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

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

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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