Management of Painful 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