diabetic neuropathy
TRANSCRIPT
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Management of Painful Neuropathy
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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
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Mechanisms of Neuropathic Pain
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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
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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.
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Nociceptive vs. Neuropathic Pain
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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
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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
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Current Treatment Options
• Tricyclic Antidepressants (e.g. Imipramine)
• Conventional Anticonvulsants (e.g. Carbamazepine)
• Opioid Analgesics
• Gabapentin
• Mecobalamin
• Pregabalin
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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
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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
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Opiod Analgesics
• Constipation• Nausea• Somnolence• Dizziness• Pruritus• Vomiting• Sweating• Frequency of AEs ≥10% of patients.
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Gabapentin
• Gabapentin, alpha -2-delta subunit voltage-gated calcium-channel
antagonist• Dose titration required to achieve
optimal level • Optimal dosage 1800mg/day in PHN
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Gabapentin
Adverse Events* Gabapentin
Dizziness 17.1%
Somnolence 19.3%
Peripheral Edema 1.7%
Ataxia 12.5%
Weight Gain 2.9%
*Gabapentin Product Monograph
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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
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Healthy Neuron Happy Life
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Analog of GABA, binds to alpha 2 delta subunit of voltage gated calcium channels.
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• Novel evidence suggest that regulation of…
• Glutamate.
• Substance P & Noradrenalin.
• Results is relief from neuro - pathic pain syndrome.
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Diabetic Peripheral Neuropathy Post Herpetic Neuralgia
Fibromyalgia
Partial Onset Seizures
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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)
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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
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Clinically Proven Efficacy
0
5
10
15
20
25
30
35
40
45
Placebo 15%
Pregabalin 600mg 39%
Reduction in Pain Symptoms
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Clinically Proven Efficacy
0
10
20
30
40
50
60
Pregabalin 300mg46%
Pregabalin 600mg 48%
Placebo18%
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Clinically Proven Efficacy
0
5
10
15
20
25
30
35
40
45
Pregabalin 300mg40%
Placebo15%
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Clinically Proven Efficacy
0
5
10
15
20
25
30
35
40
45
50
Pregabalin 300/600mg46%
Placebo30%
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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%
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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
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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
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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
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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.
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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
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Wishing You A Healthy Life