1. Management of Neuropathic Pain
Mazen M. Dimachkie, M.D.

2. Disclosures
Speaker Bureau
Depomed
Merck
Pfizer
Grants

3. OBJECTIVES Heterogeneity of painful peripheral neuropathy
Evidence-based diagnostic approach
Pain mechanisms
Neuropathic pain management
Evidence-based guidelines

4. Neuropathic Pain
Pain as a direct consequence of a lesion or disease affecting the somatosensory system
Descriptors and diurnal pattern
Pain carries physical and emotional burdens and leads to increased healthcare utilization
Chronic pain or mobility impairment may lead to depression, anxiety and loss of self-esteem
This becomes part of a vicious cycle that feeds into and amplifies the negatives of painful peripheral neuropathy

5. Peripheral Neuropathies
PN affects 2.4 to 7% of the population
CDC National Diabetes Fact Sheet 2011:
25.8 million diabetics
60-70% mild to severe neuropathy forms
35% of U.S. adults aged > 20 years prediabetes
26.4% of diabetic patients have painful neuropathy
The Neuropathy Association estimates > 20 million (6.5%), 50% markedly symptomatic, 150 causes
JNNP 1997;62:
Diabetes Care Jul;29(7):

6. ARIZONA
Banner Good Samaritan  Neuropathy Center
ILLINOIS
The Neuropathy Center at Edward Hines, Jr. VA Hospital
  NEW YORK
Peripheral Neuropathy Center at Columbia University
CALIFORNIA - LOS ANGELES
Neuropathy Center at University of Southern California
KANSAS
The University of Kansas Neuropathy Center
NEW YORK
Peripheral Neuropathy Center at Weill Medical College of Cornell University
CALIFORNIA - SAN FRANCISCO
University of California at San Francisco Neuropathy Center
LOUISIANA
The Neuropathy Center of Excellence at Louisiana State University HSC
OHIO
The Neuropathy Center at Ohio State University
FLORIDA - JACKSONVILLE
University of Florida and Shands Jacksonville Neuropathy Center
MICHIGAN
University of Michigan Neuropathy Center
TENNESSEE
The Neuropathy Center of Excellence at Vanderbilt University Medical Center
FLORIDA - MIAMI
University of Miami Miller School of Medicine Neuropathy Center
  MISSOURI
The Neuropathy Center at Saint Louis University
 UTAH
The Peripheral Neuropathy Center at The University of Utah

7. Peripheral Neuropathy Classification
Modality:
Sensory: small and/or large fiber
Motor
Sensori-motor
Autonomic
Temporal profile
Symmetric or asymmetric
Length-dependence or neuronopathy
Proximal and / or distal
Upper motor neuron signs
Axon loss or demyelinating

8. Electrodiagnostic Testing Nerve Conduction Studies
Low amplitude in axon loss
Myelin loss disorders:
Prolonged distal latency
Markedly reduced NCV
Delayed F-wave latency
Conduction block

9. North America – South America (NA – SA) Neuropathy Project Khan et al, AAN 2006
PN Categories NA % SA
Immune-mediated 20 18
Diabetic 13 23
Hereditary 27 10
Infections / Inflammatory 5 14
Systemic / Metabolic / Toxic 7 12
Cryptogenic 28
Total # cases
1090
1034

10. AAN Practice Parameter Evaluation of DSPN
Screening laboratory tests may be considered for all patients with polyneuropathy (Level C)
Serum glucose, B12 with metabolites (MMA ± HC) and serum immunofixation provide the highest yield of abnormality (Level C)
Genetic testing should be conducted in hereditary neuropathies (Level A)
Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C)
Neurology 2009;72:

11. AAN Practice Parameter Evaluation of DSPN
Autonomic testing in suspected autonomic neuropathy (Level B) & distal small fiber sensory PN (Level C)
Nerve biopsy: insufficient evidence in DSPN but is generally accepted in amyloid neuropathy, mononeuropathy multiplex, and atypical CIDP (Level U)
Skin biopsy may be considered for the diagnosis of DSPN, esp. CSPN (Level C)
Neurology 2009;72:

12. Normal Epidermal Nerve fiber Density
Proximal Thigh
Distal Leg

13. To schedule a skin biopsy, please call 913-588-0656
Small Fiber Neuropathy: Length-dependent decrease in Epidermal Nerve Fiber Density
Proximal Thigh: Decreased Epidermal Nerve Fiber Density
Distal Leg: Absent Epidermal Nerve Fibers
To schedule a skin biopsy,
please call

14. Neuropathic Pain Mechanisms
Peripheral Sensitization
Lancet Neurol Aug;9(8):807-19

15. Neuropathic Pain Mechanisms
Central Sensitization
Lancet Neurol Aug;9(8):807-19

16. Central sensitization
Mechanistic Approach to Treatment
Brain
Descending inhibition
TCAs
SSRIs SNRIs (Duloxetine)
NSRIs Opiates
Tramadol
NE/Serotonin Opiate receptors
Central sensitization
Peripheral sensitization
Ca++ : GBP, OXC, LTG, LVT, PGB
NMDA: Ketamine, TPM
Dextromethorphan Methadone
2° neuron
PNS
Na+
CBZ OXC
PHT TCA TPM LTG
Mexiletine
Lidocaine
Spinal cord
Others Capsaicin
NSAIDs COX-2 inhibitors Levodopa
Adapted from
Beydoun, 2001

17. Neuropathic pain Multidimensional management
Treatment of underlying cause of nerve damage
Pharmacological therapy
Non-pharmacological therapy

18. Other Treatments: Non-pharmacological therapy
Lifestyle modification, PT & OT
Podiatric care & diabetic orthopedic shoes
Pain psychologist & Cognitive Behavioral Rx
Complementary & alternative medicine: acupuncture, supplements etc
TENS
Interventional / regional anesthesia
Neuro-stimulation
J Diabetes Complications Jun 18. [Epub ahead of print]

19. Painful Peripheral Neuropathy Treatment Goals
Setting the expectation with emphasis on function: work, recreation & sleep
This is addition to significant reduction of pain scores by 30-50%
Types of pharmacotherapies:
Antidepressants
Anticonvulsants
Topical agents
Analgesics
Opioid drugs

20. Antidepressants: TCAs & SSRIs
>9 TCA and/or SSRI clinical trials in DPN or PHN
Tricyclic antidepressants (TCAs) highly effective: amitriptyline, nortriptyline and desipramine
TCA effect independent of depression comorbidity
Selective serotonin reuptake inhibitors (SSRIs) less effective than TCAs:
Fluoxetine no different than placebo in DPN
Paroxetine less effective than imipramine in DPN
Escitalopram rs6318 SNP in the serotonin receptor 2C gene associated with 75% moderate or better pain relief
Br J Clin Pharmacol Nov;30(5): Neurology Oct 8;59(7):
Neurology Apr;37(4):589-96
N Engl J Med May 7;326(19):1250-6
Pain Aug;42(2):135-44
Eur J Clin Pharmacol Nov;67(11):1131-7

21. SNRI Antidepressants: Venlafaxine
Increases synaptic serotonin/NE (SNRI) by inhibiting reuptake
RCT: ER significantly reduces pain intensity in DPN
Doses of mg a day, not 75 mg
Useful as add on to GBP in DPN: improved pain, QOL, sleep and mood
112.5 mg bid may be as effective as imipramine 75 mg BID in a 3-way crossover, 4-wk RCT in DPN (n=15) and non-diabetic cases (n=17, CSPN = 11)
Relatively well tolerated; side effect of nausea and somnolence
Pain Aug;110(3):
J Clin Neuromuscul Dis Dec;3(2):53-62
Neurology Apr 22;60(8):1284-9

22. SNRI Antidepressants: Venlafaxine in Oxaliplatin Neuropathy
RCT: 50 mg 1 h prior oxaliplatin & ER 37.5 mg b.i.d. from days 2 to 11 vs PBO
N = 48, patients with oxaliplatin-induced acute neurotoxicity
Completers 20/24 venlafaxine and 22/24 PBO
Primary end point percentage of patients with a 100% pain relief based on the NRS pain scale
Full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03)
Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%)
Ann Oncol Jan;23(1):200-5

23. SNRI Antidepressants: Duloxetine
SNRI released in Fall 2004 with higher, more balanced affinity for NE/5HT reuptake sites
First FDA approved agent DPN (also approved for fibromyalgia)
Effective at 60 and 120 mg/d not 20 mg/d
Higher AE incidence with 120 mg dose
Pain. 2005;116(1-2): Pain Med. 2005;6(5):346-56 .

24. Duloxetine Adverse events (largely dose-dependent)
Nausea, somnolence, dizziness, constipation, dry mouth
Drug interactions
MAOIs (wait 14 days)
TCAs, Phenothiazines, Type 1C antiarrhythmics, Quinolone antibiotics and Cimetidine
Precautions: closed-angle glaucoma and hepatotoxicity
Black box warnings: suicide risk

25. Anticonvulsants: Gabapentin
Most commonly prescribed AED for pain
Does not bind to plasma proteins
Does not induce hepatic enzymes
Excreted unchanged in urine
Mechanisms of action: binds to 2 subunit of presynaptic voltage-dependent Ca channel
Also increases CNS levels of GABA
Life Sci May 8;80(22):
Neurology. 2002;58(3):368-72
Epilepsy Res. 2002;49(3):203-10

26. Gabapentin RCTs for PHN Label
JAMA 1998;280:
8-week trial
229 patients titrated up to 3600 mg/day
Average daily pain score dropped from 6.3 to 4.2 on GBP vs. 6.5 to 6.0 for placebo (p<0.001)
33% reduction in pain score vs. 8% reduction on placebo
43% with significant improvement vs. 12% on placebo
Pain 2001;94:
Mean Change (SE)
*P<0.01 (for both doses of gabapentin)

27. Gabapentin: DPN & Chemo Neuropathy
RCT 8 wk in 165 DPN patients GBP vs PBO:
Mean daily pain scores lower in GBP group (p<.001)
26% pain-free vs. 15% on placebo at 8 wks
Improved quality of life & sleep
GBP vs. amitriptyline cross-over study in DPN
No significant difference
RCT cross-over in 115 Chemo-induced neuropathy
6 wk epochs of GBP 2700 mg vs. PBO
2-week washout period
No benefit of GBP vs. placebo on 0-10 pain rating scale
JAMA 1998;280:
Arch Intern Med ;159(16):1931-7
Cancer 2007;110:2110

28. Gabapentin, Nortriptyline or Combo
Double-blind, double-dummy, crossover trial, DPN & PHN
56 patients randomized in a 1:1:1 ratio to receive one of three sequences of daily oral GBP, nortriptyline, & combo
Duration of each treatment period 6-week, 45 completers
Primary outcome mean daily pain at maximum tolerated dose
Mean daily pain levels in 45 completers compared to baseline (5.4):
GBP
NTP 2.9
Combo*
Well tolerated, most common AE dry mouth esp. with NTP
*p<0.05 vs. others
Lancet Oct 10;374(9697):

29. Lamotrigine DPN RCT vs PBO, n=59 HIV neuropathy RCT n=42
Numerical pain scale reduction 6.4 to 4.2 and with PBO 6.5 to 5.3 (p < 0.001)
Effective at doses of 200 – 400 mg daily
HIV neuropathy RCT n=42
Better pain reduction in 9 LTG vs 20 PBO
13 drop out, 5 due to mild to moderate rash
Chemo-induced neuropathy RCT n= 131
300 mg vs. PBO x 10 wks
No significant difference in average pain scores (0-10) or on secondary outcomes
Neurology 2001;57:505-9
Neurology 2000;54:2115-9
Cancer 2008;112:2802-8

30. Anticonvulsants: Pregabalin
Approved on 12/31/04:
DPN mg TID
PHN mg BID
Fibromyalgia mg BID
Neurology 2004;63: Curr Med Res Opin. 2006;22:

31. Anticonvulsants: Pregabalin
Similar mechanism as gabapentin
Initiate at therapeutic dose, onset of action by day 2-3
Linear pharmacokinetics across therapeutic doses
DPN adverse events on 150, 300 mg & 600 mg daily:
Dizziness (9, 23 & 29%)
Somnolence (6, 13 & 16%)
Peripheral edema (6, 9 & 12%)
Weight gain (4, 4 & 6%)
Dry mouth (2, 5 & 7%)
Blurry vision (1, 3 & 6%)
SAE: suicide risk
Am J Ther ;17(6):577-85

32. DLX vs PGB in DPN & CSPN Retrospective chart review
N=143; both drugs at different times n = 51, only one n= 92
Majority DPN & CSPN
Overall responders: DLX 41% PGB 48%
Discontinuation DPN: DLX 66%, PGB 59%
DPN & CSPN
DLX
(59 mg)
PGB
(217 mg)
Much Improved
21%
33%
Adverse events
38%
30%
Both are probably effective for DPN & CSPN neuropathic pain
* Differences NS
Int J Neurosci. 2011;121:521-7

33. Tramadol in DPN Centrally-acting: Binds μ-opioid receptors
Weak inhibitor of NEP/5HT reuptake
RCT tramadol (n=65; mg) vs PBO (n= 66):
Effective in DPN
Mean dose 210 mg/d
No effect on sleep
AEs: nausea, constipation, HA & somnolence
Neurology 1998;50:1842

34. Analgesics Opiate: Oxycodone CR in DPN RCT n=159
Dose 10 mg BID increased Q 3 d to maximum 60 mg BID
Primary efficacy was pain intensity at days 28 & 42
Results at mean dose of 37 mg/d (10-100):
Effective in moderate to severe DPN pain
Adverse events in 96% vs. 68% on PBO!
Constipation 42%
Somnolence 40%
Nausea 36%
Dizziness 32%
Neurology 2003; 60:

35. Morphine SR , Gabapentin or Combo
Four-period (5 wks) crossover trial (35 DPN; 22 PHN)
Active placebo (lorazepam 1.6 mg/d)
Morphine SR 120 mg/d (60 mg/d)
Gabapentin 3200 mg /d (2400 mg/d)
Morphine SR 60 mg/d + gabapentin 2400 mg/d
Mean daily pain levels over 7 days at maximally tolerated dose in 41 completers (N=57) compared to baseline (5.72):
Active PBO (1.38 mg)
Morphine SR (45.3 mg)
Gabapentin (2207 mg)
Morphine SR + GBP* (34.3 mg; 1705 mg)
Combination had lower mood interference, higher vitality & social functioning scores than morphine alone
AEs Combination:
more constipation than gabapentin
more dry mouth than morphine
Dose adjusted for
>60 yo or <60 kg
*p<0.05 vs. others
Gilron et al. NEJM 2005;352(13):1324–34

36. Substantial pain relief
Lidocaine 5% patch in PHN ‘Enriched enrollment' study design
28 day cross-over (n=32) 12
Lidocaine patch 5% 11
Vehicle patch 10 9 8 7
No. of patients 6 5 4 3 2 1
Moderate pain relief
Substantial pain relief
Complete pain relief
78% preferred lidocaine vs. 9% placebo (p<0.001)
Pain 1999;80:

37. Capsaicin 8% Patch
Selectively binds TRPV1 receptor, cation channel overexpressed in intact nociceptive sensory nerves
TRPV1 receptor activation at 38 C → high levels of intracellular calcium & substance P depletion
Capsaicin cream % of limited use
8% patch mean pain score change from wk 2-12: -33.8% NGX-4010 vs +4.9% PBO in PHN
AE: pain, transient burning, itch, skin irritation & HTN
2 RCTs in HIV DSPN:
mean pain reduction of 22.8% vs. 10.7% PBO
mean pain reduction of 29.5% vs. 24.5% PBO
Pain Med. 2010;11:600-8
Neurology Jun 10;70(24):
J Acquir Immune Defic Syndr. 2012;59(2):126-33

38. Gabapentin ER in PHN
RCT, n= 158, enrichment design, gastric-retentive technology GBP ER x 4 weeks:
1800 mg PM vs 600 mg AM, 1200 mg PM vs PBO 1 or 2 x daily
≥50% decrease from baseline in ADP score: 25.5%, 28.8%, and 11.8% (p<0.05)
Sleep interference scores improved
AE: dizziness (22.2%, 11.3%, and 9.8%) somnolence (9.3%, 7.5%, and 7.8%)
Pooled data analysis from 2 clinical trials:
dizziness (11% vs PBO 2%) somnolence (5% vs PBO 3%)
Clin J Pain. 2009;25(3):185-92
J Pain Res. 2012;5:

39. PHN Pain Pharmacotherapy 2012
AAN Practice Parameter (Level A)
TCA, GBP, PGB, opioids & lidocaine patch
Capsaicin 8% patch
Gabapentin ER
Nerve block
Neurology Sep 28;63(6):959-65
Pain Med. 2010;11:600-8
Clin J Pain. 2009;25(3):185-92

40. DPN Pain Pharmacotherapy 2012
PGB (Level A)
Amitriptyline, DLX, GBP, venlafaxine, Na valproate Opioids (tramadol, morphine, oxycodone CR) Capsaicin, isosorbide dinitrate Percutaneous electrical stimulation (Level B)
Venlafaxine add-on to GBP Lidocaine patch (Level C)
Desipramine or imipramine, fluoxetine, NTP+fluphenazine, topiramate, vitamins & ALA (Level U)
Neurology. 2011;76(20):

41. Painful Peripheral Neuropathy Conclusions
Discuss patient expectations in managing chronic neuropathic pain
Selection based on efficacy, AE and comorbidity
Multiplicity of drugs
A variety of mechanisms
Indications limited to PHN, DPN & fibromylagia
Comparative effectiveness studies are needed in a wider variety of neuropathic pain etiologies