Understanding the Pain Pathway & NMDA Receptors

Pain Pathway

• Nerve endings are affected (nociceptors) which leads to action potentials being fired.
• Sensory nerves transmit signals to the central nervous system (CNS).
• Stimuli traveling through the CNS are either amplified or desensitized.
• Pain information enters the brain.
• The cerebral cortex perceives pain.

NMDA Receptor

• NMDA (N-Methyl D-Aspartate) receptors become active during depolarization, causing a large calcium amplification.
• The area where glutamate is increased is the main point, which leads to increased pain.
• This activation causes increased calcium binding.
• Ketamine and methadone are drugs that inhibit NMDA receptors.
• Amantadine, initially an antiviral drug, has notable side effects in humans.
• A rare side effect is associated with pre-existing seizure dogs.
• Preferred metabolism occurs in the liver and is cleared by the kidneys with reduced dosing.
• Increased inflammation is associated with increased age, leading to an imbalance in the chronic pain and immune system.

Fascia

• White connective tissue found directly under the skin, with deeper bands connecting muscles and tendons.
• Fascia creates connections between bones.
• "Interstitium" surrounds organs and vessels.
• It is responsible for fluid balance, support, and structure to tissue and organs.
• Fascia modulates force generation and mechanosensory fine-tuning.
• "Sticky" fascia can cause tissue pain.
• Viscoelastic changes occur rapidly.

Connective Tissue

• Connective tissue serves as the "home of the immune system."
• Connective tissue provides scaffolding and structural support for cancer cells and tumors.
• Stretching connective tissue leads to reduced inflammation.
• Sustained tension in the soft tissues of the back can be a source of pain if tissue inflammation persists.
• Fibroblasts change slowly, producing extracellular matrix (ECM) in about 10 minutes.

Opioids

• Opioids are preferred in acute pain management.
• For example, fentanyl and morphine act as Mu agonists which up-regulate pathways.
• Opioids are controversial in chronic or long-term pain as they down-regulate pathways.
• Extended NSAID treatment of over 6 months is associated with decreased progression of arthritis and pain in osteoarthritis.
• Monitoring for any disease changes within organs is important

Gabapentin

• Gabapentin is an anti-epileptic medication that also treat chronic pain.
• It also reduces stress in cats for veterinary visits.
• Side effects include sedation, ataxia, hypersalivation, and vomiting.
• Gabapentin binds to GABAa receptors, causing hyperpolarization by increasing chloride channel activity at the alpha delta subunit.
• Used to decrease heavy neuronal firing, which requires pain to be in an amplified state, but is not helpful for acute pain management.

Obesity

• Obesity can increase inflammation
• Weight reduction is analgesic, with more impact than non-steroidal medications.

Regenerative Therapy

• Small volumes of biologically active substances are injected into joints and soft tissues to promote tissue repair and reduce pain.
• It is indicated for osteoarthritis, perioperative, or postoperative conditions.
• Examples are Synovetin OA uses radioactive therapy to target synoviocytes with inflammation cycle.
• Monoclonal antibodies against nerve growth factor (NGF) neutralize NGF activity which reduces nociceptor sensitization and NGF-mediated inflammation.
• Use Ranevetmab in dogs and Frunevetmab in cats to treat osteoarthritis pain.
• Exercise caution using these in neuro patients

Osteoarthritis

• SP and CGRP neurotransmitters are related to osteoarthritis pain and both are upregulated by nerve growth factors.
• SP initiates/causes progression of osteoarthritis.
• Anti-NG monoclonal antibodies neutralize NGFs to decrease transmission of OA pain.

Non-Pharma treatments

• "Physical medicine" such as thermal therapies with ice and heat, massage, acupuncture, laser, shock wave are beneficial.
• Integrating homeostatic neurotransmitter systems with the nervous system is important when targeting pain.
• Targets Opioidergic, Serotonergic, Noradrenergic, and Andocannabinoid

Tissue Deformation

• The deformation of connective tissue complex.
• Mechano-transduction occurs from interaction with fascia networks.
• Leads to "intrinsic" healing in soft tissues.
• Stretching and exercise are important while fibroblasts respond.
• Facial modulation includes, acupuncture, massage, manual therapy, and stretching/exercise.

Therapeutic Laser

• Penetration of photons of light energy into tissue stimulates chromophores in mitochondria.
• A biphasic dose response observed with lower doses stimulating healing and higher doses potentially inhibiting healing.

De-amplifying Neuromodulation

• Acupuncture is a type of fascial modulation
• Motion is key
• Vagal nerve stimulation can be through exercise.
• Vagal nerve stimulation stimulates the parasympathetic nervous system (PSNS).
• Focus on Drugs, Diet and Meditation

Local Anesthetics

• Local anesthetics blocks initiation and conduction of APs in nerve fibers, which blocks transduction of pain.
• Essential part of multimodal analgesic plan.
• The MOA is Sodium ion channel blockade from inside nerve cell, which prevents depolarization and blocks nerve cell conduction.
• Local anesthetics have a transient effect due to metabolism or hydrolyzation.
• Systemic absorption increases with vasodilation, which decreases the duration.
• Add epinephrine to increase duration.

Sensation Loss

• Sensation disappears in the order of pain, cold, warmth, touch, joint, then deep pressure.

Local Anesthetic Types

• Procaine, tetracaine, and benzocaine may cause Methemoglobinemia sprayed on cat's larynx, proceed with caution.
• Lidocaine is common with fast onset, short duration.
• Lidocaine is anesthetic sparing, promotes GI, anti-inflammatory, and anti-shock
• Increased amount of drug to penetrate nerves and block Na channels, increases onset
• Bupivacaine has a longer time to onset and has longer duration.
• Lowest margin of safety and systemic cardiotoxicity is a concern since it goes straight to the heart, Never give IV!!
• Approved in dog pain management for Cruciate Ligament surgery
• Use moving needle infiltration technique and make sure injecting in all tissue layers.
• Ropivacaine is similar to bupivacaine but is more expensive. Pure S-enantiomer exerts less CV & CNS toxicity. Common in equine lameness blocks.
• Mepivacaine does not have vasodilator effects.

Local Adverse Reactions

• Avoid injecting in inflamed/infected or neoplasia area.
• Use a smaller gauge needle.
• Allow adequate time for post anesthetic administration and to monitor for adverse reactions.
• Neuro toxicity manifests as changes such as seizures, coma, muscle twitching, and rapid eye movement.
• Cardio toxicity impacts occur later, with respiratory arrest and death stemming from prior neuro signs development

Treatment

• Stop local anesthetic admission and start CPR if in cardio arrest.
• Supportive care depending on clinical signs.

Species Variations

• Cats are highly prone to Methemoglobinemia and forming Heinz bodies from anemia.
• Inhalant anesthesia decreases lidocaine metabolism over 2mg/kg.
• Cats have limited ability to metabolize local anesthetics so they are prone to toxicity.
• Lambs/kids are prone to overdose as they have small body mass and high vascularization during dehorning or castration procedure.

Local Anesthetic Adjuncts

• Other drugs included in local anesthetic techniques can cause unpredictable results such as shorter duration.
• Examples include Opioids to cause potential MOA but preservative free Morphine can cause synergistic side effects. Also caution Alpha 2 agonists.

Ketamine

• Ketamine works by blocking NMDA, Sodium, and Potassium channels.
• Side effects include increased HR and BP.

Epinephrine

• Epinephrine acts as a vasoconstrictor, increasing duration of action by delaying absorption.
• Ensure caution so you don't use on distal extremities because it can cause tissue necrosis.

Sodium Bicarbonate

• Added to lidocaine to reduce injection site pain by increasing diffusion for analgesic effect.
• Dose at a 1:9 ratio

Local Anesthetic - Equipment Required

• Basic Equipment- Hypodermic needles with a sharp bevel and stylet + Syringes.
• Advanced Equipment- Peripheral Nerve Stimulator, Insulated needles with injection port. Ultrasound to aid in visualization of nerve, Epidural catheter kit.

Aspirate

• ALWAYS aspirate prior to injection!

Local and Regional Nerve Blocks

• blocks include Line block, Field block, Splash block, Ring block, Inverted L Block. A splash block be be used ex) enucleation sx.
• Diffusion Catheter/Soaker Catheter administer analgesic boluses within incision when placed prior to closure and to maintain incision pain.
• Intercostal Block- At the caudal edge and proximal to the spine. Block 2-3 spaces caudally and cranially.
• Intraperitoneal (abdominal cavity) and Intratesticular blocks
• Thoracic includes caudal edge and proximal to spine + block 2-3 intercostal cranial and caudal

Blocks/Regional Nerve Blocks

• Block types include Intratesticular block (split 2mg/kg lidocaine) and Ophthalmic/Ear Block (Retrobulbar targets high risk patients) Intraorbital block **- more effective when injection inside foreman.
• Dental block, Thoracic limb block, IV Bier block are used to block areas

Pelvic Limb Nerve Block

• To block the front limb, use the brachial plexus block; be cautious for hemorrhage, Horner's syndrome, and pneumothorax. Radia and Thoraacic/cervica are use for regional approach
• The sciatic nerve should be distally blocked. For the hind limb, Bupivacaine + Dexmedetomidine is preferable to Femoral/Saphenous Nerve block. Suffice to perform foot and hock surgery.
• TAP block is used abdominal analgesia. Insert into landmarked lines where spinal processes connects the L7 to wings of iileum. Inject while monitoring with lig flavum sensation.

Cat Nerve Block

• More recent Caudal Epidural aids urethral obstructions and can be used instead of general anesthesia and can be achieved by coccygeal block. With intra-articular blocks be cautious so you don't inject toxic joint meds

Anesthesia and Normal Ventilation

• Anesthesia blocks PERCEPTION of pain so gas exchange can occur properly.
• Must use bicarb and sucralfate + monitor pH
• Acidosis and Electrolyte common after anesthesia
• Must maintain inspiration- "manual IPPV". Do NOT take hand off b/c you must open and close valve while squeezing bag while maintain gas
• To keep IPPV you must maintain inspiration- "manual IPPV". Do NOT take hand off b/c you must open and close valve while squeezing bag. Or you can use mechanical, but only on specialty clinics

IPPV Implications

• Without adequate ventilation, the first big risk is pulmonary arrest, so you must ventilate at beg Sx
• Pt with fractured rib cases where you must monitor the paradoxical breathing + manage SA: Horses (50/70). In all cases to manage fractured ribs and or horse SA

Negative effect of IPPV

• Impeding venous and excessive pressure leads to air build up in lungs.
• Low BP-ADH release
• Excessively low blood pressure leads to ADH release so you must exceed 20cm H20 when ventilating to avoid over inflation and also control hyperinflation

Effective Ventilation Parameter

• Effective ventilation parameter is in range of 35/45mm Hg while PIP is below 20cm H20 during ventilation. PEEP= end expiration.

Artificial Ventilation

• Anesthesia needs controlled ventilation because it needs elim by inhalant anesthetics. Hypercania occurs increased pCO2 levels and increases pressure, with MOST the the ventilator cycles at this point
• Artificial ventilation needs controlled ventilation because it should be eliminated by the anesthetic. Therefore it will lead to Hypercania
• Tachpnea= hypoxemia.

Importance of Weaning

• Pt may not spont breath- so you must still do manual and frequency checks. Anesthetic drugs delay spont ventilation

Blood Gas

• Arterial: Evaluate respiratory vs gas exchange, GOLD: Oxygen ventilation status 80/110 mmhg
• You must pull any air bubbles. Use arterial= small animals with femoral arterial Large animals with <10 min ice storage

Blood-Gas Status

• paO2+ FiO2- oxygen molecules depend on fio to pressure
• With blood fluid: Assess metabolic status which fixes CO2 transfer, increase will alter changes such as the RR status must also be altered depending on blood gas status. The bicarb should always lead and be in charge for 85% of the situation.

Volume

• Pt may go into hyper or hypo with O2 into tissues + avoid or drops

Tranfuse

• Products that lead to anemia must be used/ avoided to protect volume, and not pump

Tranfusion Adverse Events

• Non immune ranges from overload to thermo dysregulation

Anesthetic Complications

• Death must typically occur <48 hrs
• Occurs most of time in 3 hrs post op and you should not cause resp arrest. Avoid equipment malfunciont by keeping adequate dept when pt has vol issue

Complication: Depths

• You can adjust the setting, give fluid and treat arrhythmia

Hypo/Hyper Volume

• Pt fluid intake because a kidney will not hold fluid, or give ventilation due to hypoventilation
• Caution w ventilation from hypo

Hypoxemia

• Caused by five facts

GERD and Metabolic issues

• Patient will get GErD during anesthesia + gas/ vomit enters
• Electrolyte or acid balance with

Neuropathic/ issues are possible, with pt's volume inbalance, dyspnea. There might be dyspnea from the antihethetics so treat based on the sx

• Stabilise prior to the actual
• You can change setting, and if under you may need to reposition also

Postdental Blindness

• Blindness in cats common from cerebral artery, caused by
• Occurs from shock of equipment from a lung malfunction

Complications: Common Causes

• You can change dept or add

Cause and concerns of over and

• Check depth and re evaluate vent and make sure they have open

Vasopressor

• Pts may have HR

Drugs

• Volume, assess type and

Dependant and

• High causes

During hypotension (caused by epi and

Cardiac Arrest

• Give epinephrine but monitor

Shock (Epinephrine)

• Causes with increase hr, co2, decrease, then look for

Cardiac

• Catheterized

CPR Details

• Cats = x5 better rates, always call it out!!!
• Check for heat and

SHAKE call Help!

• And then monitor EKG
• Can mouth to mouth with

CPR Details

• You must assess and or

No Pulse

• Then connect EKG to see