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Cross-Linked Hyaluronic Acid Injection for Neuropathic Pain

Case presentation and superficial radial nerve injection technique
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The patient was seen again in mid-October 2016. He reported that after the August 2016 intervention, he had ongoing and complete remission of burning pain in all pain sites. His chief complaints were a dull/sharp pain (different sensations of pain—some sharp, some dull, depending on the nerve fibers involved) to palmar and dorsal surfaces of the hand and a painful tightness around both wrists. The tightness is due to the nerve root damage in his cervical spine that involves those fibers that form all 3 main nerves of the hand (SRN, MN, and UN).

The patient noted an increase in cervical spine rotation range of motion (ROM) by 50%, as well as a 50% reduction in his cervicobrachial pain at the C5-C6 and C4 proximal shoulder regions. He presented for augmentation XL-NMA of the bilateral MN and SRN—the UN and cervicobrachial regions remained improved and were not treated.

How It Works: Mechanisms of Action

Table 1 outlines the proposed mechanisms of action, which are multifactorial. They are ordered with regard to their temporal proximity to the evolving antinociception as noted over time—from the most immediate effects in the first 10 minutes after injection to the enduring and prolonged relief noted at 1 year or more in some cases.

CL-HA acts as a physical protective shield that forms a compartment that blunts the activation of spontaneous activity in the C fibers and Remak bundle afferency, as well as any aberrant nociceptive ephapse.10 Because of CL-HA’s polyanionic nature, its massive molecule (500 MDA to 100 GDa) may completely depolarize the action potential due to the size of its negative charge and prevent any transmission of the signal. The LMW/HMW mismatch correction results in TNFα-stimulated gene 6 protein modulation of the regional inflammatory response. This stabilizes and restores the immunoneural cross-talk dysregulation at the level of the extracellular neural matrix, essentially blocking what is thought to be causing the chronification of pain.11-14

In essence, after injury or insult to the extracellular neural matrix (ECNM), an initial acute phase of overt clinical inflammation supervenes, with attendant tissue swelling and activation of Aδ and C-fiber nociceptors. However, once this becomes chronic, the tissue inflammation and immuno-neural cross-talk becomes persistent but subclinical. Chronification would occur by virtue of a re-entry, positive feedback loop, thereby sustaining and maintaining the proinflammatory, pronociceptive state, blocking entry into the healing and restoration phase (Table 2). It is self-sustaining due to a LMW/HMW-HA mismatch, likely the result of a CD44/CD168 (RHAMM) gene aberration.

Injection of CL-HA at this point results in loop interruption by correcting the LMW/HMW-HA mismatch, permitting interleukin (IL)-1β and TNFα induction of TSG-6 for inflammatory moderation, by modulation and down-regulation of the interaction between LMW-HA and CD44. This then allows for normal progression to the ECNM anti-inflammatory, antinociceptive phase, as CD44 and RHAMM (CD168) are now able to properly interact with HMW-HA. To understand this mechanism, please refer to Table 2, which illustrates the relevant cytokine cascade and neuroimmunology after ECNM injury.

The foregoing considered, CL-HA may be regarded as a super-mega Dalton form of HA. As such, it augments and sustains many times over the restorative and healing molecular biological normative functions of the body’s HMW-HA, including:

  • Anti-inflammatory response
  • Inhibition of scar formation
  • Formation of functional super-structure aggregates
  • Immunosuppression
  • Antiangiogenesis
  • Increased ability to bind fibrinogen for clotting
  • Stimulation of peripheral blood monocytes
  • Production of growth factors and matrix components

Thus, the injection of CL-HA into the ECNM may result in:

  • Interruption of this loop
  • Correction of the mismatch
  • Entry into the healing and restoration phase (Table 2)
  • Returning the ECNM to homeostasis

Spooky Action at a Distance Confirmed?15

When discussing this case report with peers, I am often asked, “But how does a treatment in the periphery, well distal from the offending lesion in the neck, effect change?” In this case, the known lesions per CR and CT myelography are identified at the spinal segmental levels, C5-C6 and C6-C7 (C6 and C7 nerve roots, respectively). These lesions compromise both the nerve roots and the anterior spinal cord, which are thereby intimately part of the known root and cord derivation of the radial nerve (ie, C5, C6, C7, C8, T1). And, of course, they would support the ongoing burning pain experienced over the dorsa of both hands. However, to understand this further, one must consider the concept of deafferentation.16

Deafferentation Pain

Deafferentation pain is simply, “…severe spontaneous pain in body parts distal to the injury despite reduced or no sensitivity to external noxious stimuli to that body part (hypoalgesia or analgesia).”16 It may result from any injury to the nervous system, both central and peripheral, including the brain, spinal cord, and peripheral nerves. The deafferentation is believed to be due to the loss of information from the periphery to the brain. More specifically, there is an interruption in the afferent sensory information passing through the spinothalamic tract to the cortex. The domain of this tract includes the transmission of pain or nociceptive input centrally to the thalamus. Though the precise mechanism remains poorly understood, this model aptly fits the case at hand (ie, there is incomplete deafferentation of those nerve roots and spinal cord segments subserving the radial nerve).

So, applying this to the patient’s burning pain over the dorsa of the hands, in light of mechanism 3 in Table 1, an injury must occur to initiate the cytokine cascade’s proinflammatory, pronociceptive state (Table 2). This would be derived from the physical injury to the affected nerve roots and spinal cord segments. However, as the ECNM is a continuous and diffuse neuro-immunological, corporeal entity surrounding all neural structures (ie, it is one throughout), then the affected sensory neurons of the involved C6 and C7 nerve roots and spinal cord segments are in both continuous physical contact and neuro-immunological contact with those overlying the dorsum of both hands.

Hence, the injury at a distance is essentially the result of the proximal ECNM’s spooky action at a distance.15  This causes CD44, CD168 (RHAMM) to detect HAT, with inflammatory cytokine release of IL-1β, IL-6 and TNFα, which in due course initiates and sustains C fiber and Aδ nociceptor activation distally (Table 2, #3). With the injury of the ECNM surrounding the SRN established distally, it may now be intervened in-situ successfully with XL-NMA to achieve CL-HA LMW/HMW-HA mismatch correction and ICAM-1 (CD54) inflammatory modulation (Table 2, #3-#5 loop).

Last updated on: June 15, 2017
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