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Dextrose Perineural Injection TherapyRegenerative Nerve Treatment
Targeting Neuropathic PainNer Ne
3er CONGRESO LATINOAMERICANO DE MEDICINA MÚSCULO-ESQUELÉTICA
ROSARIO, ARGENTINA
September 15, 2016
Liza Maniquis-Smigel, MDHawaii Center for Regenerative Orthopedic Medicine
Physical Medicine & RehabilitationHil d H l l H ii
John Lyftogt, MD• Sports medicine family
practice physician from New Zealand
• Studied traditional prolotherapy in 2002
• discovered that SQ injection of dextrose is effective. (Neural Prolotherapy)
• Father of Dextrose Perineural Injecton Treatment
CHRONIC PAINIASP
A NEW definition of Neuropathic Pain‘‘A pain caused by
a lesion or disease in the SOMATOSENSORY
SYSTEMSomato Sensory System’’
Commentary: A new definition of neuropathic pain2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2011.06.017
A new definition of neuropathic painInternational Association for the Study of Pain (IASP)
The current therapy for neuropathic pain is not satisfactory. More than two-thirds of
neuropathic pain patients obtain insufficient pain relief
and this poor response is likely related to our failure to target relevant pain-
generating mechanisms in individual patients
Commentary: A new definition of neuropathic painInternational Association for the Study of Pain (IASP)
Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2011.06.017
CENTRALIZATION OF PAIN
PAIN IN THE 20TH CENTURYCentralization of Pain
(BURNED INTO THE BRAIN)
Ronald Melzack, (born July 19, 1929, Montreal, Quebec)Melzack was the
recipient of the 2010 Grawemeyer Award
Pledge to Turn the Tide on Opiod EPIDEMICAugust, 2016
UNITED STATES SURGEON GENERALVivec Murthy, MD, MBA
• Since 1999, opiod overdose deaths have quadrupled and opiod prescriptions have increased-for every adult in America to have a bottle of pills.
• 2 million people have Rx opiod use disorder, contributing to increased heroin use and spread of HIV & Hep C.
• Amount of pain Americans have reported have not changed.
Canadian Pain Society May 24 2013
Severe Neuropathic Pain Only 1/4 Respond to Standard Drug Protocols
What Else Is There?
Presentation at the Canadian Pain Society in Winnipeg 2013 found
only 23.7% of severe neuropathic pain victims responded to Canadian Pain Society drug protocols for neuropathic pain
Conclusion: this poor response is related to our failure to target relevant pain generating mechanism.
Somato Sensory Pathways (vertical)
Propriocepsis Muscle tension, tendon stretch
Fine Discriminative TouchLight touch, pressure, vibration
Pain and Temperaturetickle and itch(Mechano-thermo-chemical nociceptive system)
FIRST ORDER NEURONS(C&Aδ fibers Capsaicin sensitive/TRPV1 nerves)
SECOND ORDER NEURONS with sub branch to Hypothalamus
THIRD ORDER NEURONSModulators:opiatesAnticonvulsantsantidepressants
DEXTROSE
21ST CENTURY-PERIPHERAL NERVE SENSITIZATION
• NEUROGENIC INFLAMMATION IS THE BASIS FOR PAIN GENERATION
• A Paradigm shift
WHAT IS Dextrose Perineural Injection Treatment?
• PIT is a regenerative nerve treatment to treat neuropathic pain and other diseases.
• Buffered D5W (Dextrose 5% in sterile water) near nerve injections, targeting sensory peptidergic nerves, relieves pain instantly and with repeated treatment, abolishesneuropathic pain and other chronic conditions.
• The proposed mechanism is dextrose mediated inhibition of neurogenic inflammation by its downregulation of TRPV1 activity on membrane of the sensory unmyelinated C fibers.
PIT TREATS SMALL FIBER NERVESIN PERIPHERAL NERVE
TRUNKS
their cutaneousand deeper branches
targeting fascial, muscular and
bony penetration points (CCI)
Sir Victor Horsley, ( 1857- 1916, British physiologist and neurosurgeon who was first to remove a spinal tumour (1887).
John Marshall FRS FRCS (1818 – 1891) was anEnglish surgeon and teacher of anatomy
NERVI NERVORUM PATHOLOGY CAUSE OF NEURALGIA/NEUROPATHIC/ CHRONIC PAIN
Professor John Marshall FRS FRCS
(1818 – 1891) English surgeon and teacher of
anatomyPresident of the Royal College of
Surgeons
BUT ALL PAIN IS IN NERVES
In 1883 Marshall and Sir Victor Horsley postulated that ‘Nervi Nervorum’
were responsible for the inflammation of the nerve trunk sheath causing “neuralgia”.
THE LANCET, December 15, 1883
Nervi Nervorum: Free Nerve Ending
NEUROMA
CHRONIC CONSTRICTIVE INJURY (CCI)“The pain of Neuralgia is more severe at certain apertures
where the nerves pass out of the osseous or fibrous framework of the body or pass round given points of bone”
Bradshaw Lecture 1883
CHRONIC CONSTRICTIVE INJURY of the supraclavicular nerves- important nerve to
treat for WHIPLASH INJURY
VALLEIX POINT 1841 CHRONIC CONSTRICTION INJURY
where the nerve emerges from the bony canal
where it pierces a muscle or aponeurosis to reach the skin
where a superficial nerve rests on a resisting surface where compression is easily made
Where it is entrapped b/w fibrous tissue
AXOPLASMIC FLOW
When intraneural pressure exceeds 30 mmHg,All axoplasmic flow stop
Interrupted Axoplasmic flow following peripheral nerve damage will result in impaired regeneration of
Peptidergic Sensory NervesThis is associated with
chronic neurogenic inflammationand
neuropathic pain
Mosconi T, Kruger L. Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural
morphometric analysis of axonal alterations. Pain. 1996; 64(1): 37-57.
Friction trauma of nervi nervorum may cause a CCI or Peripheral Entrapment Neuropathy
Professor Emeritus in Anatomy
Lawrence Kruger, Ph.D.UCLA
MACROSCOPIC IMAGE
NEUROPATHIC SWELLING AND INFLAMMATION
IN AMORTON’S NEUROMA
Due to a nervi nervorum injury caused by friction
against the deep transverse tarsal
ligament
Morton’s neuroma: caused by friction against the deep transverse tarsal
ligament
PERIPHERAL ENTRAPMENT NEUROPATHIES Kopell and Thompson 1963
Superior Cluneal (L 1 or 2 or 3) nerve entrapment (intussusception/friction
injury) in Osteo-fibrous tunnelA common cause of recurrent lumbago
Fig. 3. A: Photographs of the SCN entrapment release procedure. The SCN is seen penetrating the thoracolumbar fasciathrough the orifice just before crossing over the iliac crest. Distal to the orifice (arrow), the SCN (arrowheads) appears pale
because of circulation disturbance attributable to nerve entrapment. B: The orifice of the thoracolumbar fascia was openedwith microscissors in a distal-to-rostral direction along the SCN. When the thoracolumbar fascia was cut, the nerve could be
seen bulging within the subfascial fat layer. C: The entrapped SCN was released from the orifice in a rostral direction from thesurrounding fat between the thoracolumbar fascia and the paraspinal muscles. D: After the SCN was released, intraoperativemanual direct compression of the SCN produced no pain. E: After the orifice was opened, the exposed SCN in the operative
field was constricted where it penetrated the orifice. The arrow points to the constriction site; the arrowheads point to the releasedSCN. The superficial circulation of the nerve improved after sufficient decompression.
Entrapment of nerves is usually caused by
trauma to Nervi Nervorum resulting in swelling and inflammation of the
epi-perineurium of nerve trunks
Nervi Nervorum are small fiber nerves with dual endocrine and sensory
function
JOHN HILTON1805-1878
Hilton's law 1863
The nerve trunk supplying a joint also supplies the overlying skin and the muscles that move
the joint.
On rest and Pain. John Hilton 1863
Nervi Nervorum
are peptidergic small fiber nerves innervating the epi-perineurium
(sheath) of nerve trunks and belong to this specific system
of small fiber nerves with dual sensory and endocrine function,
PIT treats nervi nervorum
of peripheral nerves injured in potential entrapment
sites of fascial and bony penetration points
PIT affects “nervi nervorum
regeneration”
• Involves injecting 1-3 cc of D5W to the subcutaneous nerves with 27-gauge 1/2" needle 1/4" deep
Lyftogt Perineural Injection Technique
• Deeper Injections at entrapment sites-fibrous openings (supraclavicular fossa)-bony openings( supraorbital fossa)-entrapped between fibrous tissue
(median nerve at carpal tunnel)-entrapped as it passes through muscle (radial nerve at supinator)
DEEP Perineural Injection Technique
NOCICEPTORS AND THE PERCEPTION OF PAIN
CONCEPT OF NOCICEPTORS
• Nociceptors are nerves that transport the impulses to the brain that leads to sensory experiences (pain). They sense noxious impulses:
mechanical/pressureheatchemical
• There are only 4 nociceptors that can inform the brain about pain. No more no less.
D5W/M5W = diagnostic tool for neuropathic pain
Mechano-sensitiveHTM Aδ, Aβ,C AδSensory afferent/ NMDA pos
Mechano-insensitiveHeat CSensory efferent andSensory afferent Peptidergic/ TRPV1 pos
Mechano-sensitive Polymodal C, AδSensory afferent/ NMDA pos
DRG
Mechano-insensitivePolymodal Silent/Awake CSensory efferent andSensory afferent Peptidergic /TRPV1 pos
Area of up-regulated TRPV1 receptors with resultant neuropathic pain (red square)
4 NOCICEPTORS
TRPV1
D5W/M5W = diagnostic tool for neuropathic pain
Mechano-sensitiveHTM Aδ, Aβ,C AδSensory afferent/ NMDA pos
Mechano-insensitiveHeat CSensory efferent andSensory afferent Peptidergic/ TRPV1 pos
Mechano-sensitive Polymodal C, AδSensory afferent/ NMDA pos
DRG
Mechano-insensitivePolymodal Silent/Awake CSensory efferent andSensory afferent Peptidergic /TRPV1 pos
L
Area of up-regulated TRPV1 receptors with resultant neuropathic pain (red square)
Lidocaine blocks both nociceptive and neuropathic pain by blocking Na+ channels on all nociceptors
How to distinguish between nociceptive and neuropathic pain
Mechano-sensitiveHTM Aδ, Aβ,C AδSensory afferent/ NMDA pos
Mechano-insensitiveHeat CSensory efferent andSensory afferent Peptidergic/ TRPV1 pos
Mechano-sensitive Polymodal C, AδSensory afferentNMDA pos
DRG
Mechano-insensitivePolymodal Silent/Awake CSensory efferent andSensory afferent Peptidergic /TRPV1 pos
D5W
Area of up-regulated TRPV1 receptors with resultant neuropathic pain (red square)
Dextrose blocks only sensocrine nociceptors
“A Nervi Nervorum block”
NP
“This is an attractive and testable hypothesis”
Four classes of Nociceptors cause Nociceptive and Neuropathic pain
• NOCICEPTIVE PAIN
• Is caused by two classes of sensory afferent nociceptors of the Somato Sensory System
• Synaptic neurons• Mainly Aδ and C-fibers• Mechano- sensitive• Orthodromic conduction of
AP’s• Receptive Fields tightly linked
to ‘maps’ in homunculus. High discriminative sense. Pain is in ‘focus’
• Glutamate (NMDA) receptors expressed on synapse
• NEUROPATHIC PAIN
• Is caused by two classes of sensocrine peptidergic neurons of the Capsaicin Sensitive Nervous System
• Non-synaptic neurons • Mainly C-fibers and some Aδ fibers• Mechano-insensitive• Orthodromic and Antidromic
conduction of AP’s• Receptive field not tightly linked to
‘maps’ in homunculus. Pain is felt ‘deep’ and poorly localised. Low discriminative sense. Pain is out of ‘focus’
• Peptidergic nociceptors with Capsaicin (TRPV1) pore expression mainly at the terminal free nerve ending and DRG
A “CAPSAICIN RECEPTOR” WAS POSTULATED IN 1975
CLONED IN 1997 AND RENAMED TRPV1 BY DR DAVID JULIUS ET AL.
Janos Szolcsanyi. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 38 (2004) 377–384
The Capsaicin receptor: A heat-activated ion channel in the pain pathway. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. Nature 1997; 389:816-
824
HISTORY OF TRPV1 PORE
THE MOLECULE RESPONSIBLE FOR NEUROGENIC INFLAMMATION AND PAIN WAS
CLONED BY DAVID JULIUS AND HIS TEAM
The Capsaicin/Vanilloid TRPV1 pore is the principle mediator of pathological pain and neurogenic inflammation
The Capsaicin receptor: A heat-activated ion channel in the pain pathway. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. Nature 1997; 389:816-824
TRPV1 is a non-specific membrane cation channel and the most important molecule of inflammation and pain
TRPV1 agonist stimulate neurogenic inflammation and painTRPV1 antagonist block neurogenic inflammation and pain (Dextrose?)
Dec Glucose?
Na+ influx results in spike formation and increased AP’s with increased nociceptionCa2+ influx results in release of neuropeptides CGRP and SP
The TRPV1 ion channel (Capsaicin receptor) is embedded in the neural membrane of “THE TIP”
TRPV1 controls the release of CGRP and SP
AP
“TRPV1 PORE”
BradykininProstaglandins
THE TIP
Neural membrane
The peptidergic sensory TRPV1 nerves changes phenotype in response to nerve
damage and nerve repairTISSUE MAINTENANCE AND RENEWAL
NEUROGENIC INFLAMMATION AND NEUROPATHIC PAIN
NERVE
REPAIR
NERVE
DAMAGE
TRPV1 is a voltage gatednon-specific membrane cation channel (controlling Na/Ca
currents) TRPV1 is the principle mediator of:
1) tissue maintenance and renewal 2) inflammation and neuropathic pain 3) pain with disease and degeneration
Depending on threshold, supra-threshold or persistent supra-
threshold stimuli of:a) Sensitive to Capsaicinb) Chemicals like Bradykinin,
prostaglandins, serotoninc) Heat (over 43 C)d) Protons (acids) pH< 6.5e) Hypoxiaf) Glycopenia (?)
BradykininProstaglandins
Neural membrane
AP
“TRPV1 PORE”
The Peptidergic Sensory System is the effector arm of the nervous system
It acts through the TRPV1 PORE
• Low TRPV1 activity results in a Trophic effect to support tissue maintenance and renewal
• High TRPV1 activity results in Neurogenic Inflammation and Neuropathic Pain
• Prolonged and high TRPV1 activity results in disease and degeneration
• (Is osteoarthritis a BYSTANDER DISEASE???)
NEUROGENIC INFLAMMATION
• When stimulated (nerve root, peripheral nerve or nociceptor), by stretch, compression or TRPV1 receptor activation, the C fibers release:– CGRP– SP
• Leads to INFLAMMATION and DEGENERATION in the tissuessurrounding and innervated by the nerves.
Known CGRP effects
• Vasodilator of pre-capillary arterioles• Upregulation of VEGF, leading to neovascularisation
and neo-neurogenesis. VEGF increases MMP1 leading to collagenolysis (degeneration of tendons)
• Increased tissue Calcium levels (Calcifications)• Stimulation of Osteoclasts (dystrophy bone)• Blocks the uptake of calcium by osteoblasts
Known Substance P Effects• Vasodilator of post-capillary venules• Causes increased vascular permeability in post-capillary
venules with protein extravasation (neovascularization)• Important regulator of the immune system.
– Activates immune cells to produce cytokines– Chemo-attractive to immune cells– Binds to mast-cells causing degranulation
• Affects the Amygdala causing depression• Stimulates CRH release in the Hypothalamus upregulating the
HPA stress response . Prolonged activation may lead to exhaustion , low levels of DHEA
• SensitiZes peptidergic nociceptors, leading to neuropathic pain with allodynia and hyperalgesia
• Impairs propriocepsis by delaying antagonist muscle reflex inhibition (neurogenic inflammation of MEP)
• Causes increased intramuscular compartment pressure-(tightness)
Describes changes in bloodflow and blood vessel permeability caused by the local release of inflammatory mediators
from small fiber neuronssuch as Substance P (SP), Calcitonin Gene-
Related-Peptide(CGRP) and neurokinin A(NKA)
Neurogenic Inflammation
Shah’s article 2008 Role of Diminished ATP
• TPs are physiological dysfunction within the neuromuscular junction.
• "With reduced blood flow and diminished ATP, muscle fibers are locked in a contracture without sufficient energy to return Ca to sarcoplasmic reticulum and restore a( re) polorized membrane potential
• Shah notes a large number of neuropeptides and cytokines involved in the genesis of myofascial TrPs
• the important role of acidity and hypoxia
D5W TRIGGER POINT INJECTIONS VERSUS SALINE AND LIDOCAINE FOR MYOFASCIAL PAIN SYNDROME
• Table 9. Comparison of Visual Analog Scale (VAS) score according to solution in patients with myofascial pain syndrome. Adapted from: Kim MY, Na YM, Moon JH. Comparison on treatment effects of dextrose water, saline, and lidocaine for trigger point injections. Journal of the Korean Academy of Rehabilitation Medicine. 1997;21:967-973. Table 7.
MeanSolution Before Immediately After 7 days after5% D/W** 6.87 4.83 2.39*Saline 6.50 5.65 3.85Lidocaine 6.95 5.14 4.05
* p** 5% Dextrose water
Role of Dextrose on Energy Homeostasis
• Large #of neuropeptides and cytokines are involved in the genesis of myofascial trigger points.
• Living cells use ATP in a manner similar to chemicals in a rechargeable battery. (1 glucose=28 ATPs)
• Metabolic stressors (glucose deprivation, hypoxia, ischemia and metabolic poisons) will shift in the ADP : ATP ratio affecting cellular energy homeostasis.
Specialized tandem pore K channels are colocalized with TRPV1 and
respond to glucoseTREK 1 Glucose sensing neurons
Glucose The electrochemical Language
D-GLUCOSE stops small fibers from firing
Glycopenia induced c fiber excitation
D-dextrose
glycopenia
Activation of C fibers by Metabolic Pertubations Mclver 1997
• Presence or absence of glucose can be detected by small fibers and has been tested by in vitro study in a corneal model of small fibers
• 563% increase in firing rate in C fibers within 10 minutes of glycopenia.
• Introduction of GLUCOSE STOP small fibers from firing. (c fiber excitation was reversed within 20 minutes with reintroducing normal baseline glucose levels)
Role of Dextrose in Energy Homeostasis
• Chronic/Neuropathic Pain, caused by small fibers, is an alarm signal indicating disturbance in energy homeostasis.
• This can be corrected by injecting dextrose in the intracellular compartment resulting in:
– 1. upregulation of tandem K+ channels resulting in analgesia
– 2. correcting an energy deficit in the neuron, providing the cell with its internal energy allowing the cell to do work ie: express DNA to make new “growth factors, macromolecules, maintain membrane potential and axoplasmic flow.
TRPV1 NOCICEPTOR ACTIVATION
BUFFERED GLUCOSE• All glucose solution, whether D5W or D50 come acidic, on average pH 4.5.
• Even sterile water comes in a pH of 5.5
• The low pH creates stability and prevents bacterial growth.
• Acids stimulate TRPV1 pore to release the neuropeptides (SubP and CGRP) that produces the pain. so you want to buffer your solution to a pH of 7.8
• Add .5 cc of 8.4% sodium bicarb per 100 ml of D5W
• Precaution: Do not keep the solution more than 24 hours, because now that the solution is basic, there is higher chance for bacterial contamination and growth.
HYPOTHESIS OF PIT EFFECT• Hypoglycemic detection is mediated by sensory neurons (TRPV1)
that are colocalized with K+ channel. NEUROGLYCOPENIA
• Glucose is a tandem pore K+ channel opener causing hyperpolarization inhibiting impulse generation and spike formation. (analgesia and reduces neurogenic inflammation)
• K+ channels are pH sensitive (<pH6.9)
• TRPV1 channels are pH sensitive (<pH 6.5)
• Protons(acids) (H+) will increase nerve excitibility and neurogenic inflammation.
Hypothesis of the Effect of Buffered Glucose
• PIT restores perineural glucose levels and pH.
• This will result in repolarization and hyperpolarization mediated by tandem pore K channels, eliminating neuropathic pain and reducing neurogenic inflammation. GLUCOSE INHIBITION
CHRONIC PAIN IS A HOMEOSTATIC SENSATION
SUMMARY: PERINEURAL TREATMENT CLINICAL OUTCOMES
• Decreased pain• Improved function• Disease modifying effect
– Connective tissue repair– Reduction in numbers of neovessels– Reduced cross section of tendon – Reduced tendon oedema– Improved architecture of collagen in
tendinosis
PARADIGM SHIFT
Hawaii DVDs for Sale $500($650 on website)
THANK YOU FOR YOUR ATTENTION!
QUESTIONS???
DIRECT EVIDENCE FOR NEUROGENIC INFLAMMATION AND ITS PREVENTION BY DENERVATION AND BY PRETREATMENT WITH
CAPSAICIN
JANCSO N, JANCSO-GABOR A, SZOLCSANYI J
BRITISH JOURNAL OF PHARMACOLOGY,CHEMOTHERAPY 1967, 34, 138-151
There exists apure neurogenic form of inflammation
Confirmation that neurogenic inflammatory reactions are based on axon reflexes in the end branching of sensory nerves as found earlier by Bayliss (1901,1923), Lewis (1927) and Krogh (1929)
Sir Victor Horsley, Mr John Marshall, the Nervi Nervorum, and Pain
More Than a Century Ahead of Their TimeArchives of Neurology 2005
Joel A. Vilensky, PhD; Sid Gilman, MD; Kenneth Caseym MD
“The ideas that Horsley and Marshall generated on the importance of the nervi nervorum in neuropathic pain
were ahead of their time, and both men should be recognized for their
remarkable insight into this putative pain-generating structure”
The Nervi NervorumMissing Link for Neuropathic Pain?
Geoffrey M. Bove* and Alan R. LightPain Forum 6(3): 181-190, 1997
Hromada J: On the nerve supply of the connective tissueof some peripheral nervous tissue system components.Acta Anat 55:343-351, 1963
Gibbs Free Energy
• Spontaneous reactions always go into direction of entropy(disorder)
• All degenerative reactions in the body are spontaneous and do not need energy.
• To reverse degeneration or spontaneous reaction, requires energy which is stored in the form of ATP
• One molecule Glucose=36 molecules of ATP