For Physicians

To gain an understanding of the developments that have led to the current hypothesis in the study and treatment and of chronic pain, one must understand the clinical work that has led to today’s ongoing current developments.

Classical prolotherapy with dextrose and other proliforants have been in use since the late 1930s. Numerous proliforants have been utilized. In classic prolotherapy, the central idea is to stimulate the body to heal injured and relaxed ligaments by injection at the enthesis. Injections initiate three phases of the healing cascade. First, the inflammatory or Signaling Cascade, followed by the Proliferation Stage and finally, the Remodeling Stage of ligamentous repair and strengthening. This process encompasses about 100 days with classical dextrose prolotherapy.   Hackett G.S. , Hemwall, G.A.,MD. & Montgomery,G.A. MD.  Ligament and Tendon Relaxation Treated by Prolotherapy.

Newer biocellular therapies are platelet rich plasma (PRP), stromal vascular fraction (SVF) or adipose derived fat stem cells and pericytes and hematogenous derived stem cell (HDSC) derived from bone marrow. Biocellular therapies have been used since the early 1990s in the United States and elsewhere. See Dr Brian Shiple’s book for further details. Click this link for a biocellular PowerPoint primer Update on Biocellula. Current research in tissue regeneration has produced deeper understanding of the role  of pericytes and the role of activated mesenchymal stem cells (MSC’s) in tissue regeneration and repair. Click the blue hyperlink introduction to pericytes in the reference section.
See the hyperlink also in the reference section for an excellent list of current literature in the application of interventional orthopedics.


The history and description of chronic pain actually began slightly prior to the Civil War. Dr. Thomas Weir Mitchell, described ‘Causalgia’ after the Civil War, where soldiers returning from battle with chronic pain developed pain that was not in the location of their original injuries. He noted that the pain was in a different nerve distribution and thus, seemed to be a condition of the nerves.

Currently, thanks to the remarkable work of a single physician in Christchurch, New Zealand, Dr. John Lyftogt has provided our current working hypothesis in chronic pain. That is neurogenic inflammation of the unregulated peptidergic sensory nervous system. His hypothesis is the upregulation of the peptidergic nervous system sensitization and swelling is responsible for the tenderness and expression of pain in chronic clinical syndromes.

Dr.Lyftogt’s work gave us a new paradigm for understanding the physical mechanical role in which the swollen nerves are trapped in tissue planes. He termed this ‘Chronic Constrictor Injury’ and ‘Friction Syndromes.’ The inflamed nerves which pass through apertures swell in deeper faschial layers. Or these swollen nerves rub across an anatomical site due to the particular position they have in relation to the movement of muscles. Activity producing pain,  can be down regulated with simple molecules such as dextrose or mannitol, when injected or applied very near the affected nerves. Superficial perineural injection (SPI).

When deeper tissue planes restrict swollen nerves, the resultant pain is dramatically reduced via subcutaneous PeriNeural injection (SPI) or Deep Perineural Injection (DPI). The current working hypothesis is that mannitol and dextrose can modulate neurogenic inflammation of the peptidergic nervous system thus improving muscle function and decrease the kinetic chain dysfunction that is created by the reciprocal inhibition produced by substance P (SP) and calcitonin related gene peptide (CGRP). See

Clinically, neurogenic pain is expressed as hyperalgesia, hypesthesia, and allodynia. The affected upregulated nerves are tender to touch and pressure and can produce local tissue texture changes such as edema or swelling. Nociceptive fibers do not express these characteristics.

Recent molecular biology advances, particularly in neuro-immunology, have led to the current working hypothesis. These neural modulating therapies change the phenotype of the calcium channels of the (TRPV-1) receptor of the upregulated peptidergic nerves in the peripheral nerve endings of sensory peptidergic nerves, as well as in the spinal cord and brain.    See reference Neuroimmune Biology for details. Recent developments in our understanding of the role of pericytes in tissue repair and maintenance has produced numerous clinical trials that our currently in progress.
It is my hypothesis that regenerative injection therapies activate the pericytes to transform into activated mesenchymal stem cells (MSC’s). Click the blue hyperlink introduction to pericytes in the reference section. Introduction to Pericytes and A Primer of MESENCHYMAL (MSC) Cell Function and Applications.

This neurogenic pain model illustrates the complex interaction between the immune system, the endocrine system and nervous system integration that involves the expression and up regulation of cytokines and other signaling proteins along with the endocrine system that are responsible for the sensitization or phenotypic TRPV-1 receptor conformation change. Which integrates the lowering of the threshold and sensitization of these nerves, both at the peripheral level, the spinal cord and central nervous system.

This conceptualization was derived as a result of the observation of treatments that are both diagnostic and therapeutic. This working hypothesis that neuropathic pain is mediated by these upregulated peptidergic sensory nerves that causes changes throughout the peripheral, spinal and central nervous system, is mediated by a family of TRPV-1 receptors. These receptors produce and up regulate neural peptides of this family of nerves.

Our understanding of how SP and CRGP upregulate and sensitize surrounding neural tissue in nearby tissue has enabled our understanding of how pain spreads and affects surrounding nerves. Neuropeptides are expressed  by the peptidergic nervous system when up regulated by injury, protons, heat or cold, or chemical signaling. The TRPV-1 receptor is polymodel has over thirty differing phenotypes and functional heterogeneity. for details see

Recent developments in high-resolution MSK ultrasound has allowed for physicians to more specifically target and precisely deliver these therapies to the areas of tendon injury or muscular injury that can be seen and examined both statically and dynamically. High resolution MSK allows visualization of the swollen tissue and painful nerves.

When the affected nerves are bathed with 5% mannitol water (5%MW) and or hydrodisected free from adherant connective tissue, pain relief and return of function is dramatic and often lasting. 5% mannitol in sterile water (5% MW) or 5% dextrose in sterile (5%DW) are similar. Mannitol delivering a slightly faster response. See the Reference Section for more information.

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