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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
MANAGEMENT OF NEUROGENIC PAIN
IN THIS MILLENNIUM
What is Pain?
• Medical DefinitionMedical Definition““Pain is an unpleasant sensory and emotional Pain is an unpleasant sensory and emotional
experience associated with actual or potential experience associated with actual or potential tissue damage or described in terms of such tissue damage or described in terms of such damage”damage”
• Operative DefinitionOperative Definition““Pain is whatever the experiencing person says Pain is whatever the experiencing person says
it is, existing whenever he/she says it does.”it is, existing whenever he/she says it does.”
International Association for the Study of Pain, 1979International Association for the Study of Pain, 1979
One is the most independent, unconventional and individualistic of all numbers
Neurological Classification Nociceptive Pain
Stimulation of somatic and visceral peripheral Stimulation of somatic and visceral peripheral nociceptors by stimuli that damage tissuenociceptors by stimuli that damage tissue
Neuropathic pain Pain resulting from non-inflammatory Pain resulting from non-inflammatory
dysfunction of the peripheral/central nervous dysfunction of the peripheral/central nervous system in the absence of stimulisystem 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
The Multiple Effects of Pain
Every discovery contains an irrational element or 4 creative intuition Khrl Popper
5
PAIN PATHWAYS
SS ACCAmygdala
Thalamus ParabrachialNucleus
Dorsal Horn
A-FibersDRG
C-Fibers
Mechanoreceptors Polymodal Nociceptors
Pain SensationDysphoria
“Anger Begins In Folly And Ends In Repentance”
Generation of pain
In any field, find the strangest thing and explore it
Nociceptive Pain
• Nociceptive pain is mediated by receptors on A–delta and C–fibers which are located in skin, bone, 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
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
Examples of Nociceptive pain
• Post–operative pain
• Pain associated with trauma
• Chronic pain of arthritis
Take time to think; it is the source of powerTake time to read; it is the foundation of wisdomTake time to work; it is the price of success
Physiology of Nociception
Pain neuron
Noxious stimulus Response
DRG
Peripheral tissueCentral nervoussystem
Two is the most gentle of all numbers and represents, diplomacy and tact
State of Normosensitivity
Low intensity stimulation
Innocuous sensation
High intensity (noxious) stimulation
PAIN“Healthy Mind and Healthy expression of Emotion go hand in Hand”
State of Hypersensitivity Spontaneous pain
Low intensity stimulation
Innocuous sensation PAIN
(Allodynia)
High intensity (noxious) stimulation
INCREASED PAIN
(Hyperalgesia)
The Truth is Fear & Immorality are two of the greatest inhibitors of Performance to progress
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
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 growingWhen they tell you to grow up, they mean stop growing
Neuropathic Pain
• PrevalencePrevalence– General population 0.6-1%General population 0.6-1%
• CausesCauses– Compression/infilitration of nerves by:Compression/infilitration of nerves by:
• TumorsTumors• Nerve Trauma secondary to proceduresNerve Trauma secondary to procedures• Nervous System InjuryNervous System Injury
Of a burning and unremitting character - F.W.PAVY
Kivun kr Assessment of Chronic Pain using fMRI
Note enhanced parietal (somatosensory association) and frontal (attention)
lobe activity in the capsaicin induced thermal hyperalgesia model (right)
Physiological pain (pre capsaicin, 48°C)
Pathological pain(post capsaicin, 43°C)
Three is the most playful of all numbers and also creative, inspirational and motivating
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
It is a great misfortune not to possess sufficient wit to speak well nor sufficient judgment to keep silent
-La Broyers character
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
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
Emerging trends in
Neuropathy Treatment
Five is the most dynamic of all numbers. It is persuasive, versatile and adaptable
• Sensations (Spontaneous Pain)– Burning– Paresthesia– Lancinating– Electric like– Raw skin– shooting
• Cardinal signs/symptoms (Evoked Pain)– Allodynia: pain from
a stimulus that does not normally evoke pain
• Thermal• Mechanical
– Hyperalgesia: exaggerated response to a normally painful stimulus
Potential Description of Neuropathic Pain (NP)
“Men of Genius Admired: Men of Wealth envied women of power feared but only women of character are trusted” A- Friedman
Effects of chronic Pain on the PatientPsychosocial & physical impairment
Insomnia AnorexiaPhysical Inactivity
Depression
DiminishedQOL
Anxiety
Physical disability,
social withdrawal, &
psychological distress
are common sequelae.
Glutamate is an excitatory neurotransmitter that may be metabolized to gamma aminobutyric acid (GABA), which is an inhibitory neurotransmitter
Normal Physiology
Knowledge without action is useless;Action without knowledge is foolish
29
In a neuropathic pain state the balance of inhibition vs excitation tips toward excitationThis tendency, which is largely glutamate driven, is what we see in neuropathic pain.
Pathophysiology: Peripheraland Central Sensitization
GLUTAMATEGLUTAMATE
GABAGABA
GLUTAMATE
GABA
Number sixth is the most loving of all numbers and is harmonious with all other number
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
Pathophysiology: Peripheraland Central Sensitization
Number seven is the most spiritual of all numbers. It is the seeker of truth.
Ca+ induced Glutamate Release
• Release of Glutamate causes Mg block to be removed from NMDA receptor
• Glutamate binds to the sites on the NMDA receptors
• Sensitises NMDA
• Opens Ca++ Channels
• Influx of Ca in post synaptic neuron
Ca+ induced Glutamate Release
We learn by thinking and the quality of the learning outcome is determined by the quality of our thoughts
R.B. Schmeck
As the calcium comes in, the NMDA receptors areactually further depolarized; this is a process that can cause continued neuropathic pain
Pathophysiology: Peripheraland Central Sensitization
Eight is the most result-oriented of all numbers and represents a balanced world
32
• In summary, calcium, once activated, increases the NMDA receptor sensitization
• It increases the release Glutamate and substance P
Pathophysiology: Peripheraland Central Sensitization
The True Art of Memory is The Art of Attention - S.Johnson
33
• 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
Post Herpetic Neuralgia (PHN)
Take time to think; it is the source of powerTake time to read; it is the foundation of wisdomTake time to work; it is the price of success
Approach to Treatment: NP & PHN
Reduce Pain
Diagnosis
Treat underlying condition/ symptomatic treatment
Improve Physical
functioning Reduce Psychological
distress
Improve overallQuality of life
Nine is the most humanitarian of all numbers. It is effort and sacrifice without the need for reward.
Neurogenic pain – Therapeutic targets
• Na + Blockade – Carbamazepine,Phenytoin,Mexiletine
• Glutamate release – Lamotrigine• Depletion of substance P – Capsaicin• Presynaptic release & Inhibition of substance P –
Serotonin agonist,opioids, clonidine.• Sympathetic blockade – Alpha adrenergic receptor
antagonist, guanethedine,Phentolamine• NMDA receptor blockers – systemic ketamine• K+ channel blockade, release of substance P -
opioids“By Nature All Men/ Women are alike butby Education widely different” - Chinese
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”
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”
Antidepressants – TCAs
• Not approved DPN & PHN
• Small therapeutic-toxic window
• 4-6 weeks• Sexual adverse effects
• QT prolongation• Arrhythmias• Antiocholinergic side
effects• Postural Hypotension• Caution for patients
with cardiac risk factors
MOA - Increase NE and 5-HT
It is not your position that makes you happy or unhappyIt is your disposition
Antidepressants – Duloxetine
Duloxetine -• SNRIs• US FDA – DPN only• No study in PHN• Hypertension• Onset 1-2 weeks• GI side effects• Sexual adverse effects
MOA – Selective Serotonin Norepinephrine Reuptake
InhibitorAs one is common to all numbers, it is often seen as the origin of all things
AEDsCarbamazepine 1. FDA approved for
Trigeminal Neuralgia2. Side effects
Oxcarbazepine1. One study for NeP2. Hyponatremia –
monitoring of serum sodium required
3. Rash – 4 % 4. Few Drug-drug interaction
Levetiracetam1. No controlled studies
Tiagabine 1. No controlled studies
Lamotrigine1. Rash 10%2. 2nd-line3. Insomnia
Topiramate1. Nagative results (3 - / 1 +)2. Weight loss (10-20%)3. Cognitive impairment4. Nephrolithiasis (1.5%)
Valproate1. Nausea2. Sedation3. Fatal Hepatotoxicity -
Enzymes 4. Hair loss5. Hematologic effect
(Platelet)6. Drug-drug interactions
Two symbolizes partnership implying that accomplishments are best through coordination.
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 trumpetsbut love sings lullabies
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
Pregabalin
Three can be seen in the divisions of a human in mind, body and spirit
PREGABALIN
• Novel analgesic, anticonvulsant & anxiolytic properties
• US FDA Approved (Dec 31, 2004) Rx for DPN / PHN and adjunct in mgt of partial seizures (adults)
“Motivation is the Spark that lights the Fire of Knowledge and fuels the engine of Accomplishment
PREGABALIN• Mechanism of action:
– Binds to A2d subunit of voltage gated Ca++ channel, reduces Ca++ influx thus reducing the release of neurotransmitters like Glutamate
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
Mechanism of action
In all of us, even in good men, there is a wild - beast nature which peers out in sleep
Does Pregabalin affect GABA ?
• Pregabalin has no effect on GABA. It does not bind to GABAA
or GABAB receptors and 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
Pharmacokinetics
• Well absorbed orally with or without food
• Tmax= 0.7 to 4 hours postdose
• Bioavailability: > 90%
• T1/2= 6 hours
• Steady state reached in 24 to 48 hours
• Metabolism & elimination: eliminated largely by renal excretion
At twenty the will rulesAt thirty the intellectAt forty the Judgment
Pharmacokinetics
Linear pharmacokinetic profileProportional absorption across the dose range
Ste
ady-
stat
e C
max
val
ues
(g/
mL)
150 300 450 600
mean Individual12
10
8
6
4
2
0
Pregabalin total daily dose (mg)
Four is reliable, punctual, systematic and dependable, doing what it says it will do.
Clinical Trials
In
Diabetic Peripheral Neuropathy
Time and Words cannot be recalled - Fuller
8 week DPN Trial - Design
Screened(n=225)
Randomised(n=146)
Pregabalin(N=76)
Placebo(N=70)
Completed trial85.5%
Completed trial88.6 %
Rosenstock J et al. Pain 2004;110: 628–638
Demographics
CharacteristicPlacebo
N = 70
Pregabalin 300 mg/day
N = 76
All patients
N = 146
Age, year: mean (SD)
60.3 (10.3) 59.2 (12.3) 59.7 (11.4)
Duration of diabetes, year: mean (SD)
9.4 (10.3) 9.3 (10.5) 9.3 (10.3)
Height, cm: mean (SD)
171.3 (10.01)
173.2 (9.59) 172.3 (9.81)
Weight, kg: mean (SD)
95.8 (20.80)
97.6 (19.83) 96.7 (20.25)
Rosenstock J et al. Pain 2004;110: 628–638
Significant reduction of pain and sleep interference at study endpoint
Sleep improved from first day of study
Parameter
Pregabalin Placebo Endpoint comparison
P valueMean
*SE Mean* SE Difference
Mean pain score
3.99 0.26 5.46 0.28 -1.47 0.0001
Mean sleep interference score
2.78 0.27 4.32 0.29 -1.54 0.0001
Rosenstock J et al. Pain 2004;110: 628–638*Least Squares
Mean pain reduction from baseline in an– 8 week DPN trial
Rosenstock J et al. Pain 2004;110: 628–638
Quality of life - at study endpoint
SF-36 health survey
Parameter
Pregabalin Placebo Endpoint comparison
P value
Mean*
SE Mean* SE Difference
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
Rosenstock J et al. Pain 2004;110: 628–638*Least Squares
A double blind, multicenter, placebo-controlled study in
DPN
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-
2110
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]
5-week, DB, multicenter, placebo-controlled study in
DPN
H. Lesser at al. NEUROLOGY 2004;63:2104-2110
>30% reduction
in pain (600mg/day)
65%
% patients
600 mg/day
48%
46%
300 mg/day
% patients
> 50 % reduction in pain
Efficacy of Pregabalin in DPN
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
Type: Randomised , double blind multicentre
Time: 6 weeks
N= 246 patients of DPN
Pregabalin 150 or 600 mg /day Vs Placebo
PREGABALIN: CLINICAL STUDIES
Clinical Global Impression
of Change (CGIC)
73%
45%
Patient Global Impression
of Change (PGIC)
85%
47%
PGB PCB PGB PCB
% Patients
improved
% Patients
improved
PGB – Pregabalin 600 mg/day PCB -- Placebo
Ralph et al. The Journal of Pain,vol6,No4[April],2005:pp 253-260
Clinical Trials
In
Post Herpetic Neuralgia
The Truth is fear and immorality are two of the greatest inhibitors
of Performance too progress
Postherpetic Neuralgia Pain Relief
• 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).
Overview
Discipline Weighs ounces Regret weighs Tons
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.
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.
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.
Postherpetic Neuralgia Pain Relief
*p=0.001 *
% p
ati
ent s
Placebo Pregabalin
Worse(N=12)
Improved(N=22)
100
Unchanged(N=50)
Worse(N=3)
Unchanged(N=11)
Improved(N=71)
0
20
80
60
40
8-week study by Dworkin et al.
PGIC – Patients were more likely to report global improvement with pregabalin than placebo.
Postherpetic Neuralgia Pain Relief
Efficacy:PHN Pain ReliefPowerful efficacy across the dose range• Starting-dose efficacy of pregabalin 150 mg/day for PHN with
mean pain reduction sustained throughout a 13 week study• Moderate-to-severe patient population, with Av age of 71 years &
pain duration of 3.4 years– Patient were allowed to remain on existing stable analgesic Rx
Placebo (n=93)Pregabalin 75 mg BID (n=87)Pregabalin 150 mg BID (n=124)Pregabalin 300 mg BID (n=62) *P0.05 vs. placebo
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
PHN:Sustained pain relief
PHN:Time to sustained pain relief
Treatment% of patients achieving Sustained Improvement
25% 50% 75%
Pregabalin 300 mg/d
Day 1 Day 2 X
Pregabalin 600 mg/d
Day 1 Day 3 Day 20
Placebo Day 8 X X
“Social Isolation is in itself a pathogenicFactor for disease production”
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
Long-term pain control by pregabalin in refractory patients of PHN and DPN
(Ref- PP. 57th A.M. of AAN April-2005)
Pain reduction of at least 30%• Pain reductions of at least 30% were reported at three
months by 61% of DPN patients, 33.3% of PHN patients; at 15 months, the proportion of responders were 54.6% and 41.2% respectively.
DPN PHN
3 months
61% 33.3%
15 months
54.6%
41.2%
(Ref- PP. 57th A.M. of AAN April-2005)
Fibromyalgia can be redefined physiologically as chronic widespread Allodynia
[Russell 2004]
Fibromyalgia
Allodynia is the situation in which pain is caused by stimulus which should ordinarily not cause pain
Fibromyalgia symptoms
PAIN
Visceral
NON—PAIN
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”
Study Design
(Arthritis Rheum 2005, April.52(4): 1264-73)
1 week Titration
Optional open label or
Withdrawal1 week Baseline
8 weeks double blind
7 week fixed dose
Phase:
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)
Pregabalin: Proportion of Responders
13.2 13.010.9
20.9*
A significantly larger proportion of patients receiving Pregabalin 450 mg/ day experienced pain relief (defined by a >50% reduction in pain from baseline to endpoint
•P = 0.003 vs placeboPlacebo 150 300 450
Pregabalin dose mg/ day
Dose in Neuropathic pain
Rarely needed,If needed can be given in patients with Ccrcl 60 ml/min
Thought is the labour of the intellectReverie is its pleasure
Beyond Neuropathy…
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
Patients with 50% seizure reduction from baseline at 12 weeks
14%
31%
40%
51%
%
pati
en
t s
*p=0.006 vs. placebo** P<0.001 vs.
placebo
**
Placebo
(n=100)
Pregabalin
75 mg BID
(n=86)
**
Pregabalin
150 mg BID
(n=90)
Pregabalin
300 mg BID
(n=89)
(Neurology 2003;60,1631-1637)
Seizure frequency reduction at 12 weeks
Placebo
(n=98)
Pregabalin
300 mg BID
(n=103)
Pregabalin
200 mg TID
(n=111)
-48%
-36%
-1%
Media
n %
change f
rom
base
line
Few
er se
izure
Neurology 2005;64,475-480
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
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. Panic disorder
A open foe may prove a curse ; but a pretended friend is worse
Pregabalin in acute GAD treatment HAM-A change scores
Treatment group
NDifference from
placeboP value
Placebo 66
Pregabalin
200 mg TID69 -3.896 0.0013
Lorazepam 2 mg TID
64 -2.346 0.0483
Feltner DE et al. Journal of Clinical Psyccjopharmacology 2003; 12:3:240-248.
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.
Pregabalin in acute GAD treatment
Treatment groupCompleted
trialAdverse
eventLack of efficacy
Placebo 71.6% 6% 4.5%
Pregabalin
200 mg TID69.7% 19.7% 0
Lorazepam 2 mg TID 52.9% 35.3% 1.5%
Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:240-248.
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
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
Most Common Side effects in controlled DPN & PHN studies
Placebo
(n=857)
Pregabalin 150 mg/d
(n=514)
Pregabalin 300 mg/d (n=633)
Pregabalin 600 mg/d (n=523)
Pregabalin all
doses (n=1831)
Dizziness 7 % 14% 27% 31% 23%
Somnolence
10% 16% 19% 14%
Peripheral edema
3% 7% 13% 14% 10%
Dry mouth 2% 5% 5% 9% 6%
Truth comes out of error sooner than that of confusion
No clinically significant Drug Interactions
• Insulin• Hypoglycemics:
glyburide, metformin• Diuretics: furosemide• Oxycodone• Gabapentin• Lorazepam• Ethanol (alcohol)
• Oral contraceptives: ethinyl estradiol, norethindrone
• Carbamazepine, Lamotrigine, Phenobarbital, Phenytoin, Tiagabine, Topiramate, Valproic acid
Pregabalin does not inhibit major CYP450 enzymes in humans. Pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions.
Summary
• Proven effective therapy for Neuropathies
• Added benefits in Fibromyalgia
• Effective in Anxiety disorders (GAD, Social Anx, panic)
• Useful as add-on therapy for partial seizures
You are what you think and not what you think you are Anonymous
0
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50
60
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80
90
1st Qtr 2nd Qtr 3rd Qtr 4th Qtr
East
West
North
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.
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 YOUTHANK YOU