Prof. A.V. SRINIVASAN , MD, DM, Ph.D, D.Sc(Hon) ,F.A.A.N, F.I.A.N,

1. MANAGEMENT OF NEUROGENIC PAIN IN THIS MILLENNIUM Prof. A.V. SRINIVASAN, MD, DM, Ph.D, D.Sc(Hon) ,F.A.A.N, F.I.A.N, EMERITUS PROFESSOR-THE TAMILNADU DR MGR MEDICAL UNIVERSITY. FORMER HEAD AND PROF OF NEUROLOGY, MADRAS MEDICAL COLLEGE 26-3-11

2. What is Pain? • Medical Definition “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” • Operative Definition “Pain is whatever the experiencing person says it is, existing whenever he/she says it does.” • International Association for the Study of Pain, 1979 One is the most independent, unconventional and individualistic of all numbers

3. Neurological Classification • Nociceptive Pain • Stimulation of somatic and visceral peripheral nociceptors by stimuli that damage tissue • Neuropathic pain • Pain resulting from non-inflammatory dysfunction of the peripheral/central nervous system in the absence of stimuli • Nociceptive and neuropathic pain are caused by different neuro–physiological processes, and therefore tend to respond to different treatment modalities Whatever the Mind can conceive and Believe, the mind can Achieve Napoleon Hill

4. The Multiple Effects of Pain Every discovery contains an irrational element or 4 creative intuition Khrl Popper

5. PAIN PATHWAYS Dysphoria Pain Sensation ACC SS Amygdala Thalamus Parabrachial Nucleus Dorsal Horn Ad-Fibers C-Fibers DRG Mechanoreceptors Polymodal Nociceptors “Anger Begins In Folly And Ends In Repentance”

6. Generation of pain In any field, find the strangest thing and explore it

7. Nociceptive Pain • Nociceptive pain is mediated by receptors on A–delta and C–fibers which are located in skin, bone, connective tissue, muscle and viscera • Nociceptive pain can be somatic or visceral in nature Reputation is made in a moment; character is built in a life time

8. Nociceptive Pain • Somatic pain tends to be well localized, constant pain that is described as sharp, aching, throbbing, or gnawing • Visceral pain, on the other hand, tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing and colicky in nature Experience can be defined as yesterday’s answer to today’s problems

9. Examples of Nociceptive pain • Post–operative pain • Pain associated with trauma • Chronic pain of arthritis Take time to think; it is the source of power Take time to read; it is the foundation of wisdom Take time to work; it is the price of success

10. Physiology of Nociception Noxious stimulus Response DRG Pain neuron Central nervous system Peripheral tissue Two is the most gentle of all numbers and represents, diplomacy and tact

11. State of Normosensitivity Low intensity stimulation High intensity (noxious) stimulation Innocuous sensation PAIN “Healthy Mind and Healthy expression of Emotion go hand in Hand”

12. State of Hypersensitivity Spontaneous pain Low intensity stimulation High intensity (noxious) stimulation Innocuous sensation PAIN INCREASED PAIN (Allodynia) (Hyperalgesia) The Truth is Fear & Immorality are two of the greatest inhibitors of Performance to progress

13. Neuropathic Pain • It is the result of injury to the pain-conducting nervous system • Disordered peripheral or central nerves • Compression, transection, infiltration, ischemia, metabolic injury Science is below the mind; Spirituality is beyond the mind

14. Neuropathic Pain • Neuropathic pain, in contrast to nociceptive pain, is described as "burning", "electric", "tingling", and "shooting" in nature • It can be continuous or paroxysmal in presentation When they tell you to grow up, they mean stop growing

15. Neuropathic Pain • Prevalence • General population 0.6-1% • Causes • Compression/infilitration of nerves by: • Tumors • Nerve Trauma secondary to procedures • Nervous System Injury Of a burning and unremitting character - F.W.PAVY

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17. Kivun kr Assessment of Chronic Pain using fMRI Physiological pain (pre capsaicin, 48°C) Pathological pain (post capsaicin, 43°C) Note enhanced parietal (somatosensory association) and frontal (attention) lobe activity in the capsaicin induced thermal hyperalgesia model (right) Three is the most playful of all numbers and also creative, inspirational and motivating

18. Neuropathic Pain & Epilepsy • There is notable similarity between the patho-physiological and biochemical mechanisms observed in epilepsy and neuropathic pain It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent -La Broyers character J Am Geriartr Soc 1995; 43: 1279-89

19. Examples of Neuropathic Pain • Trigeminal Neuralgia • Diabetic & Other painful polyneuropathies • PHN • Trauma to major nerve trunks • Cancer related • Spinal cord disorders like multiple sclerosis and injuries • Brainstem & hemispheric injuries and Strokes NATURE, TIME AND PATIENCE are the 3 great physicians

20. This session is bought to you from the makers of Number four is the most practical of all numbers, with attention and a sharp eye for details

21. Emerging trends in Neuropathy Treatment Five is the most dynamic of all numbers. It is persuasive, versatile and adaptable

22. Sensations (Spontaneous Pain) Burning Paresthesia Lancinating Electric like Raw skin shooting Cardinal signs/symptoms (Evoked Pain) Allodynia: pain from a stimulus that does not normally evoke pain Thermal Mechanical Hyperalgesia: exaggerated response to a normally painful stimulus Potential Description of Neuropathic Pain (NP) “Men of Genius Admired: Men of Wealth envied women of power feared but only women of character are trusted” A- Friedman

23. Effects of chronic Pain on the Patient Psychosocial & physical impairment Insomnia Anorexia Physical Inactivity Depression Anxiety Diminished QOL Physical disability, social withdrawal, & psychological distress are common sequelae.

24. Normal Physiology Glutamate is an excitatory neurotransmitter that may be metabolized to gamma aminobutyric acid (GABA), which is an inhibitory neurotransmitter Knowledge without action is useless;Action without knowledge is foolish

25. Pathophysiology: Peripheral and Central Sensitization In a neuropathic pain state the balance of inhibition vs excitation tips toward excitation This tendency, which is largely glutamate driven, is what we see in neuropathic pain. GABA GABA GLUTAMATE GLUTAMATE Number sixth is the most loving of all numbers and is harmonious with all other number 29

26. Pathophysiology: Peripheral and Central Sensitization The process by which a sensory nerve terminal synapses with a second order neuron that is going to be able to process pain, largely depends on how much excitatory input i.e. glutamate is released Number seven is the most spiritual of all numbers. It is the seeker of truth.

27. Ca+ induced Glutamate Release

28. Ca+ induced Glutamate Release • Release of Glutamate causes Mg block to be • removed from NMDA receptor • Glutamate binds to the sites on the NMDA receptors • Sensitises NMDA • Opens Ca++ Channels • Influx of Ca in post synaptic neuron We learn by thinking and the quality of the learning outcome is determined by the quality of our thoughts R.B. Schmeck

29. Pathophysiology: Peripheral and Central Sensitization As the calcium comes in, the NMDA receptors are actually further depolarized; this is a process that can cause continued neuropathic pain Eight is the most result-oriented of all numbers and represents a balanced world

30. Pathophysiology: Peripheral and Central Sensitization • In summary, calcium, once activated, increases the • NMDA receptor sensitization • It increases the release Glutamate and substance P The True Art of Memory is The Art of Attention - S.Johnson 32

32. Post Herpetic Neuralgia (PHN) • Viral Infection: Varicella zoster • Causes inflammation of the nerves • Results in painful skin lesions • Sores mainly occur on back and stomach • May occur also on face or mouth Take time to think; it is the source of power Take time to read; it is the foundation of wisdom Take time to work; it is the price of success

33. Approach to Treatment: NP & PHN Diagnosis Treat underlying condition/ symptomatic treatment Reduce Pain Improve overall Quality of life Improve Physical functioning Reduce Psychological distress Nine is the most humanitarian of all numbers. It is effort and sacrifice without the need for reward.

34. Neurogenic pain – Therapeutic targets • Na + Blockade – Carbamazepine,Phenytoin,Mexiletine • Glutamate release – Lamotrigine • Depletion of substance P – Capsaicin • Presynaptic release & Inhibition of substance P – Serotonin agonist,opioids, clonidine. • Sympathetic blockade – Alpha adrenergic receptor antagonist, guanethedine,Phentolamine • NMDA receptor blockers – systemic ketamine • K+ channel blockade, release of substance P - opioids “By Nature All Men/ Women are alike butby Education widely different” - Chinese

35. Neurogenic pain – Therapeutic targets • GABA mediated inhibition – Valproic acid • GABA release & synthesis – Gabapentin • Inhibition of dorsal horn – Norepinephrine, SSRI, Tricyclic antidepressants. • Desensitisation of Vanilloid receptor- Nerve Growth Factor.(NGF) • PAIN KILLERS –USE WITH CAUTION. • MAY LEAD TO ULCERATION WHEN PAIN IS NOT FELT. “Serious, sincere, systematic study surely secures supreme success”

37. Therapies to reduce pain • Analgesics • Antidepressants – TCAs • Duloxetine • Anticonvulsants – Carbamezapine • Gabapentin “The Truth is fear and immorality are two of the greatest inhibitors of Performance to progress”

38. Not approved DPN & PHN Small therapeutic-toxic window 4-6 weeks Sexual adverse effects QT prolongation Arrhythmias Antiocholinergic side effects Postural Hypotension Caution for patients with cardiac risk factors Antidepressants – TCAs MOA - Increase NE and 5-HT It is not your position that makes you happy or unhappy It is your disposition

39. Duloxetine- SNRIs US FDA – DPN only No study in PHN Hypertension Onset 1-2 weeks GI side effects Sexual adverse effects Antidepressants – Duloxetine MOA – Selective Serotonin Norepinephrine Reuptake Inhibitor As one is common to all numbers, it is often seen as the origin of all things

40. Carbamazepine FDA approved for Trigeminal Neuralgia Side effects Oxcarbazepine One study for NeP Hyponatremia – monitoring of serum sodium required Rash – 4 % Few Drug-drug interaction Levetiracetam No controlled studies Tiagabine No controlled studies Lamotrigine Rash 10% 2nd-line Insomnia Topiramate Nagative results (3 - / 1 +) Weight loss (10-20%) Cognitive impairment Nephrolithiasis (1.5%) Valproate Nausea Sedation Fatal Hepatotoxicity - Enzymes Hair loss Hematologic effect (Platelet) Drug-drug interactions AEDs Two symbolizes partnership implying that accomplishments are best through coordination.

41. Gabapentin • First-line drug for NeP • No drug interaction • Drawbacks • Bioavailability – 60% • Absorption – variable • Response – Variable (interindividual ) • Dose - 1200 – 3600 mg/day (unpredictable) • Titration – 3-8 weeks • Approved for PHN only Hate screeches, fear squeals; conceits trumpets but love sings lullabies

42. Treatment: Problem & Solution • Many patients, however, are refractory to these and other treatments because of inadequate pain relief or intolerable side effects. • Thus, additional safe and effective treatments are needed for patients A good teacher is a perpetual learner

43. Pregabalin Three can be seen in the divisions of a human in mind, body and spirit

44. PREGABALIN • Novel analgesic, anticonvulsant & anxiolytic properties • US FDA Approved (Dec 31, 2004) Rx for DPN / PHN and adjunct in mgt of partial seizures (adults) “Motivation is the Spark that lights the Fire of Knowledge and fuels the engine of Accomplishment

45. PREGABALIN • Mechanism of action: • Binds to A2d subunit of voltage gated Ca++ channel, reduces Ca++ influx thus reducing the release of neurotransmitters like Glutamate

46. PREGABALIN • Linear pharmacokinetic profile • High bioavailability (> 90%) • Onset of action as early as 1-3 days Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule

47. Mechanism of action In all of us, even in good men, there is a wild - beast nature which peers out in sleep

48. Does Pregabalin affect GABA ? • Pregabalin has no effect on GABA. It does not bind to GABAA or GABAB receptors and therefore is not an agonist or antagonist. • Pregabalin is not metabolically converted to GABA and does not alter GABA uptake or degradation at nerve terminals. • Studies show that high doses of pregabalin do not alter whole-brain GABA concentration. “Knowledge can be communicated but not Wisdom” - Hermann Hesse

49. Pharmacokinetics • Well absorbed orally with or without food • Tmax= 0.7 to 4 hours postdose • Bioavailability: > 90% • T1/2= 6 hours • Steady state reached in 24 to 48 hours • Metabolism & elimination: eliminated largely by renal excretion At twenty the will rules At thirty the intellect At forty the Judgment

50. Pharmacokinetics Linear pharmacokinetic profile Proportional absorption across the dose range 12 Individual mean 10 8 6 Steady-state Cmax values (g/mL) 4 2 0 600 450 300 150 Pregabalin total daily dose (mg) Four is reliable, punctual, systematic and dependable, doing what it says it will do.