:2 proportion = 1,641 mOsm/L; phenol 1 % – 1:1 proportion = 2,052 mOsm/L; phenol 1.25 % n % dextrose solution, a 1:1 dilution is used • Glycerine 10–25 % solution can be used as a single agent or combined with phenol and local anesthetic; lately also used as neural therapy 4. Particulates—Attract macrophages that secrete growth factors for tissue healing • Medical-grade pumice suspension • Talcum 5. Biologic agents • Platelet-rich plasma – Autologous blood • Stem cells – Requires harvesting of the stem cells n Bone marrow derived—iliac crest aspiration n Adipose tissue derived—liposuction

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Relevant Anatomy • Arthur Steindler and J.V. Luck [12] published a fundamental work describing the clinical anatomy related to the diagnosis of low back pain based on procaine injections. – Posterior divisions of the spinal nerves (the dorsal median nerves or DMN) provide the sensory supply to multiple structures: Ligamentous structures such as supraspinous, interspinous, iliolumbar, sacroiliac, sacrotuberous, and sacrospinous ligaments. Tendon attachments Origins and insertions of the aponeuroses of the tensor fascia lata, gluteal muscles, and thoracolumbar fascia. – Steindler and Luck also pointed out that these structures are interrelated anatomically and functionally. They stated that based on the clinical presentations alone, no definite diagnosis can be made ◆ Five postulated criteria have to be met to prove that causal relationship exists between the structure and pain symptoms: Contact with the needle must aggravate the local pain Contact with the needle must aggravate or elicit the radiation of pain Procaine infiltration must suppress local tenderness Procaine infiltration must suppress radiation of pain Positive leg signs must disappear

Fig. 48.5 Injection sites for low back pain. Black dots represent injection sites. A supraspinatus ligament, B interspinous ligament; C sacroiliac ligament; D iliolumbar ligament; E sacrotuberous ligament; F sacrospinous ligament; G insertion of gluteus maximus; H insertion of gluteus medius; I acetabular attachments of hip joint capsule; J sacrococcygeal ligament; K facet joint capsule; L thoracolumbar fascia attachment on to transverse process L2 to L5; M apex of spinous process attachments of supraspinous ligament and dorsal layer of thoracolumbar fascia; N trochanteric attachment of gluteal tendons; O lesser trochanter (Image courtesy of Felix Linetsky, MD)

Technique • It is recommended that physicians interested in RIT train with an RIT expert. – Preceptorships are available through the American – Academy of Regenerative Orthopedic Medicine (www.aarom.org) – Textbooks on the subject are also available (see Suggested Reading). • Example: Low back pain (Fig. 48.5) – Identify the areas of tenderness by palpation; if not comfortable with palpatory approach further confirm areas of injection with ultrasound or fluoroscopy (Fig. 48.6) Spinous processes PSIS Iliolumbar ligament Facets Sacrotuberous ligament (proximal and distal) – Injection at the fibro-osseous junction Needle must touch bone

Fig. 48.6 Fluoroscopic landmarks for injections (image courtesy of Andrea Trescot, MD)

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Fig. 48.7 General injection sites. Schematic drawing demonstrating sites of tendon origins and insertions, (enthesis) of the paravertebral musculature in the cervical, thoracic, lumbar, and pelvic regions with parts of the upper and lower extremities. Clinically significant enthesopathies with small fiber neuropathies and neuralgias are common at the locations identified by dots. Dots also represent most common locations of needle insertion and RIT injections. (Note: not all of the locations are treated in each patient). Modified from Sinelnikov Atlas of Anatomy, Volume 1, Meditsina, Moskow, 1972 by Tracey James. All rights reserved. No part of this picture may be reproduced or transmitted in any form or by any means without written permission from Felix Linetsky MD

Inject small amounts (usually 0.5–1 mL at each needle insertion or reinsertion) of the injectate; total volume depends on the number of sites injected, but total volume should be under 20 cm3 to limit local anesthetic toxicity Advances of diagnostic ultrasound allow precise placements of injectates at the sites of soft tissue pathology specifically fibromuscular interface, into the ligaments or tendons, large or small joints or their components • The technique is applicable “from the head to the toes” (Fig. 48.7)

Clinical Indications • Osteoarthritis, spondylolysis and spondylolisthesis • Painful enthesopathies, tendinosis, or ligamentosis secondary to sprains or strains from overuse, occupational and postural conditions known as Repetitive Motion Disorders • Painful hypermobility, instability, and subluxations of the axial joints secondary to ligament laxity accompanied by restricted range of motion at reciprocal segment(s) that improve temporarily with manipulation

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• Posterior column sources of nociception refractory to steroid injections, nonsteroidal anti-inflammatory therapy (NSAID), and radiofrequency procedures • Postsurgical cervical, thoracic, and low back pain (with or without instrumentation) • Recurrent painful rib subluxations at the costotransverse, costovertebral, and sternochondral articulations • Vertebral compression fractures with a wedge deformity that exert additional stress on the posterior ligamentotendinous complex

Side Effects and Contraindications • Main side effects are due to needle trauma and inadvertent needle placement – Pain – Stiffness – Bleeding – Bruising – Soreness – Swelling • Serious risks are very rare but may include: – Nerve, ligament, tendon injury – Spinal headache – Pneumothorax – Nerve damage – Spinal cord injury – Disc injury – Infection • Allergic or anaphylactic reactions to the proliferants may also occur – For instance, sodium morrhuate is a fish oil product and should be avoided in persons with a fish allergy • Regenerative injection therapy to the spine carries similar risk as any spinal injection – Spinal cord injury – Death No injections should be done by untrained practitioners

Billing • There is no code for PRP or stem cell injections • Because of misinterpreted studies, regenerative injection therapy is considered “experimental” and therefore not covered by insurance

References 1. Dorman TA. Diagnosis and injection techniques in orthopedic medicine. Baltimore: Williams and Wilkins; 1991. 2. Gedney EH. Special technic hypermobile joint: a preliminary report. Osteopath Profession. 1937;9:30–1.

3. Kellgren JH. On the distribution of pain arising from deep somatic structures with charts of segmental pain areas. Clin Sci. 1939;4:35–46. 4. Feinstein B, Langton JN, Jameson RM, Schiller F. Experiments on pain referred from deep somatic tissues. J Bone Joint Surg. 1954;36:981–96. 5. Hackett GS. Joint ligament relaxation treated by fibro-osseous proliferation. 1st ed. Springfield: Charles C. Thomas; 1956. 6. Kayfetz DO, Blumenthal LS, Hackett GS, Hemwall GA, Neff FE. Whiplash injury and other ligamentous headache–its management with prolotherapy. Headache. 1963;3:21–8. 7. Ravin TH. Tensegrity to tendonitis. Prolotherapy lecture series. Denver: American Academy of Musculoskeletal Medicine; 2012. 8. Frank CB. Ligament structure, physiology and function. J Musculoskelet Neuronal Interact. 2004;4(2):199–201. 9. Hackett GS. Ligament & tendon relaxation (skeletal disability)— treated by prolotherapy (fibro-osseous proliferation). 3rd ed. Springfield: Charles C. Thomas; 1958. 10. Weaver A, Keystone E, Mease PJ, Ritchlin CT. New applications for TNF inhibition 2000 [31/1/13]. Available from: http://www. medscape.org/viewarticle/418418_2. 11. Ferrari M, Zia S, Valbonesi M, Henriquet F, Venere G, Spagnolo S, et al. A new technique for hemodilution, preparation of autologous platelet-rich plasma and intraoperative blood salvage in cardiac surgery. Int J Artif Organs. 1987;10(1):47–50. 12. Steindler A, Luck JV. Differential diagnosis of pain low in the back; allocation of the source of pain by the procaine hydrochloride method. JAMA. 1938;110:106–13.

Suggested Reading Ravin TH, Cantieri MS, Pasquarello GJ. Review of principles of prolotherapy. Denver: American Academy of Musculoskeletal Medicine; 2008. Hauser R, Maddela HS, Alderman D, et al. International medical editorial board consensus statement on the use of prolotherapy for musculoskeletal pain. J Prolother. 2011;3(4):745–64. Gordin K. Comprehensive scientific overview on the use of platelet rich plasma prolotherapy (PRPP). J Prolother. 2011;3(4): 813–25. Alderman DD, Alexander RW, Harris GR, Astourian PC. Stem cell prolotherapy in regenerative medicine: background, theory and protocols. J Prolother. 2011;3(3):689–708. The following are available at www.AAROM.org Linetsky F, Botwin K, Gorfine L, Miguel R, Ray A, Trescot A, et al. Position paper of the Florida academy of pain medicine on regenerative injection therapy: effectiveness and appropriate usage. Pain Clin. 2002;4(3):38–45. Linetsky F, Derby R, Parris W, et al. Regenerative injection therapy (chapter 35). In: Manchikanti L, Slipman CW, Fellows B, editors. Low back pain: an interventional approach to diagnosis and treatment. Paducah: ASIPP Publishing; 2002. Linetsky F, Miguel R, Torres F. Treatment of cervicothoracic pain and cervicogenic headaches with regenerative injection therapy. Curr Pain Headache Rep. 2004;8(1):41–8. Linetsky F, Trescot A, Manchikanti L. Regenerative injection therapy (chapter 9). In: Manchikanti L, Singh V, editors. Interventional techniques in chronic non-spinal pain. Paducah: ASIPP Publishing; 2009. p. 87–98. Linetsky F, Alfredson H, Crane D, Centeno C. (2013) Treatment of chronic painful musculoskeletal injuries and disease with regenerative injection therapy (RIT): Regenerative injection therapy, principles and practice (Chapter 81). In: Deer TR (ed.) Comprehensive treatment of chronic pain by medical intervention, and integrative approaches. pp.889–912