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CROSS LINKED - HYALURONIC ACID - A PARADIGM SHIFT IN THE TREATMENT OF NEUROPATHIC PAIN
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CROSS-LINKED HYALURONIC ACID - A PARADIGM SHIFT
IN THE TREATMENT OF NEUROPATHIC PAIN
John A. Campa III, MD - Attending Neurologist

Neuropathic Pain Center For Clinical Research & Treatment, Albuquerque, New Mexico, USA

Statement of Problem
Persistent neuropathic pain presents a special challenge to the clinician as current treatment regimens routinely include opioids, anti-neuropathic adjuvants and nerve blocks. However, at best, only modest pain control is achieved, and they are hindered by dose limiting side effects, e.g., impaired cognition, constipation and tolerance. Hence, a method of treatment that is safe, provides prolonged, significant relief, without side effects, dose limitations, and does not affect cardiovascular stability, would be ideal.
While the literature describes the use of cross-linked hyaluronic acid (CL-HA) as a cosmetic dermal filler for soft- tissue augmentation1, we believe our study is the first to assess its safety and efficacy in the treatment of neuropathic pain.

Naturally occurring HA
Hyaluronic acid (HA), a proteoglycan, is a linear, anionic, polysaccharide2, composed of glucuronic acid and N-acetylglucosamine units, naturally occurring throughout the extracellular matrix of skin (56%)3, connective, epithelial and neural tissues.1,2  Its molecular weight is 5-10 million Daltons3 in healthy tissues.
 
Non-Cross-linked Hyaluronic acid structure.
Cross-linked HA
Cross-linked HA commercially available and FDA approved, non-animal source, cosmetic agents are multiple, and include Juvéderm®4 (Allergan) HA content 22-26 mg/ml, molecular weight, 2.5 million Daltons5 and Restylane®6 (Medicis) HA content 20 mg/ml, molecular weight, 1 million Daltons5. It is the cross-linking of the HA (normally a liquid, metabolized in a day) that binds its individual polymeric chains, resulting in the formation of a viscoelastic hydrogel, accounting for its longevity (6-12 mos.), and its hygroscopic ability to absorb 1000 times its weight in water.1

Aim
The aim of this study is to assess the safety and efficacy of cross-linked hyaluronic acid in the treatment of neuropathic pain.

Materials & Methods
A 34 month retrospective chart review was performed, identifying 15 patients (7 female/8 male) with persistent, neuropathic pain (Table-1). The average age was 51yrs. (22-85 yrs.), with a mean pain duration of 66 mos., range, 4-200 mos. Among this group, twenty-two separate neuropathic pain syndromes were identified and initially subjected to differential local anesthetic neural blockade to determine the most reactive neural point overlying the relevant peripheral nerve innervating the painful area.   Pending a positive response and after the initial anesthetic block subsided, i.e., 72 hrs. later, targeted, neural matrix antinociception injection of CL-HA was then performed (XL-NMA™ injection method7, Fig. 1-5). Pretreatment VAS pain scores ranged from 6-10/10, with an average of 7.5/10. Note, the use of FDA approved cosmetic CL-HA agents in this study was off-label.
Pain locations included: Face, 1 (5%); Spine, 6 (27%): Cervical, 1 (5%); Thoracic, 3 (14%); Lumbosacral, 2 (9%); Shoulder, 1 (5%); Elbow, 2 (9%); Wrist, 2 (9%); Thigh, 1 (5%); Feet, 9 (41%).

The injectate consisted of CL-HA agents with a fixed HA concentration of 24 mg/ml and a variable cross-linking value of 9-11%. Average dose given was 0.15 cc, range: 0.05-0.2 cc. The injection was administered either through a 27G needle, or via a variable length, atraumatic blunt-tip 27G microcannula (DermaSculpt®), after a 21G injection port was prepared. The results were assessed by the degree and duration of pain relief from a single injection.

Results
All patients injected achieved pain relief, with the average post-procedure VAS pain score being 1.5/10. The range was 0-3.5/10. The average time to achieve pain relief was 24 hrs., and the range was from 0-48 hrs. Average duration of pain relief was 7.7 mos., and ranged from 2.5-18+ months. There were no untoward reactions or effects.
 
Discussion
The aim of this study, to assess the safety and efficacy of cross-linked hyaluronic acid in the treatment of neuropathic pain, is clearly supported by the impressive results, as noted above. In particular, that all patients benefited from all perspectives, including: pain level reduction, promptness of reduction, duration of reduction and the absence of untoward  reactions. Nonetheless, though the results are compelling, the mechanism or mechanisms underlying these dramatic findings requires additional study, and will likely be multifactorial in nature.

Mechanisms of primary consideration at the level of the extracellular neural matrix would include:

1) CL-HA as a physical, protective shielding and compartment: Blunting activation of spontaneous activity in C-fiber and Remak bundle afferency as well as aberrant nociceptive ephapse8;
2) CL-HA anionic depolarization: Polyanionic nature results in a sustained action potential refractory state;
3) CL-HA LMW/HMW-HA (Low Molecular Weight/High Molecular Weight) Mismatch Restoration & ICAM-1 (Intercellular Adhesion Molecule-1) inflammatory modulation: Resulting in modulation of regional, inflammatory activation, thereby stabilizing and restoring ECM (Extra-Cellular Matrix) post-injury, immuno-neural cross-talk dysregulation at the level of the extracellular neural matrix that resulted in the chronification of pain in the first place10.

Conclusions
We conclude that targeted, neural sensory antinociception injection of cross-linked hyaluronic acid is a safe and effective method of treating neuropathic pain. Its routine use should be considered early in the treatment of this patient group.

References
1. Bogdan Allemann I, Baumann L. Hyaluronic acid gel preparations in the treatment of facial wrinkles and folds. Clin Interv Aging. 2008; 3(4): 629-34.
2. Atkins, E, Sheehan, J. Structure of Hyaluronic Acid. Nature New Biol. 1972; Feb 23; 235(60): 253-4.  
3. Ågerup, B, Wik, O. NASHATM, The Monograph. Q-Med AB. 2008; 1-24.
4. Allergan, Inc, Juvéderm Gel, package insert.
5. Lim, L. Executive Summary Dermal Filler Devices, Public Advisory Committee Meeting. FDA. 2008; Nov 18: 1-41.
6. Medicis Aesthetics Inc, Restylane Gel, package insert.
7. Campa, JA. Novel indication and technique for the use of cross-linked hyaluronic acid in the management of pain. Patentscope. 2014; PCT Application No. 20140349958; patent pending. https://patentscope.wipo.int/search/en/search.jsf
8. Vorvolakos, K, Isayeva, I, Do Luu, HM, Patwardhan, D, Pollack, S. Ionically cross-linked hyaluronic acid: wetting, lubrication, and viscoelasticity of a modified adhesion gel. Med Devices (Auckl). 2011; 4:1-10.
9. Chen, J, Abatangelo, G. Functions of hyaluronan in wound repair. Wound Rep Reg. 1999; 7: 79–89.
10. Tajerian, M, Clark, D. The role of the extracellular matrix in chronic pain following injury. Pain. 2015;156: 366-370.

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