Management of
Neuropathic Pain
Mazen M. Dimachkie, M.D.
Disclosures
Speaker Bureau
 Depomed
 Merck
 Pfizer
Grants
 Pfizer
OBJECTIVES
 Heterogeneity of painful peripheral neuropathy
 Evidence-based diagnostic approach
 Pain mechanisms
 Neuropathic pain management
 Evidence-based guidelines
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
Peripheral Neuropathies
 PN affects 2.4 to 7% of the population
JNNP 1997;62:310-318
 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
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf
Diabetes Care. 2006 Jul;29(7):1518-22
 26.4% of diabetic patients have painful neuropathy
 The Neuropathy Association estimates > 20 million
(6.5%), 50% markedly symptomatic, 150 causes
ARIZONA
Banner Good Samaritan
Neuropathy Center
ILLINOIS
NEW YORK
The Neuropathy Center at
Peripheral Neuropathy Center
Edward Hines, Jr. VA Hospital at Columbia University
CALIFORNIA - LOS ANGELES KANSAS
Neuropathy Center at
The University of Kansas
University of Southern
Neuropathy Center
California
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
FLORIDA - MIAMI
University of Miami Miller
School of Medicine
Neuropathy Center
MISSOURI
The Neuropathy Center at
Saint Louis University
TENNESSEE
The Neuropathy Center of
Excellence at Vanderbilt
University Medical Center
UTAH
The Peripheral Neuropathy
Center
at The University of Utah
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
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
North America – South America
(NA – SA) Neuropathy Project
Khan et al, AAN 2006
PN Categories
Immune-mediated
NA
%
20
SA
%
18
Diabetic
13
23
Hereditary
27
10
Infections / Inflammatory
5
14
Systemic / Metabolic / Toxic
7
12
Cryptogenic
28
23
Total # cases
1090
1034
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;72:185-192
AAN Practice Parameter
Evaluation of DSPN
 Autonomic testing in suspected
autonomic neuropathy
& distal small fiber sensory PN
(Level B)
(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;72:177-184
Normal Epidermal Nerve fiber
Density
Proximal Thigh
Distal Leg
Small Fiber Neuropathy: Lengthdependent 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 913-588-0656
Neuropathic Pain Mechanisms
Peripheral Sensitization
Lancet Neurol. 2010 Aug;9(8):807-19
Neuropathic Pain Mechanisms
Central Sensitization
Lancet Neurol. 2010 Aug;9(8):807-19
Mechanistic Approach to
Treatment
Brain
Descending
inhibition
NE/Serotonin
Opiate receptors
Peripheral
sensitization 2° neuron
PNS
TCAs
SSRIs
SNRIs (Duloxetine)
NSRIs
Opiates
Tramadol
Central sensitization
Ca++ : GBP, OXC, LTG, LVT, PGB
NMDA: Ketamine, TPM
Na+
CBZ
OXC
PHT
TCA
TPM
LTG
Mexiletine
Lidocaine
Spinal cord
Adapted from
Beydoun, 2001
Dextromethorphan
Methadone
Others
Capsaicin
NSAIDs
COX-2 inhibitors
Levodopa
Neuropathic pain
Multidimensional management
 Treatment of underlying cause of nerve
damage
 Pharmacological therapy
 Non-pharmacological therapy
Other Treatments:
Non-pharmacological therapy
 Lifestyle modification, PT & OT
J Diabetes Complications. 2012 Jun 18. [Epub ahead of print]
 Podiatric care & diabetic orthopedic shoes
 Pain psychologist & Cognitive Behavioral Rx
 Complementary & alternative medicine:
acupuncture, supplements etc
 TENS
 Interventional / regional anesthesia
 Neuro-stimulation
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
Antidepressants: TCAs & SSRIs
 >9 TCA and/or SSRI clinical trials in DPN or PHN
 Tricyclic antidepressants (TCAs) highly effective:
amitriptyline, nortriptyline and desipramine
Br J Clin Pharmacol. 1990 Nov;30(5):683-91. Neurology. 2002 Oct 8;59(7):1015-21
 TCA effect independent of depression comorbidity
Neurology. 1987 Apr;37(4):589-96
 Selective serotonin reuptake inhibitors (SSRIs) less
effective than TCAs:
 Fluoxetine no different than placebo in DPN
N Engl J Med. 1992 May 7;326(19):1250-6
 Paroxetine less effective than imipramine in DPN
Pain. 1990 Aug;42(2):135-44
 Escitalopram rs6318 SNP in the serotonin
receptor 2C gene associated with 75% moderate
or better pain relief Eur J Clin Pharmacol. 2011 Nov;67(11):1131-7
SNRI Antidepressants:
Venlafaxine
 Increases synaptic serotonin/NE (SNRI) by inhibiting
reuptake
 RCT: ER significantly reduces pain intensity in DPN
Pain. 2004 Aug;110(3):697-706
 Doses of 150-225 mg a day, not 75 mg
 Useful as add on to GBP in DPN: improved pain, QOL,
sleep and mood
J Clin Neuromuscul Dis. 2001 Dec;3(2):53-62
 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)
Neurology. 2003 Apr 22;60(8):1284-9
 Relatively well tolerated; side effect of nausea and
somnolence
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. 2012 Jan;23(1):200-5
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):109-1
Pain Med. 2005;6(5):346-56
.
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
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 voltagedependent Ca channel
Life Sci. 2007 May 8;80(22):2015-24
 Also increases CNS levels of GABA
Neurology. 2002;58(3):368-72
Epilepsy Res. 2002;49(3):203-10
Gabapentin
RCTs for PHN Label
Pain 2001;94:215-224
 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
Mean Change (SE)
JAMA 1998;280:1837-42
Gabapentin 1800 mg (n=115)
0.0
Gabapentin 2400 mg (n=108)
Placebo (n=111)
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0
1
2
3
4
5
6
Week
*P<0.01 (for both doses of gabapentin)
7
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
JAMA 1998;280:1831-36
 GBP vs. amitriptyline cross-over study in DPN
 No significant difference
Arch Intern Med. 1999 ;159(16):1931-7
 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
Cancer 2007;110:2110
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
3.2
 NTP
2.9
*p<0.05 vs. others
 Combo*
2.3
 Well tolerated, most common AE dry mouth esp. with NTP
Lancet. 2009 Oct 10;374(9697):1252-61
Lamotrigine
 DPN RCT vs PBO, n=59
 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
Neurology 2001;57:505-9
 Better pain reduction in 9 LTG vs 20 PBO
 13 drop out, 5 due to mild to moderate rash
Neurology 2000;54:2115-9
 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
Cancer 2008;112:2802-8
Anticonvulsants:
Pregabalin
 Approved on 12/31/04:
 DPN 50-100 mg TID
 PHN 75-300 mg BID
 Fibromyalgia 75-225 mg BID
Neurology 2004;63:2104-10
Curr Med Res Opin. 2006;22:375-84.
Anticonvulsants:
Pregabalin
 Similar mechanism as gabapentin
 Initiate at therapeutic dose, onset of action by day 2-3
Am J Ther. 2010 ;17(6):577-85
 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
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%
* Differences NS
Both are probably
effective for DPN &
CSPN neuropathic pain
Int J Neurosci. 2011;121:521-7
Tramadol in DPN
Centrally-acting:
Binds μ-opioid receptors
Weak inhibitor of NEP/5HT reuptake
RCT tramadol (n=65; 50-400 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
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
Somnolence
Nausea
Dizziness
42%
40%
36%
32%
Neurology 2003; 60:927-934
Morphine SR , Gabapentin or Combo
 Four-period (5 wks) crossover trial (35 DPN; 22 PHN)
 Active placebo (lorazepam 1.6 mg/d)
Dose adjusted
 Morphine SR 120 mg/d
(60 mg/d)
for
>60 yo or <60 kg
 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
4.49 (1.38 mg)
 Morphine SR
3.70 (45.3 mg)
 Gabapentin
4.15 (2207 mg) *p<0.05 vs. others
 Morphine SR + GBP*
3.06 (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
Gilron et al. NEJM 2005;352(13):1324–34
Lidocaine 5% patch in PHN
‘Enriched enrollment' study design
28 day cross-over (n=32)
12
11
10
9
8
7
6
5
4
3
2
1
0
Lidocaine patch 5%
No. of patients
Vehicle patch
Moderate
pain relief
Substantial
pain relief
Complete
pain relief
78% preferred lidocaine vs. 9% placebo (p<0.001)
Pain 1999;80:533-538
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 0.075-0.1% of limited use
 8% patch mean pain score change from baseline @
wk 2-12: -33.8% NGX-4010 vs +4.9% PBO in PHN
Pain Med. 2010;11:600-8
 AE: pain, transient burning, itch, skin irritation & HTN
2008 Jun 10;70(24):2305-13
 2 RCTs in HIV DSPN: Neurology.
J Acquir Immune Defic Syndr. 2012;59(2):126-33
 mean pain reduction of 22.8% vs. 10.7% PBO
 mean pain reduction of 29.5% vs. 24.5% PBO
Gabapentin ER in PHN
 RCT, n= 158, enrichment design, gastricretentive 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%)
Clin J Pain. 2009;25(3):185-92
 Pooled data analysis from 2 clinical trials:
dizziness
(11% vs PBO 2%)
somnolence (5% vs PBO 3%)
J Pain Res. 2012;5:203-208
PHN Pain
Pharmacotherapy 2012
 AAN Practice Parameter 2004 (Level A)
TCA, GBP, PGB, opioids & lidocaine patch
Neurology. 2004 Sep 28;63(6):959-65
 Capsaicin 8% patch
Pain Med. 2010;11:600-8
 Gabapentin ER
Clin J Pain. 2009;25(3):185-92
 Nerve block
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):1758-65
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