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

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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