MANAGEMENT OF NEUROGENIC PAININ THIS MILLENNIUMProf. A.V. SRINIVASAN, MD, DM, Ph.D,      D.Sc(Hon) ,F.A.A.N, F.I.A.N,    E...
What is Pain?• Medical Definition   “Pain is an unpleasant sensory and emotional     experience associated with actual or ...
Neurological Classification  Nociceptive Pain    Stimulation of somatic and visceral peripheral     nociceptors by stimu...
The Multiple Effects of PainEvery discovery contains an irrational element or 4 creative intuition                        ...
PAIN PATHWAYS                             DysphoriaPain Sensation                       ACC       SS                      ...
Generation of painIn any field, find the strangest thing and explore it
Nociceptive Pain• Nociceptive pain is mediated by receptors on  A–delta and C–fibers which are located in  skin, bone, con...
Nociceptive Pain• Somatic pain tends to be well localized,  constant pain that is described as sharp,  aching, throbbing, ...
Examples of Nociceptive pain• Post–operative pain• Pain associated with trauma• Chronic pain of arthritis        Take time...
Physiology of NociceptionNoxious stimulus                                             Response                            ...
State of Normosensitivity   Low intensity stimulation   High intensity (noxious) stimulation    Innocuous sensation       ...
State of Hypersensitivity                 Spontaneous pain      Low intensity stimulation     High intensity (noxious) sti...
Neuropathic Pain• It is the result of injury to the pain-  conducting nervous system• Disordered peripheral or central ner...
Neuropathic Pain• Neuropathic pain, in contrast to nociceptive  pain, is described as "burning", "electric",  "tingling", ...
Neuropathic Pain• Prevalence  – General population 0.6-1%• Causes  – Compression/infilitration of nerves by:    •   Tumors...
Kivun kr Assessment of Chronic                 Pain using fMRI              Physiological pain                      Pathol...
Neuropathic Pain & Epilepsy• There is notable similarity between the  patho-physiological and biochemical  mechanisms obse...
Examples of Neuropathic Pain• Trigeminal Neuralgia• Diabetic & Other painful polyneuropathies• PHN• Trauma to major nerve ...
This session is bought                   to you from                 the makers ofNumber four is the most practical of all...
Emerging trends                   in          Neuropathy TreatmentFive is the most dynamic of all numbers. It is persuasiv...
Potential Description of             Neuropathic Pain (NP)• Sensations (Spontaneous       • Cardinal signs/symptoms  Pain)...
Effects of chronic Pain on the Patient      Psychosocial & physical impairment  Insomnia                  Physical        ...
Normal PhysiologyGlutamate is an excitatory neurotransmitter thatmay be metabolized to gamma aminobutyric acid(GABA), whic...
Pathophysiology: Peripheral       and Central SensitizationIn a neuropathic pain state the balance ofinhibition vs excitat...
Pathophysiology: Peripheral          and Central Sensitization  The process by which a sensory nerve terminal synapses   w...
Ca+ induced Glutamate       Release
Ca+ induced           Glutamate Release• Release of Glutamate causes Mg block to be  removed from NMDA receptor• Glutamate...
Pathophysiology: Peripheral               and Central Sensitization   As the calcium comes in, the NMDA receptors are   ac...
Pathophysiology: Peripheral         and Central Sensitization• In summary, calcium, once activated, increases the  NMDA re...
33
Post Herpetic Neuralgia (PHN)• Viral Infection: Varicella zoster• Causes inflammation of the nerves• Results in painful sk...
Approach to Treatment: NP & PHN                          DiagnosisTreat underlying condition/ symptomatic treatment       ...
Neurogenic pain – Therapeutic targets• Na + Blockade –  Carbamazepine,Phenytoin,Mexiletine• Glutamate release – Lamotrigin...
Neurogenic pain – Therapeutic targets• GABA mediated inhibition – Valproic acid• GABA release & synthesis – Gabapentin• In...
Therapies to reduce pain  • Analgesics  • Antidepressants – TCAs  • Duloxetine  • Anticonvulsants – Carbamezapine  • Gabap...
Antidepressants – TCAs• Not approved DPN              • QT prolongation  & PHN                         • Arrhythmias• Smal...
Antidepressants – Duloxetine                   Duloxetine -                   • SNRIs                   • US FDA – DPN onl...
AEDsCarbamazepine                             Lamotrigine1.    FDA approved for                    1.    Rash 10%      Tri...
Gabapentin•   First-line drug for NeP•   No drug interaction•   Drawbacks       Bioavailability – 60%       Absorption –...
Treatment: Problem &         Solution• Many patients, however, are refractory to these and  other treatments because of in...
PregabalinThree can be seen in the divisions of a human in mind, body and spirit
PREGABALIN• Novel analgesic, anticonvulsant & anxiolytic properties• US FDA Approved (Dec 31, 2004) Rx for DPN / PHN and  ...
PREGABALIN• Mechanism of action:  – Binds to A2d subunit of voltage gated Ca++ channel,    reduces Ca++ influx thus reduci...
PREGABALIN• Linear pharmacokinetic profile• High bioavailability (> 90%)• Onset of action as early as 1-3 days     Learn t...
Mechanism of actionIn all of us, even in good men, there is awild - beast nature which peers out in sleep
Does Pregabalin affect GABA ?• Pregabalin has no effect on GABA. It does not bind to  GABAA or GABAB receptors and therefo...
Pharmacokinetics• Well absorbed orally with or without food• Tmax= 0.7 to 4 hours postdose• Bioavailability: > 90%• T1/2= ...
Pharmacokinetics    Linear pharmacokinetic profile    Proportional absorption across the dose range                       ...
Clinical Trials                  InDiabetic Peripheral   NeuropathyTime and Words cannot be recalled - Fuller
8 week DPN Trial - Design                              Pregabalin        Completed trial                                (N...
Demographics                                 Pregabalin 300   All patients                    Placebo Characteristic      ...
Significant reduction of pain and sleep       interference at study endpoint                Pregabalin       Placebo      ...
Mean pain reduction from baseline     in an– 8 week DPN trial       Rosenstock J et al. Pain 2004;110: 628–638
Quality of life - at study endpoint                 Pregabalin       Placebo      Endpoint                                ...
A double blind, multicenter,placebo-controlled study in DPN Time: 5 weeks Patients with a 1-to 5 year history of DPN (n = ...
5-week, DB, multicenter,     placebo-controlled study in DPN           65%                            48%                 ...
Efficacy of Pregabalin in DPN    Type: Randomised , double blind multicentre    Time: 6 weeks    N= 246 patients of DPN   ...
PREGABALIN: CLINICAL                   STUDIES                       PGB – Pregabalin 600 mg/day                       PCB...
Clinical Trials                            In              Post Herpetic                NeuralgiaThe Truth is fear and imm...
Postherpetic Neuralgia Pain              Relief               Overview• The efficacy of pregabalin for PHN was established...
Postherpetic Neuralgia Pain             Relief8-week study by Sabatowski et al.• 8-week study that compared pregabalin 150...
Postherpetic Neuralgia Pain              Relief8-week study by Sabatowski et al.• The proportion of responders at the 150 ...
Postherpetic Neuralgia Pain                   Relief     8-week Study by Dworkin et al     • 8-week study reported by Dwor...
Postherpetic Neuralgia Pain                       Relief    8-week study by Dworkin et al.  PGIC – Patients were more like...
Efficacy:PHN Pain ReliefPowerful efficacy across the dose range• Starting-dose efficacy of pregabalin 150 mg/day for PHN  ...
PHN: Rapid onset of action – from              day1 After day 1, the avg pain score in patients treated withpregabalin was...
PHN:Sustained pain relief
PHN:Time to sustained pain relief                  % of patients achieving Sustained ImprovementTreatment                 ...
Treatment of refractory            Neuropathic pain• Long-term exposure to pregabalin achieved clinically  meaningful, sus...
Long-term pain control by pregabalin in  refractory patients of PHN and DPN           (Ref- PP. 57th A.M. of AAN April-2005)
Pain reduction of at least 30%• Pain reductions of at least 30% were reported at three  months by 61% of DPN patients, 33....
Fibromyalgia  Fibromyalgia can be redefined physiologically as  chronic widespread Allodynia  [Russell 2004]Allodynia is t...
Fibromyalgia symptoms       PAIN                         NON—PAIN    Visceral                          Fatigue          ...
Study Design                                   8 weeksPhase:                           double blind              Optional ...
Pain Score*                                                                         Pregabalin                            ...
Pregabalin: Proportion of              Responders                                A significantly larger                   ...
Dose in Neuropathic pain                                            Rarely needed,                                        ...
Beyond Neuropathy…
Epilepsy• Four clinical trials show that pregabalin is efficacious  in the add-on therapy of partial seizures, even in  hi...
Patients with 50% seizure reduction         from baseline at 12 weeks                 *p=0.006 vs. placebo                ...
Seizure frequency reduction at 12                     weeks                                           Pregabali   Pregabal...
Sleep modulation   • Sleep disturbance was common in epilepsy and was     associated with a negative effect on Quality of ...
Pregabalin as anxiolytic•    Mechanism of action: Activation of     neurotransmission in fear circuits underlies     sympt...
Pregabalin in acute GAD treatment                      HAM-A change scores   Treatment                      Difference fro...
Pregabalin in acute GAD treatment                     HAM-A No. of responders (%)    Treatment group                   N  ...
Pregabalin in acute GAD treatment                            Completed       Adverse        Lack of   Treatment group     ...
Pregabalin may have several         advantages compared to     benzodiazepines/ antidepressants1. Less abuse potential2. L...
Favorable Safety and tolerability• Pregabalin is well tolerated.• Most adverse events are mild to moderate in  intensity, ...
Most Common Side effects in      controlled DPN & PHN studies             Placebo   Pregabali   Pregabalin   Pregabalin   ...
No clinically significant Drug               Interactions• Insulin                   • Oral contraceptives:• Hypoglycemics...
Summary•   Proven effective therapy for    Neuropathies                                      90•   Added benefits in Fibro...
The future… In all nations, history is disfigured by fable,till at last evidence (philosophy) comes to enlighten man; and ...
Dedicated to my family formaking everything worthwhile
READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOU
Management of neurogenic pain in this millennium
Management of neurogenic pain in this millennium
Management of neurogenic pain in this millennium
Management of neurogenic pain in this millennium
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Management of neurogenic pain in this millennium

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Management of neurogenic pain in this millennium

  1. 1. MANAGEMENT OF NEUROGENIC PAININ THIS MILLENNIUMProf. 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. 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, 1979One is the most independent, unconventional and individualistic of all numbers
  3. 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. 4. The Multiple Effects of PainEvery discovery contains an irrational element or 4 creative intuition Khrl Popper
  5. 5. PAIN PATHWAYS DysphoriaPain Sensation ACC SS Amygdala Thalamus Parabrachial Nucleus Dorsal Horn Aδ-Fibers C-Fibers DRGMechanoreceptors Polymodal Nociceptors 5 “Anger Begins In Folly And Ends In Repentance”
  6. 6. Generation of painIn any field, find the strangest thing and explore it
  7. 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 natureReputation is made in a moment; character is built in a life time
  8. 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. 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. 10. Physiology of NociceptionNoxious stimulus Response DRG Pain neuron Central nervousPeripheral tissue system Two is the most gentle of all numbers and represents, diplomacy and tact
  11. 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. 12. State of Hypersensitivity Spontaneous pain Low intensity stimulation High intensity (noxious) stimulationInnocuous sensation PAIN INCREASED PAIN (Allodynia) (Hyperalgesia) The Truth is Fear & Immorality are two of the greatest inhibitors of Performance to progress
  13. 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. 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. 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
  16. 16. Kivun kr Assessment of Chronic Pain using fMRI Physiological pain Pathological pain (pre capsaicin, 48°C) (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
  17. 17. 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
  18. 18. 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
  19. 19. This session is bought to you from the makers ofNumber four is the most practical of all numbers, with attention and a sharp eye for details
  20. 20. Emerging trends in Neuropathy TreatmentFive is the most dynamic of all numbers. It is persuasive, versatile and adaptable
  21. 21. Potential Description of Neuropathic Pain (NP)• Sensations (Spontaneous • Cardinal signs/symptoms Pain) (Evoked Pain) – Burning – Allodynia: pain from a – Paresthesia stimulus that does not – normally evoke pain Lancinating • Thermal – Electric like • Mechanical – Raw skin – Hyperalgesia: – shooting exaggerated response to a normally painful stimulus “Men of Genius Admired: Men of Wealth envied women of power feared but only women of character are trusted” A- Friedman
  22. 22. Effects of chronic Pain on the Patient Psychosocial & physical impairment Insomnia Physical Anorexia Depression Anxiety InactivityPhysical disability,social withdrawal, & Diminishedpsychological distress QOLare common sequelae.
  23. 23. Normal PhysiologyGlutamate is an excitatory neurotransmitter thatmay be metabolized to gamma aminobutyric acid(GABA), which is an inhibitory neurotransmitter Knowledge without action is useless; Action without knowledge is foolish
  24. 24. Pathophysiology: Peripheral and Central SensitizationIn a neuropathic pain state the balance ofinhibition vs excitation tips toward excitationThis tendency, which is largely glutamate driven, is what we see in neuropathic pain. GABA GABA GABA GLUTAMATE GLUTAMATE Number sixth is the most loving of all numbers and is 29 harmonious with all other number
  25. 25. 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 releasedNumber seven is the most spiritual of all numbers. It is the seeker of truth.
  26. 26. Ca+ induced Glutamate Release
  27. 27. Ca+ induced Glutamate Release• Release of Glutamate causes Mg block to be removed from NMDA receptor• Glutamate binds to the sites on the NMDA receptor• Sensitises NMDA• Opens Ca ++ Channels• Influx of Ca in post synaptic neuronWe learn by thinking and the quality of the learning outcome is determined by the quality of our thoughts R.B. Schmeck
  28. 28. 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 painEight is the most result-oriented of all numbers and represents a balanced world
  29. 29. 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
  30. 30. 33
  31. 31. 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
  32. 32. Approach to Treatment: NP & PHN DiagnosisTreat underlying condition/ symptomatic treatment Reduce Pain Improve overall Improve Quality of life Physical functioning Reduce Psychological distress Nine is the most humanitarian of all numbers. It is effort and sacrifice without the need for reward.
  33. 33. 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 but by Education widely different” - Chinese
  34. 34. 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”
  35. 35. 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”
  36. 36. Antidepressants – TCAs• Not approved DPN • QT prolongation & PHN • Arrhythmias• Small therapeutic- • Antiocholinergic side toxic window effects• 4-6 weeks • Postural Hypotension• Sexual adverse • Caution for patients effects with cardiac risk factors MOA - Increase NE and 5-HTIt is not your position that makes you happy or unhappyIt is your disposition
  37. 37. Antidepressants – Duloxetine Duloxetine - • SNRIs • US FDA – DPN only • No study in PHN • Hypertension • Onset 1-2 weeks • GI side effects • Sexual adverse effects MOA – Selective Serotonin Norepinephrine Reuptake InhibitorAs one is common to all numbers, it is often seen as the origin of all things
  38. 38. AEDsCarbamazepine Lamotrigine1. FDA approved for 1. Rash 10% Trigeminal Neuralgia 2. 2nd-line2. Side effects 3. InsomniaOxcarbazepine Topiramate1. One study for NeP 1. Nagative results (3 - / 12. Hyponatremia – +) monitoring of serum sodium required 2. Weight loss (10-20%)3. Rash – 4 % 3. Cognitive impairment4. Few Drug-drug 4. Nephrolithiasis (1.5%) interaction ValproateLevetiracetam 1. Nausea1. No controlled studies 2. Sedation 3. Fatal Hepatotoxicity -Tiagabine Enzymes1. No controlled studies 4. Hair loss 5. Hematologic effect (Platelet) 6. Drug-drug interactions Two symbolizes partnership implying that accomplishments are best through coordination.
  39. 39. 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
  40. 40. 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
  41. 41. PregabalinThree can be seen in the divisions of a human in mind, body and spirit
  42. 42. 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
  43. 43. PREGABALIN• Mechanism of action: – Binds to A2d subunit of voltage gated Ca++ channel, reduces Ca++ influx thus reducing the release of neurotransmitters like Glutamate
  44. 44. 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
  45. 45. Mechanism of actionIn all of us, even in good men, there is awild - beast nature which peers out in sleep
  46. 46. 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
  47. 47. 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 At twenty the will rules• Metabolism & elimination: eliminated largely by renal At thirty the intellect excretion At forty the Judgment
  48. 48. Pharmacokinetics Linear pharmacokinetic profile Proportional absorption across the dose range 12 mean Individual Steady-state Cmax values (µg/mL) 10 8 6 4 2 0 150 300 450 600 Pregabalin total daily dose (mg)Four is reliable, punctual, systematic and dependable, doing what it says it will do.
  49. 49. Clinical Trials InDiabetic Peripheral NeuropathyTime and Words cannot be recalled - Fuller
  50. 50. 8 week DPN Trial - Design Pregabalin Completed trial (N=76) 85.5%Screened Randomised (n=225) (n=146) Placebo Completed trial (N=70) 88.6 % Rosenstock J et al. Pain 2004;110: 628–638
  51. 51. Demographics Pregabalin 300 All patients Placebo Characteristic mg/day N = 70 N = 146 N = 76Age, year: mean 60.3 (10.3) 59.2 (12.3) 59.7 (11.4)(SD)Duration ofdiabetes, year: 9.4 (10.3) 9.3 (10.5) 9.3 (10.3)mean (SD)Height, cm: mean 171.3 173.2 (9.59) 172.3 (9.81)(SD) (10.01)Weight, kg: mean 95.8 97.6 (19.83) 96.7 (20.25)(SD) (20.80) Rosenstock J et al. Pain 2004;110: 628–638
  52. 52. Significant reduction of pain and sleep interference at study endpoint Pregabalin Placebo Endpoint comparison Mean SE Mean* SE Difference Parameter * P valueMean pain 3.99 0.26 5.46 0.28 -1.47 0.0001scoreMean sleep 2.78 0.27 4.32 0.29 -1.54 0.0001interferencescore Sleep improved from first day of study Rosenstock J et al. Pain 2004;110: 628–638 *Least Squares
  53. 53. Mean pain reduction from baseline in an– 8 week DPN trial Rosenstock J et al. Pain 2004;110: 628–638
  54. 54. Quality of life - at study endpoint Pregabalin Placebo Endpoint comparisonSF-36 health Mean SE Mean* SE Differencesurvey *Parameter P valueBodily pain 53.83 2.24 14.92 1.13 -4.41 0.0033Mental health 40.83 3.04 57.02 3.21 -16.19 0.0002Vitality 1.42 0.13 1.79 0.13 0.37 0.0364 *Least Squares J et al. Pain 2004;110: 628–638 Rosenstock
  55. 55. A double blind, multicenter,placebo-controlled study in DPN Time: 5 weeks Patients with a 1-to 5 year history of DPN (n = 338 ) Randomised to receive Pl. or Pr[75 or 300 or 600mg]Conclusions:Pregabalin demonstrated early and sustainedimprovement in pain and a beneficial effect onsleep, which were confirmed by positive patientglobal impression. H. Lesser at al. NEUROLOGY 2004;63:2104-
  56. 56. 5-week, DB, multicenter, placebo-controlled study in DPN 65% 48% 46% % %patients patients >30% 600 300 mg/day mg/day reduction in pain > 50 % reduction in pain (600mg/day) H. Lesser at al. NEUROLOGY 2004;63:2104-
  57. 57. Efficacy of Pregabalin in DPN Type: Randomised , double blind multicentre Time: 6 weeks N= 246 patients of DPN Pregabalin 150 or 600 mg /day Vs PlaceboConclusions:Pregabalin 600mg/day significantly decreases mean painscore to 4.3 [Vs 5.6 for placebo,P=.0002]Increases the proportion of patients who had a>50%decrease from baseline pain[39% vs 15%for placebo,p=.002]. Ralph et al. The Journal of Pain,vol6,No4[April],2005:pp 253-260
  58. 58. PREGABALIN: CLINICAL STUDIES PGB – Pregabalin 600 mg/day PCB -- Placebo 73% 85% % % 45% 47% Patients Patientsimproved improved PGB PCB PGB PCB Clinical Global Patient Global Impression Impression of Change (CGIC) of Change (PGIC) Ralph et al. The Journal of Pain,vol6,No4[April],2005:pp 253-260
  59. 59. Clinical Trials In Post Herpetic NeuralgiaThe Truth is fear and immorality are two of the greatest inhibitors of Performance too progress
  60. 60. Postherpetic Neuralgia Pain Relief Overview• The efficacy of pregabalin for PHN was established in 3 studies.• Patients had a Avg baseline pain score of ≥4 on an 11-point numerical pain rating scale from 0 (no pain) to 10 (worst possible pain). Discipline Weighs ounces Regret weighs Tons
  61. 61. Postherpetic Neuralgia Pain Relief8-week study by Sabatowski et al.• 8-week study that compared pregabalin 150 (n=81) or 300 (n=76) mg/day with placebo (n=81).• Treatment with pregabalin 150 mg and 300 mg/day resulted in significant treatment effects on endpoint mean pain scoreSabatowski et al. Pain 2004; 109:26-35.
  62. 62. Postherpetic Neuralgia Pain Relief8-week study by Sabatowski et al.• The proportion of responders at the 150 mg/day (26%) and 300 mg/day (28%) dosages were significantly greater than for placebo (10%).• For each dosage, a significant decrease in pain was seen at week 1 and continued throughout the study.• Pregabalin also improved sleep and this was seen at week 1 and continued throughout the study. Sabatowski et al. Pain 2004; 109:26-35.
  63. 63. Postherpetic Neuralgia Pain Relief 8-week Study by Dworkin et al • 8-week study reported by Dworkin et al. • Patients in this study were randomized to – Pregabalin 600 mg/day for those with Ccr >60 mL/min or – 300 mg/day for Ccr clearance between 30- 60 mL/min, o – placebo.Dworkin et al. Neurology 2003; 60:1274-1283.
  64. 64. Postherpetic Neuralgia Pain Relief 8-week study by Dworkin et al. PGIC – Patients were more likely to report global improvement with pregabalin than placebo. 10 0 *p=0.001% patients 80 * 60 40 20 0 Worse UnchangedImproved Worse UnchangedImproved (N=12) (N=50) (N=22) (N=3) (N=11) (N=71) Placebo Pregabalin
  65. 65. Efficacy:PHN Pain ReliefPowerful efficacy across the dose range• Starting-dose efficacy of pregabalin 150 mg/day for PHN with mean pain reduction sustained throughout a 13 week study• Moderate-to-severe patient population, with Av age of 71 years & pain duration of 3.4 years – Patient were allowed to remain on existing stable analgesic Rx Placebo (n=93) Pregabalin 75 mg BID (n=87) Pregabalin 150 mg BID (n=124) Pregabalin 300 mg BID (n=62) *P≤0.05 vs. placebo
  66. 66. PHN: Rapid onset of action – from day1 After day 1, the avg pain score in patients treated withpregabalin was lower than in patients receiving placebo
  67. 67. PHN:Sustained pain relief
  68. 68. PHN:Time to sustained pain relief % of patients achieving Sustained ImprovementTreatment 25% 50% 75%Pregabalin Day 1 Day 2 X300 mg/dPregabalin Day 1 Day 3 Day 20600 mg/dPlacebo Day 8 X X “Social Isolation is in itself a pathogenic Factor for disease production”
  69. 69. Treatment of refractory Neuropathic pain• Long-term exposure to pregabalin achieved clinically meaningful, sustained pain relief in patients with neuropathic pain who were refractory to other therapies, including – Tricyclic antidepressants, – Gabapentin, and – Analgesics PP 57th A.M. of AAN April- 2005
  70. 70. Long-term pain control by pregabalin in refractory patients of PHN and DPN (Ref- PP. 57th A.M. of AAN April-2005)
  71. 71. Pain reduction of at least 30%• Pain reductions of at least 30% were reported at three months by 61% of DPN patients, 33.3% of PHN patients; at 15 months, the proportion of responders were 54.6% and 41.2% respectively. DPN PHN 3 61% 33.3% months 15 54.6 41.2% months % (Ref- PP. 57th A.M. of AAN April-2005)
  72. 72. Fibromyalgia Fibromyalgia can be redefined physiologically as chronic widespread Allodynia [Russell 2004]Allodynia is the situation in which pain is caused by stimulus which should ordinarily not cause pain
  73. 73. Fibromyalgia symptoms PAIN NON—PAIN  Visceral  Fatigue  Cognitive Dysfunction  Sleep Disturbance  Depression/Anxiety  Autonomic“Character gets you out of bed commitment moves you to action faith, hope and Discipline follow through to completion”
  74. 74. Study Design 8 weeksPhase: double blind Optional open label 1 week 1 week or Baseline Titration 7 week fixed dose Withdrawal (Arthritis Rheum 2005, April.52(4): 1264-73)
  75. 75. Pain Score* Pregabalin significantly reduced mean pain score after 1 week of treatment Pregabalin 450 mg/ day significantly reduced mean pain score at endpoint (P=0.0009 vs placebo)•Primary Endpoint – pain noted in a diary on a scale of 0 (no pain) to 20 (worst possible pain)
  76. 76. Pregabalin: Proportion of Responders A significantly larger proportion of patients receiving Pregabalin 450 20.9* mg/ day experienced pain relief (defined by a 10.9 >50% reduction in pain 13.2 13.0 from baseline to endpoint •P = 0.003 vs placeboPlacebo 150 300 450 Pregabalin dose mg/ day
  77. 77. Dose in Neuropathic pain Rarely needed, If needed can be given in patients with Ccrcl ≥60 ml/min Thought is the labour of the intellect Reverie is its pleasure
  78. 78. Beyond Neuropathy…
  79. 79. Epilepsy• Four clinical trials show that pregabalin is efficacious in the add-on therapy of partial seizures, even in highly refractory patients.• Pregabalin represents an important advance in the adjunctive treatment of partial onset seizures. – Significant dose-related reductions in seizure frequency are seen in as many as three of four patients – onset of anticonvulsant activity occurring by the second day of treatment – efficacy being maintained ³ 2 years. “ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy
  80. 80. Patients with 50% seizure reduction from baseline at 12 weeks *p=0.006 vs. placebo ** ** P<0.001 vs. placebo * patients * 51 % 40 % 31 % 14 % % Place Pregaba Pregabali Pregabali bo lin n n (n=10 75 mg 150 mg 300 mg 0) BID BID BID (n=86) (n=90) (n=89)(Neurology 2003;60,1631-1637)
  81. 81. Seizure frequency reduction at 12 weeks Pregabali Pregabali n n Place 300 mg 200 mg bo BID TID (n=98 (n=103) (n=111) ) -1% - 36%Fewer seizure - 48% %na de M Neurology 2005;64,475-480 i
  82. 82. Sleep modulation • Sleep disturbance was common in epilepsy and was associated with a negative effect on Quality of Life. – Pregabalin improved sleep disturbance in patients with epilepsy, and – This effect appeared to be independent of the drug’s ability to suppress daytime seizuresIt is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  83. 83. Pregabalin as anxiolytic• Mechanism of action: Activation of neurotransmission in fear circuits underlies symptoms in anxiety disorders. Pregabalin reduces neurotransmission in activated neuronal circuits by reducing the release of neurotransmitters• Efficacy: Studies have established the anxiolytic actions of pregabalin in 1. Generalized anxiety disorder, 2. Social phobia and 3. A opendisorder prove a curse ; but Panic foe may a pretended friend is worse
  84. 84. Pregabalin in acute GAD treatment HAM-A change scores Treatment Difference from N P value group placebo Placebo 66 Pregabalin 69 -3.896 0.0013 200 mg TID Lorazepam 2 64 -2.346 0.0483 mg TIDFeltner DE et al. Journal of Clinical Psyccjopharmacology 2003; 12:3:240- 248.
  85. 85. Pregabalin in acute GAD treatment HAM-A No. of responders (%) Treatment group N Responders (%) Placebo 66 43.9 Pregabalin 200 mg TID 61 59.0 Lorazepam 2 mg TID 64 54.7Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:240- 248.
  86. 86. Pregabalin in acute GAD treatment Completed Adverse Lack of Treatment group trial event efficacy Placebo 71.6% 6% 4.5% Pregabalin 69.7% 19.7% 0 200 mg TID Lorazepam 2 mg TID 52.9% 35.3% 1.5%Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:240- 248.
  87. 87. Pregabalin may have several advantages compared to benzodiazepines/ antidepressants1. Less abuse potential2. Less likely to be associated with withdrawal symptoms3. Lack of interdose anxiety4. Benign in its effects on psychomotor performance compared to benzodiazepines.5. Advantage of a rapid onset of action6. Lack of sexual side effects Experience can be defined as yesterday’s answer to today’s problems
  88. 88. Favorable Safety and tolerability• Pregabalin is well tolerated.• Most adverse events are mild to moderate in intensity, occur during the first week of treatment, and tend to resolve over time• Discontinuation rates were low.• No cardiovascular, ophthalmologic, renal, hepatic or neurological concerns were noted in studies.• Regarding diabetes control, pregabalin had no effect on glycosylated hemoglobin A1c.  “Fools Admire but of men of sense approve” - A. Pope
  89. 89. Most Common Side effects in controlled DPN & PHN studies Placebo Pregabali Pregabalin Pregabalin Pregabal (n=857) n 150 300 mg/d 600 mg/d in all mg/d (n=633) (n=523) doses (n=514) (n=1831)Dizziness 7% 14% 27% 31% 23%Somnolenc 10% 16% 19% 14% ePeripheral 3% 7% 13% 14% 10% edemaDry mouth 2% 5% 5% 9% 6% Truth comes out of error sooner than that of confusion
  90. 90. No clinically significant Drug Interactions• Insulin • Oral contraceptives:• Hypoglycemics: ethinyl estradiol, glyburide, metformin norethindrone• Diuretics: furosemide • Carbamazepine,• Oxycodone Lamotrigine,• Gabapentin Phenobarbital,• Lorazepam Phenytoin, Tiagabine,• Ethanol (alcohol) Topiramate, Valproic acid Pregabalin does not inhibit major CYP450 enzymes in humans. Pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions.
  91. 91. Summary• Proven effective therapy for Neuropathies 90• Added benefits in Fibromyalgia 80 70 60 50 East• Effective in Anxiety disorders 40 West (GAD, Social Anx, panic) 30 North 20 10 0• Useful as add-on therapy for 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr partial seizures You are what you think and not what you think you are Anonymous
  92. 92. The future… In all nations, history is disfigured by fable,till at last evidence (philosophy) comes to enlighten man; and when it arrives in the midst of this darkness, it finds the human mind so blinded by centuries of error, that it can hardly undeceive it. Essai sur Les Moeurs – Voltaire.Five is the experimenter and the explorer as it is adventurous and courageous.
  93. 93. Dedicated to my family formaking everything worthwhile
  94. 94. READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOU

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