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Prof. A.V. SRINIVASAN
    INSTITUTE OF NEUROLOGY
    MADRAS MEDICAL COLLEGE
            CHENNAI.3

Three Pronged Approach to
  Migraine, Epilepsy and
   Neuropathic Pain –
 Role of Oxcarbamazepine
    19-09-2004, Thrissur, Kerala
Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine
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.
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.
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
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
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
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
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
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
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
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
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
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
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
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 drugs

We possess by nature the factors out of which personality can be made, and to
organize them into effective personal life is every man’s primary responsibility
                                                        - Harry Emerson Fosdick
Combinations based on drug interactions
         Least useful                     Rationale
Carbamazepine with phenytoin   Phenytoin induces carbmazepine
                               metabolism, leaading to need for
                               much higher carbamazepine
                               doses
Phenobarbital with             Phenobarbital is a powerful
carbamazepine                  inducer of CYP 450 system
Phenytoin, valproate           Valproate decreases
Valproate with phenobarbital   phenobarbital metabolism
Valproate 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
Combinations based on drug interaction
         Least useful                     Rationale
Felbamate with phenytoin,      Many drug – drug interactions
carbamazepine and valproate


Useful
Gabapentine with any drug      No drug interaction

Valproate 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”
Combinations based on mechanism of action
         Most useful                        Rationale
Carbamazepine or phenytoin with Widely different mechanisms of
gabapentine, tiagabine,         actions
topiramate, felbamate

Least Useful
Carbamazepine and phenytoin      Similar mechanisms of actions

Tiagabine, gabapentine and       Similar mechanisms of actions
vigabatrin


               Knowledge without action is useless;
               Action without knowledge is foolish
Combinations based on side effects
Possibly useful                   Rationale
Valproate with felbamate or       Felbamate and topiramate have
topiramate                        been associated with weight loss,
                                  valproate with weight gain
Least useful
Carbamazepine and valproate in Valproate and carbamazepine
women 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;
“ 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 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
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 drugs

We possess by nature the factors out of which personality can be made, and to
organize them into effective personal life is every man’s primary responsibility
                                                        - Harry Emerson Fosdick
Combinations based on drug interactions
         Least useful                     Rationale
Carbamazepine with phenytoin   Phenytoin induces carbmazepine
                               metabolism, leaading to need for
                               much higher carbamazepine
                               doses
Phenobarbital with             Phenobarbital is a powerful
carbamazepine                  inducer of CYP 450 system
Phenytoin, valproate           Valproate decreases
Valproate with phenobarbital   phenobarbital metabolism
Valproate 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
Combinations based on drug interaction
         Least useful                     Rationale
Felbamate with phenytoin,      Many drug – drug interactions
carbamazepine and valproate


Useful
Gabapentine with any drug      No drug interaction

Valproate 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”
Combinations based on mechanism of action
         Most useful




Carbamazepine or phenytoin with Widely different mechanisms of
gabapentine, tiagabine,
                Knowledge withoutactions is useless;
                                   action
topiramate, felbamate
                 Action without knowledge is foolish
Combinations based on side effects
Possibly useful                   Rationale
Valproate with felbamate or       Felbamate and topiramate have
topiramate                        been associated with weight loss,
                                  valproate with weight gain
Least useful
Carbamazepine and valproate in Valproate and carbamazepine
women 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;
Oxcarbazepine
Pharmaco 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
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-aminopyridine

T T
 he ruth is fear and immorality are two of the greatest
        inhibitors of Performance to progress
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”
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 faeces
Imagination is more Important than Knowledge
Pharmacokinetic …contd
Parent – 2 hours
MHD – 9 hours
Median tmax – 4.5% (3 – 13 hours)
Steady state MHD – 2- 3 days
Linear – 300 – 2400 mg

   “You have got to be before you can do and
           do before you can have”
Pharmacokinetic …contd

  Distribution
  Volume - 49 litres (40% - bound to protein)
  Binding independent of serum concentration
  MHD do not bind to alpha1 acid Glycoprotein



We learn by thinking and the quality of the learning outcome
        is determined by the quality of our thoughts
                                           R.B. Schmeck
Metabolism and excretion
Liver – cytosolic enzyme – MHD
Conjugation with glucuronic acid
4% oxidised to DHD
Excreted by kidney(95% in urine, 4% - feces,
1% unchanged)

           “Peace Rules the day where
             Reason Rules the mind”
                                          Colling
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
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
Summary of randomized, double-blind controlled
  trials for new antiepileptic medication involving
            children with partial seizures*
AED (study)          Design        Seizure type Control             Subjects
Oxcarbazepine       Monotherapy    Recent-onset         Phenytoin   children
(Guerreiro et al)                  seizures
Oxcarbazepine       Monotherapy    Recent-onset         Placebo     Adults and
(Sachdeo et al)                    seizures                         children
Oxcarbazepine       Monotherapy    Refractory partial   Placebo     Adults and
(Schachter et al)                  seizures                         children
Oxcarbazepine       Conversion to Refractory partial    300 mg      Adults and
(Beydoun et al)     monotherapy, seizures                           children
                    high Vs low
Oxcarbazepine       Adjunctive     Refractory partial   Placebo     children
(Glauser et al)     therapy        seizures
Dosage in Adults (above 16 yrs)
                        Starting     Increment Titration Max.dose
                          dose                  period
Initiation as          600 mg/day    300 mg/day        Till a dose of   2400 mg/day
monotherapy            (BID)         every 3rd day     1200 mg/day
                                                       is reached
Conversion to    600 mg/day          600 mg/day        2-4 weeks        2400 mg/day
monotherapy from                     weekly
PHT/VAL/CBZ
 The concomitant AEDs should be completely withdrawn over 3-6 weeks
From CBZ (in           1.5 time of   Immediate                -         1200 mg/day
allergic reaction)     CBZ           discontinuation
                                     of CBZ
Adjunctive             600 mg/day    600 mg/day        Till a dose of   1200 mg/day
Therapy                              weekly            1200 mg/day
                                                       is reached

                     “ Woman needs society demands”
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 mg

Titration period – Targeted dose can be achieved over
                    2 weeks


A woman’s desire for revenge outlasts all her other
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 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
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
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
Oxcarbazepine: dosing guidelines
          for children >4 years


                                     Increase by maximum of
Start
                                     10 mg/kg/day
8-10 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
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 earlier

The Truth is fear and im oralityare two of the greatest
                        m
        inhibitors of Performance to progress
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 control

It is a great misfortune not to possess sufficient wit to speak well
              nor sufficient judgment to keep silent
                                               La Broyers character
Conclusions from controlled
     trials and clinical use

 In summary, oxcarbazepine is a
preferred first-line and first-choice
   treatment of partial epilepsy


Every discovery contains an irrational element or
               4 creative intuition
                                 - Karl Popper
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
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
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
Neuropathic Pain

• Prevalence
  – General population 0.6-1%


• Causes
  – Compression/infilitration of nerves by:
    •   Tumors
    •   Nerve Trauma secondary to procedures
    •   Nervous System Injury
The Pathophysiology


 Knowledge about the pathogenesis of
neuropathic pain has grown significantly
        over the last 2 decades
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
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)
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
The allodynia and hyperalgesia associated with
 neuropathic pain may be best explained by:

1) The development of spontaneous activity of afferent
   input
2) 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 cells
4) Elimination of intrinsic modulatory systems
5) Up regulation of receptors in the dorsal horn which
   mediate excitatory processes
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
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
C-fibre Conduction




 TTXr                             VGCC
                    DRG




SNS/SNS2   PN1,SCP6/PN4, BI,BII   N-type CC
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
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
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)
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
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
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
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
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
Prevalence of Polyneuropathy
(Variable depending on criteria)
All patients   Type 1   Type 2
with
polyneuropathy
Symtomatic       54%    45%
plyneuropathy
Neuropathy       15%    13%
impairment
scale.+ 7               (Rochester
abnormal tests          study)
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)
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
Pathogenesis

1.Metabolic
2.Vascular -reduced endoneural blood flow
  and nerve ischemia
3.Oxidative stress
4.Autoimmune
5.Neurohormonal growth factor deficiency

      Knowledge without action is useless;
      Action without knowledge is foolish
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
                                  2
Protein kinase C deficiency
                                      Microvasculopathy
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;
Pain perception-central
                                   Limbic     Affect behavior


Localization Discrimination         INSULA
                                               Ant.cingulate
Primary sensory     Secondary
    cortex        sensory cortex


                        Emotional response   Medial thalamus
  Lateral thalamus
Generation of pain
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
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
Teachers are reservoirs from which, through the process of education,
                  the students draw the water of life
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
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.
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
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
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
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
Differntial diagnosis

 •   Claudication
 •   Radiculopathy
 •   Charcoat’s neuroarthropathy
 •   Plantar fasciitis
 •   Tarsal tunnel syndrome
 •   Osteoarthritis
A great many people think they are thinking when they
       are merely re arranging their prejudices
                                          W. James
Skin Biopsy PGP 9.5 staining
Skin biopsy – various sites
Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine
Three pronged approach to migraine epilepsy and neuropathic pain–role of oxcarbamazepine
Dedicated to my family for
making everything worthwhile
READ not to contradict or confute
 Nor to Believe and Take for Granted
 but TO WEIGH AND CONSIDER


 THANK YOU
My sincere thanks to G. Kakuthan for his
      meticulous computer work

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

  • 1. Prof. A.V. SRINIVASAN INSTITUTE OF NEUROLOGY MADRAS MEDICAL COLLEGE CHENNAI.3 Three Pronged Approach to Migraine, Epilepsy and Neuropathic Pain – Role of Oxcarbamazepine 19-09-2004, Thrissur, Kerala
  • 3. 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.
  • 4. 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.
  • 5. 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
  • 6. 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
  • 7. 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
  • 8. 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
  • 9. 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
  • 10. 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
  • 11. 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
  • 12. 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
  • 13. 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
  • 14. 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
  • 15. 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
  • 16. 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 drugs We possess by nature the factors out of which personality can be made, and to organize them into effective personal life is every man’s primary responsibility - Harry Emerson Fosdick
  • 17. Combinations based on drug interactions Least useful Rationale Carbamazepine with phenytoin Phenytoin induces carbmazepine metabolism, leaading to need for much higher carbamazepine doses Phenobarbital with Phenobarbital is a powerful carbamazepine inducer of CYP 450 system Phenytoin, valproate Valproate decreases Valproate with phenobarbital phenobarbital metabolism Valproate 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
  • 18. Combinations based on drug interaction Least useful Rationale Felbamate with phenytoin, Many drug – drug interactions carbamazepine and valproate Useful Gabapentine with any drug No drug interaction Valproate 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”
  • 19. Combinations based on mechanism of action Most useful Rationale Carbamazepine or phenytoin with Widely different mechanisms of gabapentine, tiagabine, actions topiramate, felbamate Least Useful Carbamazepine and phenytoin Similar mechanisms of actions Tiagabine, gabapentine and Similar mechanisms of actions vigabatrin Knowledge without action is useless; Action without knowledge is foolish
  • 20. Combinations based on side effects Possibly useful Rationale Valproate with felbamate or Felbamate and topiramate have topiramate been associated with weight loss, valproate with weight gain Least useful Carbamazepine and valproate in Valproate and carbamazepine women 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;
  • 21. “ Social Isolation is in itself a pathogenic Factor for disease production”
  • 22. Speak obligingly even if you cannot oblige
  • 23. Science is below the mind; Spirituality is beyond the mind
  • 24. A woman’s desire for revenge outlasts all her other emotions
  • 25. The world shall perish not for lack of wonders but lack of wonder
  • 26. NATURE, TIME AND PATIENCE are the 3 great physicians
  • 27. 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
  • 28. 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 drugs We possess by nature the factors out of which personality can be made, and to organize them into effective personal life is every man’s primary responsibility - Harry Emerson Fosdick
  • 29. Combinations based on drug interactions Least useful Rationale Carbamazepine with phenytoin Phenytoin induces carbmazepine metabolism, leaading to need for much higher carbamazepine doses Phenobarbital with Phenobarbital is a powerful carbamazepine inducer of CYP 450 system Phenytoin, valproate Valproate decreases Valproate with phenobarbital phenobarbital metabolism Valproate 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
  • 30. Combinations based on drug interaction Least useful Rationale Felbamate with phenytoin, Many drug – drug interactions carbamazepine and valproate Useful Gabapentine with any drug No drug interaction Valproate 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”
  • 31. Combinations based on mechanism of action Most useful Carbamazepine or phenytoin with Widely different mechanisms of gabapentine, tiagabine, Knowledge withoutactions is useless; action topiramate, felbamate Action without knowledge is foolish
  • 32. Combinations based on side effects Possibly useful Rationale Valproate with felbamate or Felbamate and topiramate have topiramate been associated with weight loss, valproate with weight gain Least useful Carbamazepine and valproate in Valproate and carbamazepine women 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;
  • 33. Oxcarbazepine Pharmaco 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
  • 34. 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-aminopyridine T T he ruth is fear and immorality are two of the greatest inhibitors of Performance to progress
  • 35. 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”
  • 36. 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 faeces Imagination is more Important than Knowledge
  • 37. Pharmacokinetic …contd Parent – 2 hours MHD – 9 hours Median tmax – 4.5% (3 – 13 hours) Steady state MHD – 2- 3 days Linear – 300 – 2400 mg “You have got to be before you can do and do before you can have”
  • 38. Pharmacokinetic …contd Distribution Volume - 49 litres (40% - bound to protein) Binding independent of serum concentration MHD do not bind to alpha1 acid Glycoprotein We learn by thinking and the quality of the learning outcome is determined by the quality of our thoughts R.B. Schmeck
  • 39. Metabolism and excretion Liver – cytosolic enzyme – MHD Conjugation with glucuronic acid 4% oxidised to DHD Excreted by kidney(95% in urine, 4% - feces, 1% unchanged) “Peace Rules the day where Reason Rules the mind” Colling
  • 40. 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
  • 41. 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
  • 42. Summary of randomized, double-blind controlled trials for new antiepileptic medication involving children with partial seizures* AED (study) Design Seizure type Control Subjects Oxcarbazepine Monotherapy Recent-onset Phenytoin children (Guerreiro et al) seizures Oxcarbazepine Monotherapy Recent-onset Placebo Adults and (Sachdeo et al) seizures children Oxcarbazepine Monotherapy Refractory partial Placebo Adults and (Schachter et al) seizures children Oxcarbazepine Conversion to Refractory partial 300 mg Adults and (Beydoun et al) monotherapy, seizures children high Vs low Oxcarbazepine Adjunctive Refractory partial Placebo children (Glauser et al) therapy seizures
  • 43. Dosage in Adults (above 16 yrs) Starting Increment Titration Max.dose dose period Initiation as 600 mg/day 300 mg/day Till a dose of 2400 mg/day monotherapy (BID) every 3rd day 1200 mg/day is reached Conversion to 600 mg/day 600 mg/day 2-4 weeks 2400 mg/day monotherapy from weekly PHT/VAL/CBZ The concomitant AEDs should be completely withdrawn over 3-6 weeks From CBZ (in 1.5 time of Immediate - 1200 mg/day allergic reaction) CBZ discontinuation of CBZ Adjunctive 600 mg/day 600 mg/day Till a dose of 1200 mg/day Therapy weekly 1200 mg/day is reached “ Woman needs society demands”
  • 44. 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 mg Titration period – Targeted dose can be achieved over 2 weeks A woman’s desire for revenge outlasts all her other
  • 45. Relative Efficacy and Tolerability - AEDs Truth comes out of error sooner than that of confusion
  • 46. Odds ratio – Meta analysis – New AEDs Thought is the labour of the intellect Reverie is its pleasure
  • 47. 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
  • 48. 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
  • 49. 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
  • 50. Oxcarbazepine: dosing guidelines for children >4 years Increase by maximum of Start 10 mg/kg/day 8-10 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
  • 51. 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 earlier The Truth is fear and im oralityare two of the greatest m inhibitors of Performance to progress
  • 52. 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 control It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent La Broyers character
  • 53. Conclusions from controlled trials and clinical use In summary, oxcarbazepine is a preferred first-line and first-choice treatment of partial epilepsy Every discovery contains an irrational element or 4 creative intuition - Karl Popper
  • 54. 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
  • 55. 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
  • 56. 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
  • 57. Neuropathic Pain • Prevalence – General population 0.6-1% • Causes – Compression/infilitration of nerves by: • Tumors • Nerve Trauma secondary to procedures • Nervous System Injury
  • 58. The Pathophysiology Knowledge about the pathogenesis of neuropathic pain has grown significantly over the last 2 decades
  • 59. 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
  • 60. 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)
  • 61. 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
  • 62. The allodynia and hyperalgesia associated with neuropathic pain may be best explained by: 1) The development of spontaneous activity of afferent input 2) 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 cells 4) Elimination of intrinsic modulatory systems 5) Up regulation of receptors in the dorsal horn which mediate excitatory processes
  • 63. 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
  • 64. 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
  • 65. C-fibre Conduction TTXr VGCC DRG SNS/SNS2 PN1,SCP6/PN4, BI,BII N-type CC
  • 66. 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
  • 67. 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
  • 68. 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)
  • 69. 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
  • 70. 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
  • 71. 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
  • 72. 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
  • 73. 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
  • 74. Prevalence of Polyneuropathy (Variable depending on criteria) All patients Type 1 Type 2 with polyneuropathy Symtomatic 54% 45% plyneuropathy Neuropathy 15% 13% impairment scale.+ 7 (Rochester abnormal tests study)
  • 75. 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)
  • 76. 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
  • 77. Pathogenesis 1.Metabolic 2.Vascular -reduced endoneural blood flow and nerve ischemia 3.Oxidative stress 4.Autoimmune 5.Neurohormonal growth factor deficiency Knowledge without action is useless; Action without knowledge is foolish
  • 78. 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 2 Protein kinase C deficiency Microvasculopathy
  • 79. 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;
  • 80. Pain perception-central Limbic Affect behavior Localization Discrimination INSULA Ant.cingulate Primary sensory Secondary cortex sensory cortex Emotional response Medial thalamus Lateral thalamus
  • 82. 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
  • 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 Teachers are reservoirs from which, through the process of education, the students draw the water of life
  • 84. 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
  • 85. 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.
  • 86. 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
  • 87. 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
  • 88. 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
  • 89. 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
  • 90. Differntial diagnosis • Claudication • Radiculopathy • Charcoat’s neuroarthropathy • Plantar fasciitis • Tarsal tunnel syndrome • Osteoarthritis A great many people think they are thinking when they are merely re arranging their prejudices W. James
  • 91. Skin Biopsy PGP 9.5 staining
  • 92. Skin biopsy – various sites
  • 95. Dedicated to my family for making everything worthwhile
  • 96. READ not to contradict or confute Nor to Believe and Take for Granted but TO WEIGH AND CONSIDER THANK YOU My sincere thanks to G. Kakuthan for his meticulous computer work