Neuropathic Pain : Strategies to Improve

Clinical Outcome

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Common conditions associated with

neuropathic painDiabetes Peripheral neuropathy

MononeuropathyRadiculopathy

Herpes zoster Radiculopathy (dermatome)

Spine surgery Radiculopathy

HIV infection or AIDS

Peripheral neuropathyMononeuropathyRadiculopathyMyelopathy

Alcoholism with neuropathy

Peripheral neuropathyMononeuropathy

Amputation NeuromaPhantom limb

Neuropathic pain

• Not a single entity or diagnosis

• Represents a variety of syndromes • Painful diabetic neuropathy • Trigeminal neuralgia

• Post-herpetic neuralgia • Improved understanding of the basic

mechanisms Whatever the Mind can conceive and Believe, the mind can Achieve Napoleon Hill

Neuropathic pain: Pathogenesis

• Altered alpha-2 delta subunit expression of calcium channels

• Central sensitization NMDA receptor activation

• Peripheral sensitization: formation of ectopic impulses

New treatment options modulate these mechanisms. e.g.

Pregabalin•Ann Pharmacother. 2005 Dec;39(12):2029-37. Epub 2005 Nov 15.

•Psychopharmacology (Berl). 2005 Dec;183(2):133-43. Epub 2005 Nov 9.

Diagnostic pointers

Distinguishing the type of pain through clinical history

• Neuropathic pain: Often worse at night

• Muscular pain: Usually worse during the day when activity is increased

• Inflammatory pain: Worse first thing in the morning and during activity

Diagnosis based on the typical

characteristics of neuropathic pain

• The presence of certain accompanying conditions (e.g. diabetes, HIV or herpes zoster infection, multiple sclerosis)

• Pain described as shooting, stabbing, lancinating, burning, or searing

• Pain worse at night

• Pain following anatomic nerve distribution

• Pain in a numb or insensate site

Clues from the examination of the patient reporting neuropathic pain

• Neurological deficit in the distribution of pain

• Anesthesia dolorosa

• Presence of allodynia

• A swollen limb that is redder and also cooler than the contralateral limb, a neurogenic process (rather than inflammation)

Two Most Important Neuropathies

• Post herpetic neuralgia

• Diabetic neuropathy related pain

Post-herpetic Neuralgia

• Varicella-zoster virus is a re-emerging infection

Acute pain that accompanies Herpes zoster usually subsides spontaneously, but in 10% of patients the pain persists and intensifies

• The incidence of Post-herpetic neuralgia increases up to 50% amongst elderly patients

Acta Chir Iugosl. 2004;51(4):53-7.

Herpes zoster

• Approximately 50% of individuals reaching 90 years of age will have had HZ

• In approximately 6% of the patients, a second attack may occur (usually several decades after the first)

Expert Opin Pharmacother. 2004 Mar;5(3):551-9.

Risk Factors for PHN

• Old age

• Female gender

• Presence of a prodrome

• Severe rash

Neurology. 2004 May 11;62(9):1545-51.

Science is below the mind; Spirituality is beyond the mind

Startling Facts of Treatment of PHN

• Lidocaine patch 5% gives relief of pain and tactile allodynia

• Corticosteroids give neither reliable protection from appearance of postherpetic neuralgia, nor shorten its duration???

• Pre-emptive treatment with low-dose tricyclics (ami- or nor-triptyline 10-25 mg nocte) from the time of diagnosis of acute shingles reduces the incidence of postherpetic neuralgia by about 50%

Drugs. 2004;64(9):937-47.

When they tell you to grow up, they mean stop growingWhen they tell you to grow up, they mean stop growing

Acyclovir treatment

• Treatment of herpes zoster with 800 mg/d of oral acyclovir within 72 hours of rash onset may reduce the incidence of residual pain at 6 months by 46% in immunocompetent adults

Arch Intern Med. 1997 Apr 28;157(8):909-12.

Of a burning and unremitting character - F.W.PAVY

Diabetic Neuropathy

• The prevalence : 7.5% in newly diagnosed diabetics when the definition is restricted to symptomatic subjects who have abnormalities on neurological examination

• The prevalence increases with the duration of diabetes, so that 25 years after the initial diagnosis of diabetes, the prevalence is 50%

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Diabetic Neuropathy

• Distal symmetric polyneuropathy

• Longest nerves are affected first

• The earliest manifestations may be primarily small-fiber

• As the disease progresses, symptoms begin in the fingertips and eventually affect the thorax and abdomen; it always advances proximally

• Nocturnal exacerbation of neuropathic symptoms (NENS)

Diabet Med. 2005 Dec;22(12):1763-5 Postgrad Med J. 2006 Feb;82(964):95-100

“Men of Genius Admired: Men of Wealth envied women of power feared but only women of character are trusted” A- Friedman

Recent advances in diagnosis of neuropathy

• Corneal confocal microscopy

• Laser Doppler flowmetry Invest Ophthalmol Vis Sci. 2004 Feb;45(2):418-22.

Invest Ophthalmol Vis Sci. 2000 Sep;41(10):2915-21

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

Neuropathic Pain: Approach to Treatment

• Diagnosis

• Treat underlying condition/Symptomatic treatment

• Reduce pain

• Improve physical function• Reduce psychological distress• Improve QoLNine is the most humanitarian of all numbers. It is effort and sacrifice without the need for reward.

Site of action of drugs used for

neuropathic pain

“By Nature All Men/ Women are alike butby Education widely different” - Chinese

BRAIN Descending ModulationAnticonvulsants

Opioids

Tricyclic Antidepressant / Selective nor epinephrine reuptake inhibitor

Central SensitizationAnticonvulsants

Opioids

NMDA – Receptor Antagonists

Tricyclic Antidepressant / Selective nor epinephrine reuptake inhibitor

Anticonvulsants

Opioids

Topical Analgesics

Local anesthetics

Tricyclic Antidepressant

PNS

Peripheral

Sensitization

SPINAL

CORD

CNS

Site of action of drugs used for

neuropathic pain

“By Nature All Men/ Women are alike butby Education widely different” - Chinese

BRAIN Descending ModulationAnticonvulsants

Opioids

Tricyclic Antidepressant / Selective nor epinephrine reuptake inhibitor

Central SensitizationAnticonvulsants

Opioids

NMDA – Receptor Antagonists

Tricyclic Antidepressant / Selective nor epinephrine reuptake inhibitor

Anticonvulsants

Opioids

Topical Analgesics

Local anesthetics

Tricyclic Antidepressant

PNS

Peripheral

Sensitization

SPINAL

CORD

CNS

Management of neuropathic pain

Patient diagnosed with neuropathic painStart treatment with the first line drugs

In case of no response after 3 months

Drugs from a second drug class may be tried Try combination therapy

“Serious, sincere, systematic study surely secures supreme success”

Pregabalin

• A new neuromodulator for neuropathic pain.

• An alpha 2-delta ligand

• A structural analogue of GABA

• Analgesic, anxiolytic and anticonvulsant activity

“The Truth is fear and immorality are two of the greatest inhibitors of Performance to progress”

Pregabalin: Mechanism of action

• Acts as a ligand of the alpha2- delta subunit of calcium channels.

• Decreased calcium entry into nerve endings

• Less glutamate released from nerve endings

Relief of neuropathic pain

It is not your position that makes you happy or unhappy it is your disposition

Site of action of Pregabalin

Nerve injury

Altered alpha (2) delta subunit expression in spinal cord and dorsal root ganglia

Neuropathic pain processing

Site of action of

Pregabalin

As one is common to all numbers, it is often seen as the origin of all things

Pregabalin and Gabapentin

• Pregabalin is a more effective analogue of gabapentin

• Pregabalin has a higher potency at the alpha 2 delta subunit of calcium channels

Two symbolizes partnership implying that accomplishments are best through coordination.

Pregabalin Pharmacokinetics

• Absorption: Almost 100%

• PPB: None

• Metabolism: Not metabolized in the liver

• Excretion: Urine

• Half-life: 6 hours

• Clinical Implications: Effective at lower dose No drug interactions

Hate screeches, fear squeals; conceits trumpets but love sings lullabies

Dose of Pregabalin

• Initial dose : 75 mg bd or 50 mg tds

• Can be increased to 300 mg/day in 1 week

• Can be increased to a maximum dose of 300 mg bd or 200 mg tds after 2-4 weeks if required

A good teacher is a perpetual learner

Side Effects

Pregabalin is usually well tolerated

• CNS: dizziness and drowsiness

• General: Weight gain in the elderly

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

Side Effects

Pregabalin is usually well tolerated

• CNS: dizziness and drowsiness

• General: Weight gain in the elderly

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

Pregabalin vs Gabapentin

• Greater affinity for the alpha 2 subunit of calcium channels : Effective at lower doses

• Better oral bioavailability: Effective at lower doses

• More potent than gabapentin: Effective at lower doses

• No pharmacokinetic variability : Lesser chances of inter -individual variability

• Favorable pharmacokinetics: No drug interactions

• Greater therapeutic index: Lesser ADR

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Clinical Experience with Pregabalin in Neuropathic Pain

Pregabalin in Post-herpetic neuralgia (PHN)• Significant dose-proportional pain relief• Rapid and sustained pain relief• Reduced interference with sleep • Improves QoL• Well tolerated

Curr Med Res Opin. 2006 Feb;22(2):375-84.

Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule

Pregabalin in Diabetic Neuropathic

Pain

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Pregabalin Placebo

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

Clinician’s and Patient’s rating of

Pregabalin

73%

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45%

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Pregabalin Placebo

“Knowledge can be communicated but not Wisdom” - Hermann Hesse

Pregabalin Effects on Health Related

Quality of Life (QoL)• Significantly reduced weekly mean

sleep interference scores

• Improvement in the mental health domain

• Body pain and vitality domains were improved in the 300 mg/day group

• Decreased sleep interference and significant improvements in health related QoL (Quality of Life) measures

Pain. 2004 May;109(1-2):26-35.

At twenty the will rules At thirty the intellect At forty the Judgment

PREGABALIN: Salient Effects in

Neuropathic Pain• Rapid and sustained analgesic action

• Significantly improves slow-wave sleep

• Reduces neuropathic pain of post herpetic neuralgia and diabetic neuropathy

• Improves health related QoL (Quality of Life)

• Well tolerated

• Has a low discontinuation rate

Four is reliable, punctual, systematic and dependable, doing what it says it will do.

CONCLUSION

Successful therapy of neuropathic pain based on :

• Accurate diagnosis

• Right choice of drugs

• Ability to maintain the QoL of the patient

Time and Words cannot be recalled - Fuller

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