MANAGEMENT OF NEUROGENIC PAIN IN THIS MILLENNIUM

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

What is Pain? Medical Definition Operative 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

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

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

“Anger Begins In Folly And Ends In Repentance”
PAIN PATHWAYS Dysphoria Pain Sensation ACC SS Amygdala Thalamus Parabrachial Nucleus Dorsal Horn Ad-Fibers C-Fibers DRG Mechanoreceptors Polymodal Nociceptors “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 power Take time to read; it is the foundation of wisdom Take time to work; it is the price of success

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

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

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

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 Described as burning, tingling, shooting, stabbing etc 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 growing

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

Kivun kr Assessment of Chronic Pain using fMRI
Physiological pain (pre capsaicin, 48°C) Pathological pain (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

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:

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

Potential Description of Neuropathic Pain (NP)
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 “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 Patient
Psychosocial & physical impairment Insomnia Anorexia Physical Inactivity Depression Anxiety Diminished QOL Physical disability, social withdrawal, & psychological distress are common sequelae.

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

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 GLUTAMATE GLUTAMATE Number sixth is the most loving of all numbers and is harmonious with all other number 29

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.

Ca+ induced Glutamate Release

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 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 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

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

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

Approach to Treatment: NP & PHN
Diagnosis Treat underlying condition/ symptomatic treatment Reduce Pain Improve overall Quality of life Improve Physical functioning Reduce Psychological distress 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 but by 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
QT prolongation Arrhythmias Antiocholinergic side effects Postural Hypotension Caution for patients with cardiac risk factors Not approved DPN & PHN Small therapeutic-toxic window 4-6 weeks Sexual adverse effects MOA - Increase NE and 5-HT It is not your position that makes you happy or unhappy It is your disposition

Antidepressants – 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

AEDs Carbamazepine Lamotrigine Oxcarbazepine Topiramate Valproate
FDA approved for Trigeminal Neuralgia Side effects Oxcarbazepine One study for NeP Hyponatremia – monitoring of serum sodium required Rash – 4 % Few Drug-drug interaction Levetiracetam No controlled studies Tiagabine Lamotrigine Rash 10% 2nd-line Insomnia Topiramate Nagative results (3 - / 1 +) Weight loss (10-20%) Cognitive impairment Nephrolithiasis (1.5%) Valproate Nausea Sedation Fatal Hepatotoxicity - Enzymes Hair loss Hematologic effect (Platelet) 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 – 3600 mg/day (unpredictable) Titration – 3-8 weeks Approved for PHN only Hate screeches, fear squeals; conceits trumpets but 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 rules At thirty the intellect At forty the Judgment

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

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

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

Demographics Characteristic Placebo N = 70 Pregabalin 300 mg/day
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
Parameter Pregabalin Placebo Endpoint comparison P value 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 (2 7.32, ) VAS score ( , ) PPI score (2 0.72, ) SF-36 health survey Bodily painb (0.70, 13.04) Mental healthb (2 1.73, 8.66) Vitalityb (2 2.13, 8.61) POMS Anger/hostility (2 3.79, 0.83) Vigor/activityb (2 0.99, 2.11) Fatigue/inertia (2 3.33, 0.51) Tension/anxiety (2 3.95, ) Total mood disturbance ( , ) Sleep improved from first day of study 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 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 0.37 0.0364 (2 7.32, ) VAS score ( , ) PPI score (2 0.72, ) SF-36 health survey Bodily painb (0.70, 13.04) Mental healthb (2 1.73, 8.66) Vitalityb (2 2.13, 8.61) POMS Anger/hostility (2 3.79, 0.83) Vigor/activityb (2 0.99, 2.11) Fatigue/inertia (2 3.33, 0.51) Tension/anxiety (2 3.95, ) Total mood disturbance ( , ) *Least Squares Rosenstock J et al. Pain 2004;110: 628–638

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:

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

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

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

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
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

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.

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.

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 mL/min, o placebo. Dworkin et al. Neurology 2003; 60:

8-week study by Dworkin et al. PGIC – Patients were more likely to report global improvement with pregabalin than placebo. 100 *p=0.001 * 80 % patients 60 40 20 Worse (N=12) Unchanged (N=50) Improved (N=22) Worse (N=3) Unchanged (N=11) Improved (N=71) Placebo Pregabalin

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

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 3 Day 20 Placebo Day 8 “Social Isolation is in itself a pathogenic Factor 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 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

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 Phase: (Arthritis Rheum 2005, April.52(4): )

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= 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
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 = vs placebo 20.9* 10.9 13.2 13.0 Placebo 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 intellect Reverie 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
*p=0.006 vs. placebo ** P<0.001 vs. placebo ** 51% * % patients * 40% 31% 14% Placebo (n=100) Pregabalin 75 mg BID (n=86) Pregabalin 150 mg BID (n=90) Pregabalin 300 mg BID (n=89) (Neurology 2003;60, )

Seizure frequency reduction at 12 weeks
Pregabalin 300 mg BID (n=103) Pregabalin 200 mg TID (n=111) Placebo (n=98) Median % change from baseline -1% -36% -48% Fewer seizure Neurology 2005;64,

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 Generalized anxiety disorder, Social phobia and 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 N Difference from placebo P value Placebo 66 Pregabalin 200 mg TID 69 -3.896 0.0013 Lorazepam 2 mg TID 64 -2.346 0.0483 Dr. Lydiard will present these slides! Feltner DE et al. Journal of Clinical Psyccjopharmacology 2003; 12:3:

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 Dr. Lydiard will present these slides! Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:

Pregabalin in acute GAD treatment
Treatment group Completed trial Adverse event Lack of efficacy Placebo 71.6% 6% 4.5% Pregabalin 200 mg TID 69.7% 19.7% Lorazepam 2 mg TID 52.9% 35.3% 1.5% Dr. Lydiard will present these slides! Feltner DE et al. Journal of Clinical Psychopharmacology 2003; 23:3:

Pregabalin may have several advantages compared to benzodiazepines/ antidepressants
Less abuse potential Less likely to be associated with withdrawal symptoms Lack of interdose anxiety Benign in its effects on psychomotor performance compared to benzodiazepines. Advantage of a rapid onset of action 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% Peripheral edema 3% 7% 13% Dry mouth 2% 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

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

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

MANAGEMENT OF NEUROGENIC PAIN IN THIS MILLENNIUM

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