diabetic neuropathy

Management of Painful Neuropathy

Neuropathic Pain

Pain initiated or caused by a primary lesion or dysfunction in the nervous system

Classification of Chronic PainInternational Association for the Study of Pain, 1994

Mechanisms of Neuropathic Pain

Development of Neuropathic Pain

Woolf and Mannion. Lancet 1999;353:1959-64

Neuropathic pain

Spontaneous pain Stimulus-evoked pain

Mechanisms

Metabolic Traumatic

ToxicIschemic

Hereditary

Compression

Infectious

Immune-related

Syndrome

Symptoms

Pathophysiology

Etiology

Nerve damage

Signs and Symptoms of Neuropathic Pain

Sign/Symptom Description (example)

Spontaneous symptoms

– Spontaneous pain1 Persistent burning, intermittent shock-like or lancinating pain

– Dysesthesias2 Abnormal unpleasant sensations e.g. shooting, lancinating, burning

– Parasthesias2 Abnormal, not unpleasant sensations e.g. tingling

Stimulus-evoked symptoms

– Allodynia2 Painful response to a non-painful stimulus e.g. warmth, pressure, stroking

– Hyperalgesia2 Heightened response to painful stimulus e.g. pinprick, cold, heat

– Hyperpathia2 Delayed, explosive response to any painful stimulus

1.Baron. Clin J Pain. 2000;16:S12-S20.2. Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.

Nociceptive vs. Neuropathic Pain

Types of Neuropathic Pain

•Peripheral NeuropathyDue to anatomical, chemical or biochemical changes to peripheral nerves

Examples include:•diabetic neuropathy•sciatica,•post-surgery•Fibromyalgia •post-herpetic neuralgia,•trigeminal neuralgia, •compression by a tumour •radiation therapy•Chemotherapy (e.g. vincristine)•pain in HIV infections

•Central NeuropathyDue to pathophysiological changes in the brain or spinal chord i.e. the primarylesion is in the CNS

Examples include: •phantom limb pain•Pain following stroke•multiple sclerosis

Most Common Neuropathic Painful Conditions

1. Radiculopathy– Cervical Radiculopathy: Restricted motion in neck; pain in neck and arms– Lumbosacral Radiculopathy: Commonly, low back pain and sciatica

2. Fibromyalgia3. Post traumatic nerve compression4. Post herpetic neuralgia5. Diabetic peripheral neuropathy6. Trigeminal neuralgia7. Phantom limb pain8. Pain following stroke9. Multiple sclerosis

Current Treatment Options

• Tricyclic Antidepressants (e.g. Imipramine)

• Conventional Anticonvulsants (e.g. Carbamazepine)

• Opioid Analgesics

• Gabapentin

• Mecobalamin

• Pregabalin

Tricyclic Antidepressants

Adverse Effects• blurred vision• cognitive changes• constipation• dry mouth• orthostatic

hypotension• Sedation• sexual

dysfunction• tachycardia• urinary retention

Tricyclic (Tertiary Amines)• Amitriptyline • Doxepin• Clomipramine • Imipramine

Tricyclic (Secondary Amines)• Desipramine• Nortriptyline • Protriptyline

Conventional AnticonvulsantsCarbamazepine• Diabetic neuropathy• Postherpetic neuralgia• CRPS type I and II• Trigeminal neuralgia

Clonazepam• Phantom pain

Phenytoin• Diabetic neuropathy• Trigeminal neuralgia

Valproic Acid• Trigeminal neuralgia• Occipital neuralgia

Adverse Effects•Dizziness•Drowsiness•Mental slowing•Drug interactions•Diplopia•Nausea & vomiting•Agranulocytosis•Aplastic anemia•Possibility of activating latent psychosis

Opiod Analgesics

• Constipation• Nausea• Somnolence• Dizziness• Pruritus• Vomiting• Sweating• Frequency of AEs ≥10% of patients.

Gabapentin

• Gabapentin, alpha -2-delta subunit voltage-gated calcium-channel

antagonist• Dose titration required to achieve

optimal level • Optimal dosage 1800mg/day in PHN

Gabapentin

Adverse Events* Gabapentin

Dizziness 17.1%

Somnolence 19.3%

Peripheral Edema 1.7%

Ataxia 12.5%

Weight Gain 2.9%

*Gabapentin Product Monograph

Gabapentin

Gabapentin

Mechanism of Action Selectively bind to the alpha2-delta subunit of Ca+ channel

Pharmacokinetic profile Non-linear (plasma concentration increases dispropotionately to dose)

Oral bioavailability 60% 900mg

47% 1200mg

34% 2400mg

33% 3600mg

Dosing TID

Time to Effective dose > 9days (titrate to effective dose of 1800mg/d)

*Gabapentin Product Monograph

Healthy Neuron Happy Life

Analog of GABA, binds to alpha 2 delta subunit of voltage gated calcium channels.

• Novel evidence suggest that regulation of…

• Glutamate.

• Substance P & Noradrenalin.

• Results is relief from neuro - pathic pain syndrome.

Diabetic Peripheral Neuropathy Post Herpetic Neuralgia

Fibromyalgia

Partial Onset Seizures

Comparative Pharmacokinetics

Pregabalin Gabapentin

FDA Approved Indications

DPN, Fibromyalgia, PHN, Partial Seizures

PHN, Epilepsy

Mechanism of Action

Selectively bind to the alpha2-delta subunit of Ca+ channel

Selectively bind to the alpha2-delta subunit of Ca+ channel

Pharmacokinetic profile

Linear (plasma concentration is dose proportionate)

Non-linear (plasma concentration increases disproportionately to dose)

Oral bioavailability > 90% all doses 60% 900mg

47% 1200mg

34% 2400mg

33% 3600mg

Dosing BID TID

Time to Effective dose

1 day (effective starting dose of 150mg/day)

> 9days (titrate to effective dose of 1800mg/d)

Clinically Evidence

•The efficacy of Gablin (pregabalin) for the management of neuropathic pain associated with DM

•4 double-blind, fixed-dose, placebo controlled, multi-center studies with twice a day (BID) and 3 times a day (TID) dosing

•Studies DPN1, DPN2, DPN3 and DPN4 enrolled a total of 1124 patients with type 1 or 2 diabetes mellitus with painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years

Clinically Proven Efficacy

0

5

10

15

20

25

30

35

40

45

Placebo 15%

Pregabalin 600mg 39%

Reduction in Pain Symptoms

Clinically Proven Efficacy

0

10

20

30

40

50

60

Pregabalin 300mg46%

Pregabalin 600mg 48%

Placebo18%

Clinically Proven Efficacy

0

5

10

15

20

25

30

35

40

45

Pregabalin 300mg40%

Placebo15%

Clinically Proven Efficacy

0

5

10

15

20

25

30

35

40

45

50

Pregabalin 300/600mg46%

Placebo30%

Clinically Proven Efficacy In DPN

Meta-analysis of 7 clinical trialsTotal number of patients 1510 (557 placebo, 953 Pregabalin)

0

10

20

30

40

50

60

70

80

90

Pregabalin 600mg80%

Pregabalin 300mg74% Pregabalin

150mg65% Placebo

54%

Fibromyalgia

0

5

10

15

20

25

30

Gablin 450mg29%

Placebo13%

> 5

0%

pa

in r

ed

uct

ion

Crofford Lj. RowbothamMC. et.alArthritis Rheum 2005 52:1264-1273

Spinal Cord Injury“The literature data suggest that Gablin

(Pregabalin) is more efficacious than Gabapentin in many important variables for

Neuropathic pain in Spinal Cord Injury”

Eur J Clin Pharmacol. 2008 Jul 8

Comparative Adverse Event Profile

Adverse Events* Pregabalin Gabapentin

Dizziness 10.7 17.1%

Somnolence 8.3 19.3%

Peripheral Edema

0.0 1.7%

Ataxia 7.1 12.5%

Weight Gain 1.2 2.9%

*Gabapentin & Pregabalin Product Monograph

FDA APPROVED DOSAGE SCHEDULE

• … Initial Dose in …• … Diabetic Peripheral Neuropathy• … Post Herpetic Neuralgia• … Partial Onset of Seizures• … Fibromyalgia

•… Is 75mg Twice daily

• … Maximum daily recommended dose is …

600mg per day.

Recommended Dosage

Dosing Parameter Low Back Pain Sciatica Spinal Cord Injury

Initial Daily Dosage

75mg 2 times daily

(150mg/day)

75mg 2 times daily

(150mg/day)

75mg 2 times daily

(150mg/day)

Maximum Daily Dosage 600mg/day 600mg/day 600mg/day

Wishing You A Healthy Life