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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

27. Ca+ induced Glutamate
Release

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

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

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

31. 33

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

51. Clinical Trials
In
Diabetic Peripheral
Neuropathy
Time and Words cannot be recalled - Fuller

52. 8 week DPN Trial - Design
Pregabalin Completed trial
(N=76) 85.5%
Screened Randomised
(n=225) (n=146)
Placebo Completed trial
(N=70) 88.6 %
Rosenstock J et al. Pain 2004;110: 628–638

53. Demographics
Pregabalin 300 All patients
Placebo
Characteristic mg/day
N = 70 N = 146
N = 76
Age, year: mean
60.3 (10.3) 59.2 (12.3) 59.7 (11.4)
(SD)
Duration of
diabetes, year: 9.4 (10.3) 9.3 (10.5) 9.3 (10.3)
mean (SD)
Height, cm: mean 171.3
173.2 (9.59) 172.3 (9.81)
(SD) (10.01)
Weight, kg: mean 95.8
97.6 (19.83) 96.7 (20.25)
(SD) (20.80)
Rosenstock J et al. Pain 2004;110: 628–638

54. Significant reduction of pain and sleep
interference at study endpoint
Pregabalin Placebo Endpoint
comparison
Mean SE Mean* SE Difference
Parameter * P value
Mean pain 3.99 0.26 5.46 0.28 -1.47 0.0001
score
Mean sleep 2.78 0.27 4.32 0.29 -1.54 0.0001
interference
score
Sleep improved from first day of study
Rosenstock J et al. Pain 2004;110: 628–638
*Least Squares

55. Mean pain reduction from baseline
in an– 8 week DPN trial
Rosenstock J et al. Pain 2004;110: 628–638

56. Quality of life - at study endpoint
Pregabalin Placebo Endpoint
comparison
SF-36 health Mean SE Mean* SE Difference
survey *
Parameter P value
Bodily pain 53.83 2.24 14.92 1.13 -4.41 0.0033
Mental health 40.83 3.04 57.02 3.21 -16.19 0.0002
Vitality 1.42 0.13 1.79 0.13 0.37 0.0364
*Least Squares J et al. Pain 2004;110: 628–638
Rosenstock

57. A double blind, multicenter,
placebo-controlled study in DPN
Time: 5 weeks
Patients with a 1-to 5 year history of DPN (n = 338 )
Randomised to receive Pl. or Pr[75 or 300 or 600mg]
Conclusions:
Pregabalin demonstrated early and sustained
improvement in pain and a beneficial effect on
sleep, which were confirmed by positive patient
global impression.
H. Lesser at al. NEUROLOGY 2004;63:2104-

58. 5-week, DB, multicenter,
placebo-controlled study in DPN
65% 48%
46%
% %
patients patients
>30% 600 300
mg/day mg/day
reduction
in pain
> 50 % reduction in pain
(600mg/day)
H. Lesser at al. NEUROLOGY 2004;63:2104-

59. Efficacy of Pregabalin in DPN
Type: Randomised , double blind multicentre
Time: 6 weeks
N= 246 patients of DPN
Pregabalin 150 or 600 mg /day Vs Placebo
Conclusions:
Pregabalin 600mg/day significantly decreases mean pain
score to 4.3 [Vs 5.6 for placebo,P=.0002]
Increases the proportion of patients who had a>50%
decrease from baseline pain[39% vs 15%for placebo,p=.002].
Ralph et al. The Journal of Pain,vol6,No4[April],2005:pp 253-260

60. PREGABALIN: CLINICAL
STUDIES
PGB – Pregabalin 600 mg/day
PCB -- Placebo
73% 85%
% %
45% 47%
Patients Patients
improved improved
PGB PCB PGB PCB
Clinical Global Patient Global
Impression Impression
of Change (CGIC) of Change (PGIC)
Ralph et al. The Journal of Pain,vol6,No4[April],2005:pp 253-260

61. Clinical Trials
In
Post Herpetic
Neuralgia
The Truth is fear and immorality are two of the greatest inhibitors
of Performance too progress

62. Postherpetic Neuralgia Pain
Relief
Overview
• The efficacy of pregabalin for PHN was
established in 3 studies.
• Patients had a Avg baseline pain score of ≥4 on
an 11-point numerical pain rating scale from 0
(no pain) to 10 (worst possible pain).
Discipline Weighs ounces Regret weighs Tons

63. Postherpetic Neuralgia Pain
Relief
8-week study by Sabatowski et al.
• 8-week study that compared pregabalin 150
(n=81) or 300 (n=76) mg/day with placebo
(n=81).
• Treatment with pregabalin 150 mg and 300
mg/day resulted in significant treatment
effects on endpoint mean pain score
Sabatowski et al. Pain 2004; 109:26-35.

64. Postherpetic Neuralgia Pain
Relief
8-week study by Sabatowski et al.
• The proportion of responders at the 150 mg/day
(26%) and 300 mg/day (28%) dosages were
significantly greater than for placebo (10%).
• For each dosage, a significant decrease in pain was
seen at week 1 and continued throughout the study.
• Pregabalin also improved sleep and this was seen at
week 1 and continued throughout the study.
Sabatowski et al. Pain 2004; 109:26-35.

65. Postherpetic Neuralgia Pain
Relief
8-week Study by Dworkin et al
• 8-week study reported by Dworkin et al.
• Patients in this study were randomized to
– Pregabalin 600 mg/day for those with Ccr >60
mL/min or
– 300 mg/day for Ccr clearance between 30- 60
mL/min, o
– placebo.
Dworkin et al. Neurology 2003; 60:1274-1283.

66. Postherpetic Neuralgia Pain
Relief
8-week study by Dworkin et al.
PGIC – Patients were more likely to report global improvement with
pregabalin than placebo.
10
0
*p=0.001
% patients
80 *
60
40
20
0
Worse UnchangedImproved Worse UnchangedImproved
(N=12) (N=50) (N=22) (N=3) (N=11) (N=71)
Placebo Pregabalin

67. Efficacy:PHN Pain Relief
Powerful efficacy across the dose range
• Starting-dose efficacy of pregabalin 150 mg/day for PHN
with mean pain reduction sustained throughout a 13
week study
• Moderate-to-severe patient population, with Av age of 71
years & pain duration of 3.4 years
– Patient were allowed to remain on existing stable analgesic Rx
Placebo (n=93)
Pregabalin 75 mg BID (n=87)
Pregabalin 150 mg BID (n=124)
Pregabalin 300 mg BID (n=62)
*P≤0.05 vs. placebo

68. PHN: Rapid onset of action – from
day1
After day 1, the avg pain score in patients treated with
pregabalin was lower than in patients receiving placebo

69. PHN:Sustained pain relief

70. PHN:Time to sustained pain relief
% of patients achieving Sustained Improvement
Treatment
25% 50% 75%
Pregabalin
Day 1 Day 2 X
300 mg/d
Pregabalin
Day 1 Day 3 Day 20
600 mg/d
Placebo Day 8 X X
“Social Isolation is in itself a pathogenic
Factor for disease production”

71. Treatment of refractory
Neuropathic pain
• Long-term exposure to pregabalin achieved clinically
meaningful, sustained pain relief in patients with
neuropathic pain who were refractory to other therapies,
including
– Tricyclic antidepressants,
– Gabapentin, and
– Analgesics
PP 57th A.M. of AAN April- 2005

72. Long-term pain control by pregabalin in
refractory patients of PHN and DPN
(Ref- PP. 57th A.M. of AAN April-2005)

73. Pain reduction of at least 30%
• Pain reductions of at least 30% were reported at three
months by 61% of DPN patients, 33.3% of PHN patients;
at 15 months, the proportion of responders were 54.6%
and 41.2% respectively.
DPN PHN
3 61% 33.3%
months
15 54.6 41.2%
months %
(Ref- PP. 57th A.M. of AAN April-2005)

74. Fibromyalgia
Fibromyalgia can be redefined physiologically as
chronic widespread Allodynia
[Russell 2004]
Allodynia is the situation in which pain is caused by stimulus
which should ordinarily not cause pain

75. Fibromyalgia symptoms
PAIN NON—PAIN
 Visceral  Fatigue
 Cognitive Dysfunction
 Sleep Disturbance
 Depression/Anxiety
 Autonomic
“Character gets you out of bed commitment moves you to action
faith, hope and Discipline follow through to completion”

76. Study Design
8 weeks
Phase: double blind Optional open label
1 week 1 week or
Baseline Titration 7 week fixed dose Withdrawal
(Arthritis Rheum 2005, April.52(4): 1264-73)

77. Pain Score*
Pregabalin
significantly
reduced mean pain
score after 1 week
of treatment
Pregabalin 450
mg/ day
significantly
reduced mean
pain score at
endpoint
(P=0.0009 vs
placebo)
•Primary Endpoint – pain noted in a diary on a scale of 0 (no pain) to 20 (worst possible pain)

78. Pregabalin: Proportion of
Responders
A significantly larger
proportion of patients
receiving Pregabalin 450
20.9* mg/ day experienced
pain relief (defined by a
10.9 >50% reduction in pain
13.2 13.0 from baseline to
endpoint
•P = 0.003 vs placebo
Placebo 150 300 450
Pregabalin dose mg/ day

79. Dose in Neuropathic pain
Rarely needed,
If needed can be
given in patients
with Ccrcl ≥60
ml/min
Thought is the labour of the intellect
Reverie is its pleasure

80. Beyond Neuropathy…

81. Epilepsy
• Four clinical trials show that pregabalin is efficacious
in the add-on therapy of partial seizures, even in
highly refractory patients.
• Pregabalin represents an important advance in the
adjunctive treatment of partial onset seizures.
– Significant dose-related reductions in seizure frequency are
seen in as many as three of four patients
– onset of anticonvulsant activity occurring by the second
day of treatment
– efficacy being maintained ³ 2 years.
“ He who cannot forgive others destroys the bridge
over which he himself must pass” - Annoy

82. Patients with 50% seizure reduction
from baseline at 12 weeks
*p=0.006 vs. placebo
**
** P<0.001 vs. placebo
*
patients
*
51
%
40 %
31
%
14 %
%
Place Pregaba Pregabali Pregabali
bo lin n n
(n=10 75 mg 150 mg 300 mg
0) BID BID BID
(n=86) (n=90) (n=89)
(Neurology 2003;60,1631-1637)

83. Seizure frequency reduction at 12
weeks
Pregabali Pregabali
n n
Place 300 mg 200 mg
bo BID TID
(n=98 (n=103) (n=111)
)
-1%
-
36%
Fewer seizure
-
48%
%na de M
Neurology 2005;64,475-480
i

84. Sleep modulation
• Sleep disturbance was common in epilepsy and was
associated with a negative effect on Quality of Life.
– Pregabalin improved sleep disturbance in patients
with epilepsy, and
– This effect appeared to be independent of the
drug’s ability to suppress daytime seizures
It is a great misfortune not to possess sufficient wit to speak well
nor sufficient judgment to keep silent
La Broyers character

85. Pregabalin as anxiolytic
• Mechanism of action: Activation of
neurotransmission in fear circuits underlies
symptoms in anxiety disorders. Pregabalin
reduces neurotransmission in activated neuronal
circuits by reducing the release of
neurotransmitters
• Efficacy: Studies have established the anxiolytic
actions of pregabalin in
1. Generalized anxiety disorder,
2. Social phobia and
3. A opendisorder prove a curse ; but
Panic foe may
a pretended friend is worse

86. Pregabalin in acute GAD treatment
HAM-A change scores
Treatment Difference from
N P value
group placebo
Placebo 66
Pregabalin
69 -3.896 0.0013
200 mg TID
Lorazepam 2
64 -2.346 0.0483
mg TID
Feltner DE et al. Journal of Clinical Psyccjopharmacology 2003; 12:3:240-
248.

87. Pregabalin in acute GAD treatment
HAM-A No. of responders (%)
Treatment group N Responders (%)
Placebo 66 43.9
Pregabalin 200 mg TID 61 59.0
Lorazepam 2 mg TID 64 54.7
Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:240-
248.

88. Pregabalin in acute GAD treatment
Completed Adverse Lack of
Treatment group
trial event efficacy
Placebo 71.6% 6% 4.5%
Pregabalin
69.7% 19.7% 0
200 mg TID
Lorazepam 2 mg TID 52.9% 35.3% 1.5%
Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:240-
248.

89. Pregabalin may have several
advantages compared to
benzodiazepines/ antidepressants
1. Less abuse potential
2. Less likely to be associated with withdrawal symptoms
3. Lack of interdose anxiety
4. Benign in its effects on psychomotor performance
compared to benzodiazepines.
5. Advantage of a rapid onset of action
6. Lack of sexual side effects
Experience can be defined as
yesterday’s answer to today’s problems

90. Favorable Safety and tolerability
• Pregabalin is well tolerated.
• Most adverse events are mild to moderate in
intensity, occur during the first week of treatment, and
tend to resolve over time
• Discontinuation rates were low.
• No cardiovascular, ophthalmologic, renal, hepatic or
neurological concerns were noted in studies.
• Regarding diabetes control, pregabalin had no effect
on glycosylated hemoglobin A1c.
“Fools Admire but of men of sense approve”
- A. Pope

91. Most Common Side effects in
controlled DPN & PHN studies
Placebo Pregabali Pregabalin Pregabalin Pregabal
(n=857) n 150 300 mg/d 600 mg/d in all
mg/d (n=633) (n=523) doses
(n=514) (n=1831)
Dizziness 7% 14% 27% 31% 23%
Somnolenc 10% 16% 19% 14%
e
Peripheral 3% 7% 13% 14% 10%
edema
Dry mouth 2% 5% 5% 9% 6%
Truth comes out of error sooner than that of confusion

92. No clinically significant Drug
Interactions
• Insulin • Oral contraceptives:
• Hypoglycemics: ethinyl estradiol,
glyburide, metformin norethindrone
• Diuretics: furosemide
• Carbamazepine,
• Oxycodone
Lamotrigine,
• Gabapentin
Phenobarbital,
• Lorazepam Phenytoin, Tiagabine,
• Ethanol (alcohol) Topiramate, Valproic
acid
Pregabalin does not inhibit major CYP450 enzymes in
humans. Pregabalin is unlikely to be involved in
significant pharmacokinetic drug interactions.

93. Summary
• Proven effective therapy for
Neuropathies
90
• Added benefits in Fibromyalgia 80
70
60
50 East
• Effective in Anxiety disorders 40 West
(GAD, Social Anx, panic) 30 North
20
10
0
• Useful as add-on therapy for 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr
partial seizures
You are what you think and not what you think you are
Anonymous

94. The future…
In all nations, history is disfigured by
fable,till at last evidence (philosophy)
comes to enlighten man; and when it
arrives in the midst of this darkness, it
finds the human mind so blinded by
centuries of error, that it can hardly
undeceive it.
Essai sur Les Moeurs – Voltaire.
Five is the experimenter and the explorer as it is adventurous and courageous.

97. Dedicated to my family for
making everything worthwhile

98. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU