Prof. A.V. SRINIVASAN    INSTITUTE OF NEUROLOGY    MADRAS MEDICAL COLLEGE            CHENNAI.3Three Pronged Approach to  M...
Prevalence                •Increases in both males and females from age 12                until approximately age 40.     ...
Classification                     International Headache Society     Migraine      Migraine with aura                    ...
Migraine attack                                 Trigger           Increased serotonergic and noradrenergic                ...
Co-morbidities                Comorbidity - presence of two or more disorders                 whose association is more li...
Migralepsy        Migraine aura                        Seizures         (headache)      Migralepsy                        ...
Migralepsy             The Migraine – Epilepsy prevalence   Risk higher in patients who get migraines with aura,   compare...
Migralepsy           Migraine and epilepsy                  a bi-directional relationship      Possible explanations :    ...
Goals                       Goals Of treatment    reduce the              diminish the                            shorten ...
Measures                      Non-pharmacologic           Reduce the patient’s exposure to triggers that may              ...
Guidelines          Indications for pharmacologic prophylaxis            US Headache Consortium Guidelines     •   recurri...
Therapy          Drug classes for Migraine Prophylaxis                β-blockers              Antidepressants           ...
Antiepileptics            With newer advances in            knowledge of                co-morbidity with                e...
Principles of rational polypharmacy• Correctly identify the epilepsy syndrome• Select the drug that    - is effective for ...
Principles of rational polypharmacy    • If addition of the second drug completely controls      seizures, consider very s...
Combinations based on drug interactions         Least useful                     RationaleCarbamazepine with phenytoin   P...
Combinations based on drug interaction         Least useful                     RationaleFelbamate with phenytoin,      Ma...
Combinations based on mechanism of action         Most useful                        RationaleCarbamazepine or phenytoin w...
Combinations based on side effectsPossibly useful                   RationaleValproate with felbamate or       Felbamate a...
“ Social Isolation is in itself a pathogenic     Factor for disease production”
Speak obligingly even if you cannot oblige
Science is below the mind; Spirituality is beyond the mind
A woman’s desire for revenge outlasts all her other emotions
The world shall perish not for lack of wonders but lack of wonder
NATURE, TIME AND PATIENCE   are the 3 great physicians
Principles of rational polypharmacy• Correctly identify the epilepsy syndrome• Select the drug that    - is effective for ...
Principles of rational polypharmacy    • If addition of the second drug completely controls      seizures, consider very s...
Combinations based on drug interactions         Least useful                     RationaleCarbamazepine with phenytoin   P...
Combinations based on drug interaction         Least useful                     RationaleFelbamate with phenytoin,      Ma...
Combinations based on mechanism of action         Most usefulCarbamazepine or phenytoin with Widely different mechanisms o...
Combinations based on side effectsPossibly useful                   RationaleValproate with felbamate or       Felbamate a...
OxcarbazepinePharmaco dynamic properties• MHD• Cognitive saccadic smooth pursuit affected  but, focused attention and writ...
In vitro In vivo pharmaco studies               (SAME AS CARBAMAZEPINE)    In vitro    • Suppresses high frequency repetit...
In vitro In vivo pharmaco studies       (SAME AS CARBAMAZEPINE)In vivo•   Marked inhibitory effect in the hippocampal disc...
Pharmacokinetic properties      (BETTER THAN CARBAMAZEPINE)             Parameter       Oxcarbazepine     MHD C max(mg/L) ...
Pharmacokinetic …contdParent – 2 hoursMHD – 9 hoursMedian tmax – 4.5% (3 – 13 hours)Steady state MHD – 2- 3 daysLinear – 3...
Pharmacokinetic …contd  Distribution  Volume - 49 litres (40% - bound to protein)  Binding independent of serum concentrat...
Metabolism and excretionLiver – cytosolic enzyme – MHDConjugation with glucuronic acid4% oxidised to DHDExcreted by kidney...
Special populations• HEPATIC IMPAIRMENT  Mild to moderate hepatic impairment – no change,  severe – not studied• RENAL IMP...
Special populations …contd• GERIATRIC USE  30 – 60% higher than younger volunteers  cause for this is the age related redu...
Summary of randomized, double-blind controlled  trials for new antiepileptic medication involving            children with...
Dosage in Adults (above 16 yrs)                        Starting     Increment Titration Max.dose                          ...
Dosage in children (4-16 years)Initiation: 8-10 mg/kg/day (Not to exceed 600 mg/day          Body weight             Targe...
Relative Efficacy and Tolerability - AEDs Truth comes out of error sooner than that of confusion
Odds ratio – Meta analysis – New AEDs      Thought is the labour of the intellect             Reverie is its pleasure
Conclusions from controlled        trials and clinical use•   Oxcarbazepine is preferred safe and effective    first-line ...
Conclusions from controlled             trials and clinical use•   Gold standard efficacy in both children and adults    w...
Titration for initial monotherapy• Start with 150 mg/day• Increase by 150 mg/day every  2 days until reach target dose of ...
Oxcarbazepine: dosing guidelines          for children >4 years                                     Increase by maximum of...
Titration for conversion to monotherapy • Immediate conversion scheme     – overnight switch from carbamazepine       to o...
Titration of oxcarbazepine               adjunctive treatment  • Start with 150 mg/day  • Increase by 150 mg/day every    ...
Conclusions from controlled     trials and clinical use In summary, oxcarbazepine is apreferred first-line and first-choic...
In conclusion-        Role of Oxcarbazepine Partial with or without generalisation Adults – Monotherapy / Adjunct Child...
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...
The Pathophysiology Knowledge about the pathogenesis ofneuropathic pain has grown significantly        over the last 2 dec...
Anatomy of Nociception• What is nociception?  – Activation of transduction in nerves that convey    information about tiss...
Pathophysiology• The hallmarks of neuropathic pain are  chronic allodynia and hyperalgesia• Allodynia is defined as pain r...
Hyperalgesia• Hyperalgesia is defined as an increased sensitivity  to a normally painful stimuli• Primary hyperalgesia, ca...
The allodynia and hyperalgesia associated with neuropathic pain may be best explained by:1) The development of spontaneous...
The Prerequisite• For neuropathic pain to manifest clinically, there is  one prerequisite – Classical thermonociceptive  p...
Pathophysiology• Any insult to the nervous system leads to  changes in its structure and function as a result  of reparati...
C-fibre Conduction TTXr                             VGCC                    DRGSNS/SNS2   PN1,SCP6/PN4, BI,BII   N-type CC
Altered peripheral afferent function in inflammatory and neuropathic pain                                 SympGgl         ...
Injury produces multiple changes in sensory  neurons – increased afferent activity and          secondary central effects ...
Kivun kr Assessment of Chronic           Pain using fMRI       Physiological pain                   Pathological pain     ...
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 ...
DIABETES MELLITUS•   1990 – 2000 – Decade of brain.•   2001-2010 - Decade of pain control & research•   India – Diabetic c...
Risk factors  For Painful neuropathy       For painless neuropathy• Hyperglycemia            •   Greater height• Hypertens...
Diabetic polyneuropathy• The most common type of diabetic  neuropathy.• Presents primarily with sensory symptoms  & pain• ...
Prevalence of Polyneuropathy(Variable depending on criteria)All patients   Type 1   Type 2withpolyneuropathySymtomatic    ...
Classification of diabetic neuropathy  Diffuse                        Focal• Distal symmetric           •   Mononeuropathi...
Types of painful neuropathies       Acute (< 6 months)            Chronic(> 6 months)• Truncal neuropathy.              • ...
Pathogenesis1.Metabolic2.Vascular -reduced endoneural blood flow  and nerve ischemia3.Oxidative stress4.Autoimmune5.Neuroh...
Oxidative stress   Hyperglycemia                    ↑ NO↑Aldose reductase activity                                      3 ...
Pain Vs nociception• Pain is a subjective phenomena, expression  depends on the emotional experience.• Both central & peri...
Pain perception-central                                   Limbic     Affect behaviorLocalization Discrimination         IN...
Generation of pain
Generation of pain• Central terminals of unmyelinated primary c-  afferents project to dorsal horn and make  contact with ...
Generation of pain   • The hallmark of neuropathic pain is chronic     allodynia & hyperalgesia.   • C-fiber sensitization...
Generation of pain• The hallmark of neuropathic pain is chronic  allodynia & hyperalgesia.• C-fiber sensitization produces...
Clinical features –      Distal symmetrical painful     sensorimotor polyneuropathy• Burning, superficial pain. Hypoalgesi...
Clinical features –                 Truncal neuropathy• Truncal polyneuropathy              • Truncal radiculopathy• Rare ...
Clinical features Insulin neuritis   • Acute painful, occurs 1 month after insulin /OHA.   • Due to rapid glycemic control...
Insulin neuritis- contd..,• Burning pain, paraesthesia, allodynia with  nocturnal exacerbation.• Depression is a feature.•...
Clinical features - Cachectic neuropathy•   In patients with a poor control of DM.•   Wt.loss is prominent.•   Severe burn...
Differntial diagnosis •   Claudication •   Radiculopathy •   Charcoat’s neuroarthropathy •   Plantar fasciitis •   Tarsal ...
Skin Biopsy PGP 9.5 staining
Skin biopsy – various sites
Dedicated to my family formaking everything worthwhile
READ not to contradict or confute Nor to Believe and Take for Granted but TO WEIGH AND CONSIDER THANK YOUMy sincere thanks...
Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine
Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine
Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine
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Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine

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Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine

  1. 1. Prof. A.V. SRINIVASAN INSTITUTE OF NEUROLOGY MADRAS MEDICAL COLLEGE CHENNAI.3Three Pronged Approach to Migraine, Epilepsy and Neuropathic Pain – Role of Oxcarbamazepine 19-09-2004, Thrissur, Kerala
  2. 2. Prevalence •Increases in both males and females from age 12 until approximately age 40. Age •Peaks between ages 35 to 40 years. •Continues to be higher in women (>2:1 ratio) after the age of menopause. •25% experience 4 or more severe attacks/month. Frequency •35% experience 1-3 severe attacks/month. •40% experience 1 or < 1 severe attack/month. •occurs about 3 times more often in women than men Gender •Women between the ages of 30 and 49 years from lower income households are at higher risk Headache. 1994;319-328., JAMA. 1992;267:64-69.
  3. 3. Classification International Headache Society Migraine Migraine with aura Ophthalmoplegic Retinal without aura migraine migraine (Classical migraine) (Common migraine) •Migraine with typical aura •Migraine with prolonged aura •Familial hemiplegic migraine •Basilar migraine •Migraine aura without headache •Migraine with acute onset aura Neurology. 1994; 44(suppl 4):S6-S10.
  4. 4. Migraine attack Trigger Increased serotonergic and noradrenergic stimulation in the brain stem Dilation or constriction of cerebral and scalp blood vessels Stimulation of branches of 5th cranial nerve (Trigeminal) Thalamus Chemoreceptor Nausea Cortex Vomiting Pain Hypothalamus - Photophobia J of Pharmacy Practice, Dec 1993; 253-270
  5. 5. Co-morbidities Comorbidity - presence of two or more disorders whose association is more likely than chance. Mood Neurologic Others disorders disorders Allergy/Asthma Depression Epilepsy GI disorders Mania Essential tremor (ulcer, IBD) Anxiety Stroke Panic Discipline Weighs ounces Regret weighs Tons
  6. 6. Migralepsy Migraine aura Seizures (headache) Migralepsy Both chronic neurologic disorders with episodic attacks Migraine and epilepsy Common symptoms Some people feel the rain; Others just get wet
  7. 7. Migralepsy The Migraine – Epilepsy prevalence Risk higher in patients who get migraines with aura, compared with patients who get migraine without aura. Median prevalence of epilepsy in migraineurs - 6% Median prevalence of epilepsy in general population – 0.5% Patients with partial and generalized forms of epilepsy are more likely to have migraines, with the biggest increase-- fourfold--in those with posttraumatic epilepsy. Family Pratice News, March 15, 2001 Opinion is ultimately determined by the feelings and not by the intellect
  8. 8. Migralepsy Migraine and epilepsy a bi-directional relationship Possible explanations : •Head injury predisposes to both migraine and epilepsy, but patients with idiopathic epilepsy also have increased risk of migraine. •An altered brain state This bi-directional relationship provides foundation for the use •Environmental factors of anti-epileptics for migraine treatment •Genetic factors Experience can be defined as yesterday’s answer to today’s problems
  9. 9. Goals Goals Of treatment reduce the diminish the shorten the frequency of severity of duration of (or eliminate) migraine migraine migraine attacks attacks attacks Prophylaxis is considered successful if the frequency, duration, and/or intensity of attack is decreased by at least 50%. Journal of Pharmacy Practice. 1993; 253-270. It is the province of the knowledge to speak and it is the privilege of the wisdomto listen - Hodly’s
  10. 10. Measures Non-pharmacologic Reduce the patient’s exposure to triggers that may cause a migraine attack to start. •missed meals Patients •too little sleep should be encouraged •excessive heat and humidity to keep a •foods such as chocolate, hard cheeses, headache alcoholic beverages, citrus fruits, nuts, diary in an excessive caffeine, and caffeine withdrawal effort to •medication such as oral contraceptives identify overuse of analgesics triggers. •strong sensory stimuli such as bright lights, glare,flickering lights, odors, smoke and prolonged exposure to heat or cold. The meek shall inherit the earth - but not its mineral rights
  11. 11. Guidelines Indications for pharmacologic prophylaxis US Headache Consortium Guidelines • recurring migraines that, in the patients opinion, significantly interfere with their daily routines, despite acute treatment • frequent headaches (more than two per week) • contraindication to adverse events or failure or overuse of acute therapies • the use of acute medication more than twice a week • presence of uncommon migraine conditions Curr Med Res Opin 17(1s):s87-s93, 2001. Our best thoughts come from others
  12. 12. Therapy Drug classes for Migraine Prophylaxis  β-blockers  Antidepressants  Calcium channel antagonists  Serotonin antagonists  Anti-epileptics  NSAIDs  Others (including riboflavin, minerals and herbs) Curr Med Res Opin 17(1s):s87-s93, 2001
  13. 13. Antiepileptics With newer advances in knowledge of co-morbidity with epilepsy, the new frontier for migraine prophylaxis is use of anti-epileptic drugs. Family Practice, 2001, Vol. 18, No. 1, 101-106 Success is a prize to be won. Action is the road to it. Chance is what may lurk in the shadows at the road side. - O. Henry
  14. 14. Principles of rational polypharmacy• Correctly identify the epilepsy syndrome• Select the drug that - is effective for the epilepsy syndrome - has the least potential for adverse effects of concern to the patient. E.g. teratogenicity, skin rash, weight gain - is most economical• Initiate treatment with one drug• If seizures are only partially controlled at maximally tolerated doses, consider polypharmacy• For the second, select one that has – A different mechanism of action – The lowest potential for metabolic interactions – The lowest potential for adverse effects It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  15. 15. Principles of rational polypharmacy • If addition of the second drug completely controls seizures, consider very slowly withdrawing the first drug after six months or more of complete control • Carefully record seizures • If two medications do not completely control seizure – Reconsider the diagnosis – Consider surgical options – Consider using more than two drugsWe possess by nature the factors out of which personality can be made, and toorganize them into effective personal life is every man’s primary responsibility - Harry Emerson Fosdick
  16. 16. Combinations based on drug interactions Least useful RationaleCarbamazepine with phenytoin Phenytoin induces carbmazepine metabolism, leaading to need for much higher carbamazepine dosesPhenobarbital with Phenobarbital is a powerfulcarbamazepine inducer of CYP 450 systemPhenytoin, valproate Valproate decreasesValproate with phenobarbital phenobarbital metabolismValproate with phenytoin Both complete for protein binding sites, reducing the value of total drug level measurement Mind is the great level of all things; human thought is the process by which human ends are ultimately answered - Daniel Webster
  17. 17. Combinations based on drug interaction Least useful RationaleFelbamate with phenytoin, Many drug – drug interactionscarbamazepine and valproateUsefulGabapentine with any drug No drug interactionValproate with lamotrigine Valproate inhibits metabolism of lamotrigine, reducing dose and cost of treatment with lamotrigine “ Social Isolation is in itself a pathogenic Factor for disease production”
  18. 18. Combinations based on mechanism of action Most useful RationaleCarbamazepine or phenytoin with Widely different mechanisms ofgabapentine, tiagabine, actionstopiramate, felbamateLeast UsefulCarbamazepine and phenytoin Similar mechanisms of actionsTiagabine, gabapentine and Similar mechanisms of actionsvigabatrin Knowledge without action is useless; Action without knowledge is foolish
  19. 19. Combinations based on side effectsPossibly useful RationaleValproate with felbamate or Felbamate and topiramate havetopiramate been associated with weight loss, valproate with weight gainLeast usefulCarbamazepine and valproate in Valproate and carbamazepinewomen of child bearing potential both may increase risk for spina bifida; valproate inhibits metabolism of 10, 11 carbamazepine epoxide, which may be teratogenic A bad teacher complains; A good teacher explains; The best teacher inspires;
  20. 20. “ Social Isolation is in itself a pathogenic Factor for disease production”
  21. 21. Speak obligingly even if you cannot oblige
  22. 22. Science is below the mind; Spirituality is beyond the mind
  23. 23. A woman’s desire for revenge outlasts all her other emotions
  24. 24. The world shall perish not for lack of wonders but lack of wonder
  25. 25. NATURE, TIME AND PATIENCE are the 3 great physicians
  26. 26. Principles of rational polypharmacy• Correctly identify the epilepsy syndrome• Select the drug that - is effective for the epilepsy syndrome - has the least potential for adverse effects of concern to the patient. E.g. teratogenicity, skin rash, weight gain - is most economical• Initiate treatment with one drug• If seizures are only partially controlled at maximally tolerated doses, consider polypharmacy• For the second, select one that has – A different mechanism of action – The lowest potential for metabolic interactions – The lowest potential for adverse effects It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  27. 27. Principles of rational polypharmacy • If addition of the second drug completely controls seizures, consider very slowly withdrawing the first drug after six months or more of complete control • Carefully record seizures • If two medications do not completely control seizure – Reconsider the diagnosis – Consider surgical options – Consider using more than two drugsWe possess by nature the factors out of which personality can be made, and toorganize them into effective personal life is every man’s primary responsibility - Harry Emerson Fosdick
  28. 28. Combinations based on drug interactions Least useful RationaleCarbamazepine with phenytoin Phenytoin induces carbmazepine metabolism, leaading to need for much higher carbamazepine dosesPhenobarbital with Phenobarbital is a powerfulcarbamazepine inducer of CYP 450 systemPhenytoin, valproate Valproate decreasesValproate with phenobarbital phenobarbital metabolismValproate with phenytoin Both complete for protein binding sites, reducing the value of total drug level measurement Mind is the great level of all things; human thought is the process by which human ends are ultimately answered - Daniel Webster
  29. 29. Combinations based on drug interaction Least useful RationaleFelbamate with phenytoin, Many drug – drug interactionscarbamazepine and valproateUsefulGabapentine with any drug No drug interactionValproate with lamotrigine Valproate inhibits metabolism of lamotrigine, reducing dose and cost of treatment with lamotrigine “ Social Isolation is in itself a pathogenic Factor for disease production”
  30. 30. Combinations based on mechanism of action Most usefulCarbamazepine or phenytoin with Widely different mechanisms ofgabapentine, tiagabine, Knowledge withoutactions is useless; actiontopiramate, felbamate Action without knowledge is foolish
  31. 31. Combinations based on side effectsPossibly useful RationaleValproate with felbamate or Felbamate and topiramate havetopiramate been associated with weight loss, valproate with weight gainLeast usefulCarbamazepine and valproate in Valproate and carbamazepinewomen of child bearing potential both may increase risk for spina bifida; valproate inhibits metabolism of 10, 11 carbamazepine epoxide, which may be teratogenic A bad teacher complains; A good teacher explains; The best teacher inspires;
  32. 32. OxcarbazepinePharmaco dynamic properties• MHD• Cognitive saccadic smooth pursuit affected but, focused attention and writing speed stimulated. Opinion is ultimately determined by the feelings and not by the intellect
  33. 33. In vitro In vivo pharmaco studies (SAME AS CARBAMAZEPINE) In vitro • Suppresses high frequency repetitive fuing of sodium dependent action potentials in cultured mouse spinal cord neurons. • Acts directly on rat corticostriatal terminals to reduce the release of excitatory amino acids, probably by inhibiting high voltage-activated Calcium currents • Inhibits the electrically and chemically induced release of excitatory amino acids in rat cortical and striatal slices • Inhibits penicillin-induced epilepty form discharges in rat hippocampal slices; an effect affected by the addition of the potassium channel blocker 4-aminopyridineT T he ruth is fear and immorality are two of the greatest inhibitors of Performance to progress
  34. 34. In vitro In vivo pharmaco studies (SAME AS CARBAMAZEPINE)In vivo• Marked inhibitory effect in the hippocampal discharge test in cats, inhibits photomyoclonic seizures in the baboon and inhibits electrically and chemically induced seizures in rats.• Significantly inhibits pilocarpine-induced status epilepticus, at clinically relevant doses, in rats compared with control animals(p=0.001)• Inhibits the tonic phase of metrazol-induced generalised tonic-clonic seizures in a dose-dependent manner in rats• Does not suppress the release of excitatory amino acids elicited by the normal ongoing electrical activity of the glutamateric and aspartatergic neurons in rats“Maintaining the right attitude is easier than regaining the right mental attitude”
  35. 35. Pharmacokinetic properties (BETTER THAN CARBAMAZEPINE) Parameter Oxcarbazepine MHD C max(mg/L) 1.05 – 1.74 5.44 – 8.85 t max (h) 1.0 – 2.0 4.0 – 6.6 AUC(mg/L . h) 5.10 – 6.84 80 – 220 Plasma protein binding(%) 60 – 67 37 – 43 Vdss (L) 49 Vdss adjusted for 0.7 – 0.8 bodyweight(L/kg) t ½ β (h) 1.0 – 2.5 6.5 – 24.3 CLR (L/h) 0.71 – 1.26 Excretion(% of dose) >96% in urine <4% in faecesImagination is more Important than Knowledge
  36. 36. Pharmacokinetic …contdParent – 2 hoursMHD – 9 hoursMedian tmax – 4.5% (3 – 13 hours)Steady state MHD – 2- 3 daysLinear – 300 – 2400 mg “You have got to be before you can do and do before you can have”
  37. 37. Pharmacokinetic …contd Distribution Volume - 49 litres (40% - bound to protein) Binding independent of serum concentration MHD do not bind to alpha1 acid GlycoproteinWe learn by thinking and the quality of the learning outcome is determined by the quality of our thoughts R.B. Schmeck
  38. 38. Metabolism and excretionLiver – cytosolic enzyme – MHDConjugation with glucuronic acid4% oxidised to DHDExcreted by kidney(95% in urine, 4% - feces,1% unchanged) “Peace Rules the day where Reason Rules the mind” Colling
  39. 39. Special populations• HEPATIC IMPAIRMENT Mild to moderate hepatic impairment – no change, severe – not studied• RENAL IMPAIRMENT Half life – increased to 19 hours, dose adjustment mandatory• PEDIATRIC USE >8 years = adults < 8years 30 – 40% lower Authority can Rarely Survive in the face of doubt’ - R. Lindner
  40. 40. Special populations …contd• GERIATRIC USE 30 – 60% higher than younger volunteers cause for this is the age related reduction in Creatinine clearance• GENDER Children, adults elderly same• RACE No specific studies “Fools Admire but men of sense approve” - A. Pope
  41. 41. Summary of randomized, double-blind controlled trials for new antiepileptic medication involving children with partial seizures*AED (study) Design Seizure type Control SubjectsOxcarbazepine Monotherapy Recent-onset Phenytoin children(Guerreiro et al) seizuresOxcarbazepine Monotherapy Recent-onset Placebo Adults and(Sachdeo et al) seizures childrenOxcarbazepine Monotherapy Refractory partial Placebo Adults and(Schachter et al) seizures childrenOxcarbazepine Conversion to Refractory partial 300 mg Adults and(Beydoun et al) monotherapy, seizures children high Vs lowOxcarbazepine Adjunctive Refractory partial Placebo children(Glauser et al) therapy seizures
  42. 42. Dosage in Adults (above 16 yrs) Starting Increment Titration Max.dose dose periodInitiation as 600 mg/day 300 mg/day Till a dose of 2400 mg/daymonotherapy (BID) every 3rd day 1200 mg/day is reachedConversion to 600 mg/day 600 mg/day 2-4 weeks 2400 mg/daymonotherapy from weeklyPHT/VAL/CBZ The concomitant AEDs should be completely withdrawn over 3-6 weeksFrom CBZ (in 1.5 time of Immediate - 1200 mg/dayallergic reaction) CBZ discontinuation of CBZAdjunctive 600 mg/day 600 mg/day Till a dose of 1200 mg/dayTherapy weekly 1200 mg/day is reached “ Woman needs society demands”
  43. 43. Dosage in children (4-16 years)Initiation: 8-10 mg/kg/day (Not to exceed 600 mg/day Body weight Targeted dose/day 20 – 29 kg 900 mg 29.1 – 39 kg 1200 mg > 39 kg 1800 mgTitration period – Targeted dose can be achieved over 2 weeksA woman’s desire for revenge outlasts all her other
  44. 44. Relative Efficacy and Tolerability - AEDs Truth comes out of error sooner than that of confusion
  45. 45. Odds ratio – Meta analysis – New AEDs Thought is the labour of the intellect Reverie is its pleasure
  46. 46. Conclusions from controlled trials and clinical use• Oxcarbazepine is preferred safe and effective first-line monotherapy and first-choice drug for partial seizures due to – safe mechanism of action – better tolerability compared with many other AEDs – proven safety in more than 250,000 patient-years NATURE, TIME AND PATIENCE are the 3 great physicians
  47. 47. Conclusions from controlled trials and clinical use• Gold standard efficacy in both children and adults with newly diagnosed and chronic partial epilepsy• Effective as monotherapy and as adjunctive therapy• Limited interactions• Individual titration “Motivation is the Spar k that lights the Fir e of Knowledge and fuels the engine of A ccomplishment
  48. 48. Titration for initial monotherapy• Start with 150 mg/day• Increase by 150 mg/day every 2 days until reach target dose of 900-1200 mg/day• If necessary you can go faster and start with up to 600 mg/day and titrate with weekly increments of up to 600 mg/day At twenty the will rules At thirty the intellect At forty the Judgment
  49. 49. Oxcarbazepine: dosing guidelines for children >4 years Increase by maximum ofStart 10 mg/kg/day8-10 mg/kg/day (approximately weekly(2-3 divided doses) based on response)Maximum dose: 51 mg/kg/day in double-blind trials 80 mg/kg/day in open-label trials A (Neurologist’s) life is like a piece of paper on which everyone who passes by leaves an impression - Chinese proverb
  50. 50. Titration for conversion to monotherapy • Immediate conversion scheme – overnight switch from carbamazepine to oxcarbazepine possible based on clinical experience • Gradual conversion scheme – start oxcarbazepine at 150 mg/day, increase every 2 days by 150 mg/day – withdraw the baseline AEDs gradually by 25% every week, starting at day 14 – in case of severe baseline tolerability issues start baseline dose reduction earlierThe Truth is fear and im oralityare two of the greatest m inhibitors of Performance to progress
  51. 51. Titration of oxcarbazepine adjunctive treatment • Start with 150 mg/day • Increase by 150 mg/day every 2 days until reach target dose of 1200 mg/day • Consider reducing the dose of the primary AED in case of side effects or increasing the dose of oxcarbazepine in case of incomplete seizure controlIt is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  52. 52. Conclusions from controlled trials and clinical use In summary, oxcarbazepine is apreferred first-line and first-choice treatment of partial epilepsyEvery discovery contains an irrational element or 4 creative intuition - Karl Popper
  53. 53. In conclusion- Role of Oxcarbazepine Partial with or without generalisation Adults – Monotherapy / Adjunct Children – Adjunct only > 4 yrs. 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
  54. 54. 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
  55. 55. 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
  56. 56. Neuropathic Pain• Prevalence – General population 0.6-1%• Causes – Compression/infilitration of nerves by: • Tumors • Nerve Trauma secondary to procedures • Nervous System Injury
  57. 57. The Pathophysiology Knowledge about the pathogenesis ofneuropathic pain has grown significantly over the last 2 decades
  58. 58. Anatomy of Nociception• What is nociception? – Activation of transduction in nerves that convey information about tissue damage to the CNS• Four Steps 1. Transduction 2. Transmission 3. Modulation 4. Perception
  59. 59. Pathophysiology• The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia• Allodynia is defined as pain resulting from a stimulus that ordinarily does not elicit a painful response (e.g. light touch)
  60. 60. Hyperalgesia• Hyperalgesia is defined as an increased sensitivity to a normally painful stimuli• Primary hyperalgesia, caused by sensitization of C– fibers, occurs immediately within the area of the injury• Secondary hyperalgesia, caused by sensitization of dorsal horn neurons, occurs in the undamaged area surrounding the injury
  61. 61. The allodynia and hyperalgesia associated with neuropathic pain may be best explained by:1) The development of spontaneous activity of afferent input2) The sprouting of large primary efferents (eg. A–beta fibers from lamina 3 into lamina 1 and 2)3) Sprouting of sympathetic efferents into neuromas and dorsal root and ganglion cells4) Elimination of intrinsic modulatory systems5) Up regulation of receptors in the dorsal horn which mediate excitatory processes
  62. 62. The Prerequisite• For neuropathic pain to manifest clinically, there is one prerequisite – Classical thermonociceptive pathways [Peripheral small sensory nerves or ST Tract & it’s cerebral projections] have to be affected by the nervous system disease Casey K, Raven press, 1991; 1-11 Drugs 2000, 60(5); 1029-52
  63. 63. Pathophysiology• Any insult to the nervous system leads to changes in its structure and function as a result of reparative processes• This state of altered properties of the nervous system is termed neuroplasticity• In patients with neuropathic pain, neuroplasticity takes the form of peripheral & central sensitization, and the main characteristic is hyperexitability Drugs 2000, 60(5); 1029-52
  64. 64. C-fibre Conduction TTXr VGCC DRGSNS/SNS2 PN1,SCP6/PN4, BI,BII N-type CC
  65. 65. Altered peripheral afferent function in inflammatory and neuropathic pain SympGgl DRG TTXr VGCC VR1, VRL1, SNS/NaN N-type CC B1,B2, ASIC3, SNS/PN3 P2X3, TNFαR1, SP CGRP
  66. 66. Injury produces multiple changes in sensory neurons – increased afferent activity and secondary central effects - Transmitters (SP, CGRP) - Receptor (VR1, P2X3) - Ion channels (TTXs, TTXr) - Physiology (↓ Cond Veloc) - Anatomy (? Cell death, basketing) SKIN CNS DRG Transganglionic ↓ Retrograde transport degeneration of trophic factors Central sprouting of A- fibres ↓ Opioid receptors
  67. 67. 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)
  68. 68. Neuropathic Pain & Epilepsy• There is notable similarity between the patho-physiological and biochemical mechanisms observed in epilepsy and neuropathic pain J Am Geriartr Soc 1995; 43: 1279-89
  69. 69. 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
  70. 70. DIABETES MELLITUS• 1990 – 2000 – Decade of brain.• 2001-2010 - Decade of pain control & research• India – Diabetic capital of the world.• Every fifth Indian will be a diabetic.• Every fifth diabetic in the world will be an Indian.• 32 million diabetics at present.• 250% rise by 2035 – 100 million
  71. 71. Risk factors For Painful neuropathy For painless neuropathy• Hyperglycemia • Greater height• Hypertension • Male gender• Dysmetabolic syndrome • Smoking HT+DM+IHD+DYSLIPIDEMIA • Total abstinence from alcohol • High HbA1C When they tell you to grow up, they mean stop growing
  72. 72. Diabetic polyneuropathy• The most common type of diabetic neuropathy.• Presents primarily with sensory symptoms & pain• May have a prominent autonomic component.• Associated with secondary complications of neuropathy Of a burning and unremitting character - F.W.PAVY
  73. 73. Prevalence of Polyneuropathy(Variable depending on criteria)All patients Type 1 Type 2withpolyneuropathySymtomatic 54% 45%plyneuropathyNeuropathy 15% 13%impairmentscale.+ 7 (Rochesterabnormal tests study)
  74. 74. Classification of diabetic neuropathy Diffuse Focal• Distal symmetric • Mononeuropathies sensorimotor neuropathy • Entrapment neuropathies -large fiber • Truncal neuropathy -small fiber • Cranial neuropathy• Autonomic • Focal amyotrophy.• Symmetric proximal lower limb motor neuropathy (Amyotrophy)
  75. 75. Types of painful neuropathies Acute (< 6 months) Chronic(> 6 months)• Truncal neuropathy. • Distal symmetrical painful• cachectic neuropathy-Acute, sensorimotor painful,wt.loss,poor control of polyneuropathy DM • Entrapment neuropathies• Insulin neuritis -Acute painful, weight loss, good control of • Difficult to treat. DM• Painful 3rd cranial nerve palsy.• Easy to treat. Speak obligingly even if you cannot oblige
  76. 76. Pathogenesis1.Metabolic2.Vascular -reduced endoneural blood flow and nerve ischemia3.Oxidative stress4.Autoimmune5.Neurohormonal growth factor deficiency Knowledge without action is useless; Action without knowledge is foolish
  77. 77. Oxidative stress Hyperglycemia ↑ NO↑Aldose reductase activity 3 Anti phospholpid antibody Ab to gangliosides. 1 GLA deficiency 4 Nerve damage 5 ↓PGI2,PG Nerve growth factor deficiency 2Protein kinase C deficiency Microvasculopathy
  78. 78. Pain Vs nociception• Pain is a subjective phenomena, expression depends on the emotional experience.• Both central & peripheral mechanisms are involved.• Link between neural function and the subjective experience. A bad teacher complains; A good teacher explains; The best teacher inspires;
  79. 79. Pain perception-central Limbic Affect behaviorLocalization Discrimination INSULA Ant.cingulatePrimary sensory Secondary cortex sensory cortex Emotional response Medial thalamus Lateral thalamus
  80. 80. Generation of pain
  81. 81. Generation of pain• Central terminals of unmyelinated primary c- afferents project to dorsal horn and make contact with secondary pain signaling neurons.• A-beta afferents project without synaptic transmission into dorsal columns and also contact dorsal horn neurons.I don’t like peripheral neuritis– it interferes with work
  82. 82. Generation of pain • The hallmark of neuropathic pain is chronic allodynia & hyperalgesia. • C-fiber sensitization produces primary hyperalgesia – from immediately within the area of injury. • Sensitization of DRG produces secondary hyperalgesia – from undamaged area surrounding the injuryTeachers are reservoirs from which, through the process of education, the students draw the water of life
  83. 83. Generation of pain• The hallmark of neuropathic pain is chronic allodynia & hyperalgesia.• C-fiber sensitization produces primary hyperalgesia – from immediately within the area of injury.• Sensitization of DRG produces secondary hyperalgesia – from undamaged area surrounding the injury It is not your position that makes you happy or unhappy It is your disposition
  84. 84. Clinical features – Distal symmetrical painful sensorimotor polyneuropathy• Burning, superficial pain. Hypoalgesia in later stages.• Defective thermal sensation.• Impaired vasomotion• Defective autonomic function• Intact DTR and power till late stages.• Progressive with increasing duration of diabetes.• Related to glycemic control & complications.
  85. 85. Clinical features – Truncal neuropathy• Truncal polyneuropathy • Truncal radiculopathy• Rare • Acute onset of pain in a• Occur in long standing DM radicular pattern• “Bandlike” Painful symptoms • Asymmetrical pain in thoracic root distribution • Patchy sensory loss is a• Motor involvement- muscle clue to the diagnosis. herniation – asymmetric bulge in abdominal wall Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule
  86. 86. Clinical features Insulin neuritis • Acute painful, occurs 1 month after insulin /OHA. • Due to rapid glycemic control. • Nerves in these patients are under general hypoxia and use glucose under anaerobic conditions. • Once glucose is normalised in blood and nerves, glucose is no longer available and the nerves undergo degeneration.Reputation is made in a moment; character is built in a life time
  87. 87. Insulin neuritis- contd..,• Burning pain, paraesthesia, allodynia with nocturnal exacerbation.• Depression is a feature.• No weight loss.• Sensory loss is mild. No motor signs.• Complete resolution in 1 year. A good teacher is a perpetual learner
  88. 88. Clinical features - Cachectic neuropathy• In patients with a poor control of DM.• Wt.loss is prominent.• Severe burning pain- continuous or intermittent.• Subjective feeling of swollen limb.• Allodynia is common- nocturnal exacerbation.• Sensory loss is mild.• No motor signs. T T he ruth is fear and immorality are two of the greatest inhibitors of Performance to progress
  89. 89. Differntial diagnosis • Claudication • Radiculopathy • Charcoat’s neuroarthropathy • Plantar fasciitis • Tarsal tunnel syndrome • OsteoarthritisA great many people think they are thinking when they are merely re arranging their prejudices W. James
  90. 90. Skin Biopsy PGP 9.5 staining
  91. 91. Skin biopsy – various sites
  92. 92. Dedicated to my family formaking everything worthwhile
  93. 93. READ not to contradict or confute Nor to Believe and Take for Granted but TO WEIGH AND CONSIDER THANK YOUMy sincere thanks to G. Kakuthan for his meticulous computer work

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