Presented by Dr.Perry Fine at Pain Management for the Elderly Course, 2010. Scribe medical events Egypt. www.scribeofegypt.org

1. Management of
Neuropathic Pain
Perry G. Fine, MD
Professor of Anesthesiology
Pain Research Center
School of Medicine
University of Utah
Salt Lake City, Utah

2. Pathophysiology of
Neuropathic Pain
• Chemical excitation of non-nociceptors
• Recruitment of nerves outside of site of injury
• Excitotoxicity
• Sodium channels
• Ectopic discharge
• Deafferentation
• Central sensitization
– maintained by peripheral input
• Sympathetic involvement
• Antidromic neurogenic inflammation

3. Multiple Pathophysiologies May Be Involved
in Neuropathic Pain
• More than one mechanism of action likely involved
• Neuropathic pain may result from abnormal peripheral nerve function
and neural processing of impulses due to abnormal neuronal
receptor and mediator activity
• Combination of medications may be needed to manage pain:
topicals, anticonvulsants, tricyclic antidepressants, serotonin-
norepinephrine reuptake inhibitors, and opioids
• In the future, ability to determine the relationship between the
pathophysiology and symptoms/signs may help target therapy

4. Pain Treatment Continuum
Least
invasive
Most
invasive
Psychological/physical approaches
Topical medications
*Consider referral if previous treatments were unsuccessful.
Systemic medications*
Interventional techniques*
Continuum not related to efficacy

5. Nonpharmacologic Options
• Biofeedback
• Relaxation therapy
• Physical and occupational therapy
• Cognitive/behavioral strategies
– meditation; guided imagery
• Acupuncture
• Transcutaneous electrical nerve stimulation

6. Dorsal
Horn
BRAIN
Pharmacologic Agents
Affect Pain Differently
Descending Modulation
Peripheral
Sensitization
Central Sensitization
PNS
Local Anesthetics
Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants
Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants
SPINAL
CORD
CNS

7. Mechanisms of Action:
Analgesic Agents
• Anticonvulsants
– sodium-channel blockade (oxcarbazepine [Trileptal])
– calcium-channel blockade (gabapentin)
• Antidepressants
– inhibit reuptake of norepinephrine and serotonin into presynaptic neurons
(duloxetine)
– sodium-channel blockade (tricyclics)
• Opioids
– block neurotransmitter-release by nociceptive fibers, thus decreasing
transmission of pain-producing signals (oxycodone)
• Topical Analgesics
– sodium-channel blockade (lidocaine patch 5%)
– vanilloid receptor (capsaicin)

8. FDA-Approved Treatments
for Neuropathic Pain
• Carbamazepine
– trigeminal neuralgia
• Duloxetine
– peripheral diabetic neuropathy
• Gabapentin
– postherpetic neuralgia
• Lidocaine Patch 5%
– postherpetic neuralgia
• Pregabalin
– peripheral diabetic neuropathy
– postherpetic neuralgia

9. Treatment Guidelines for Diabetic Peripheral
Neuropathic Pain
Reason for
Agent Type Recommendation Agent Names
First tier ≥2 RCTs in DPN Duloxetine, oxycodone CR, pregabalin,
TCAs
Second tier 1 RCT in DPN and ≥1 in other
painful neuropathies
Carbamazepine, gabapentin,
lamotrigine, tramadol, venlafaxine ER
(Effexor)
Topical Mechanism of action Capsaicin, lidocaine
Other ≥1RCTs in other painful
neuropathies or other evidence
Bupropion (Wellbutrin), citalopram
(Celexa), methadone (Dolophine),
paroxetine (Paxil), phenytoin (Dilantin),
topiramate (Topamax)
Adapted from Argoff CE, et al. Mayo Clin Proc. 2006;81:S12-S25.
CR = controlled release; DPN = diabetic peripheral neuropathy; ER = extended release RCT= randomized controlled
trial; TCAs = tricyclic antidepressants.

10. Interventional Treatments
for Neuropathic Pain
• Neural blockade
– sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and
causalgia)
• Neurolytic techniques
– alcohol or phenol neurolysis
– pulse radio frequency
• Stimulatory techniques
– spinal cord stimulation
– peripheral nerve stimulation
• Medication pumps
CRPS = complex regional pain syndrome.

11. Comparison of Neuropathic Pain Treatment
Guidelines, Excluding Trigeminal Neuralgia*
Medication Class
NeuPSIG
Guidelines
CPS
Guidelines
EFNS Guidelines
TCAs First line First line
First line for PPN,
PHN, and CP
Calcium channel α2-δ
ligands (gabapentin and
pregabalin)
First line First line
First line for PPN,
PHN, and CP
SNRIs (duloxetine and
venlafaxine)
First line Second line Second line for PPN
*Only nontopical medications and nonopioid drugs considered first- or second-line in 1 of the guidelines are presented.
CP = central pain. CPS = Canadian Pain Society. EFNS = European Federation of Neurological Societies. NeuPSIG = Neuropathic Pain Special
Interest Group. NP = neuropathic pain. PHN = postherpetic neuralgia. PPN = painful polyneuropathy. SNRI = serotonin-norepinephrine reuptake
inhibitor. TCAs = tricyclic antidepressants.
Adapted from: O’Connor AB, Dworkin RH. Am J Med. 2009;122:S22-S32.

12. Efficacy of Anticonvulsants in Treating
Neuropathic Pain: Older Anticonvulsants
Condition Carbamazepine Oxcarbazepine Phenytoin
Sodium
Valproate
Diabetic neuropathy Yes (mod) ? (high) ? (mod) Yes (high)
Postherpetic neuralgia Yes (mod) 0 0 Yes (high)
Trigeminal neuralgia Yes (high) 0 0 0
Spinal cord injury pain 0 0 0 No (mod)
Poststroke pain No (mod) 0 0 0
HIV neuropathy 0 0 0 0
Pain in patients with Guillain-
Barré syndrome
Yes (mod) 0 0 0
Cancer-related neuropathic pain 0 0 ? (mod/high) 0
Stomatodynia 0 0 0 0
TMJ dysfunction and associated
myofascial pain
0 0 0 0
Chronic lumbar radicular pain 0 0 0 0
Postamputation phantom limb
pain
0 0 0 0
Fibromyalgia syndrome 0 0 0 0
CRPS I 0 0 0 0
Neuropathic pain not otherwise
specified
? (mod) 0 Yes (mod) No (high)
CRPS = complex regional pain syndrome. HIV = human immunodeficiency virus. TMJ = temporomandibular joint.
Adapted from: Goodyear-Smith F, Halliwell J. Clin J Pain. 2009;25:528-536.

13. Efficacy of Anticonvulsants in Treating
Neuropathic Pain: Newer Anticonvulsants
Condition Lamotrigine Vigabatrin Tiagabine Topiramate Levetiracetam
Diabetic neuropathy ? (high) 0 0 No (high) 0
Postherpetic neuralgia 0 0 0 0 ? (low)
Trigeminal neuralgia Yes (mod) 0 0 No (mod) 0
Spinal cord injury pain ? (high) 0 0 0 0
Poststroke pain Yes (high) 0 0 0 0
HIV neuropathy Yes* (high) 0 0 0 0
Pain in patients with
Guillain-Barré syndrome
0 0 0 0 0
Cancer-related
neuropathic pain
0 0 0 0 0
Stomatodynia 0 0 0 0 0
TMJ dysfunction and
associated myofascial
pain
0 0 0 0 0
Chronic lumbar radicular
pain
0 0 0 No (mod) 0
Postamputation phantom
limb pain
0 0 0 0 0
Fibromyalgia syndrome 0 0 0 0 0
CRPS I 0 0 0 0 0
Neuropathic pain not
otherwise specified
No (mod) 0 ? (mod) 0 0
*Efficacious in patients on antiretroviral therapy but evidence is inconclusive for patients not receiving antiretroviral therapy.
Adapted from: Goodyear-Smith F, Halliwell J. Clin J Pain. 2009;25:528-536.

14. Efficacy of Anticonvulsants in Treating
Neuropathic Pain: GABA Analogs
GABA = gamma aminobutyric acid. GBP = gabapentin.
Adapted from: Goodyear-Smith F, Halliwell J. Clin J Pain. 2009;25:528-536.
Condition GBP Pregabalin
Diabetic neuropathy Yes (high) Yes (high)
Postherpetic neuralgia Yes (high) Yes (high)
Trigeminal neuralgia 0 0
Spinal cord injury pain Yes (high) Yes (high)
Poststroke pain 0 0
HIV neuropathy Yes (high) 0
Pain in patients with Guillain-
Barré syndrome
Yes (mod) 0
Cancer-related neuropathic
pain
Yes (high) 0
Stomatodynia 0 0
TMJ dysfunction and
associated myofascial pain
0 0
Chronic lumbar radicular pain 0 0
Postamputation phantom
limb pain
Yes (high) 0
Fibromyalgia syndrome 0 Yes (high)
CRPS I No (high) 0
Neuropathic pain not
otherwise specified
Yes (high) 0

15. Are Serotonergic Antidepressants Effective in
Diabetic Peripheral Neuropathic Pain (DPNP)?
Author,
Year
Number
of
Patients
Active
Drug
Dose
(mg/day)
Placebo
Controlled
?
Effective for
Pain?
Goodnick P,
et al. 2000 12 Sertraline 62 No
Yes
(100% patients)
Goodnick P,
et al. 1997 8 Sertraline 150 No Yes
Wilson RC.
1999 31 Trazodone 50-100 No
22.6% complete
relief and
61.3%
symptomatic
relief

16. Are TCAs Effective in DPNP?
Author,
Year
Number of
Patients
Active
Drug
Dose
(mg/day)
Placebo
Controlled?
Effective for
Pain?
Sindrup RH, et
al. 1989
9 IMI Variable Yes Yes
Sindrup RH, et
al. 1990
14 IMI Variable No
Yes, if
concentration
>400-500
mmol/L
Max MB, et al.
1987
29 AMI Variable Yes Yes
Young RJ,
Clarke BF.
1985
71 IMI or AMI Variable No
Yes in 72.3% of
patients
Kvinesdal B,
et al. 1984
12 IMI Variable Yes Yes
Langohr HD,
et al. 1982
48 CLO vs ASA
150
1500
Active
Control
Yes
CLO>ASA
Turkington
RW. 1980
59 IMI and AMI
100
100
Active
Control
100% response
to drug vs 0%
response to
active control
AMI = amitriptyline. ASA = acetylsalicylic acid. CLO = clomipramine. IMI = imipramine.

17. Is Venlafaxine Effective in DPNP?
VEN = venlafaxine. XR = extended release.
Author,
Year
Number of
Patients
Active
Drug
Dose
(mg/day)
Placebo
Controlled?
Effective for
Pain?
Davis JL,
Smith RL.
1999
11 VEN 37.5-75 No
100% patients,
75-100%
reduction
in pain
Lithner F.
2000
11 VEN 225 No Yes
Kiayias J, et
al. 2000
8 VEN 75 Yes
Yes 100%
patients
Rowbotham
MC, et al.
2004
244 VEN XR
75, 150,
225 vs
placebo
Yes
Yes at 150 and
225 mg

18. Is Duloxetine Effective in DPNP?
Author,
Year
Number of
Patients
Active
Drug
Dose
(mg/day)
Placebo
Controlled?
Drug
Effective for
Pain?
Goldstein DJ,
et al. 2005 457 Duloxetine 20, 60, 120 Yes
Yes, at 60
and 120 mg

19. Head-to-head Trials for
DPNP: Antidepressants vs Anticonvulsants
Author,
Year
Number of
Patients
Active
Drug
Dose
(mg/day)
Placebo
Controlled?
Drug
Effective for
Pain?
Dallocchio C,
et al. 2000
13 GBP
12 AMI
GBP vs AMI
2400
30-90
N/A GBP>AMI
Morello CM, et
al. 1999
27 GBP vs AMI 225 N/A GBP = AMI

20. Head-to-head Trials for DPNP:
Antidepressants vs Antidepressants
CIT = citalopram. DESIP = desipramine. FLUOX = fluoxetine. MAP = maprotiline. MIA = mianserin.
Author,
Year
Number of
Patients
Active
Drug
Dose
(mg/day)
Placebo
Controlled?
Effective for
Pain?
Vrethem M, et
al. 1997
37
AMI
vs
MAP
75
75
Yes
Yes
AMI>Map>Placeb
o
Max MB, et al.
1992
38
46
AMI
vs
DESIP
vs
FLUOX
vs Placebo
105
111
40
Yes
AMI = DESIP
AMI>Placebo
DESIP>Placebo
FLUOX =
Placebo
Sindrup SH,
et al. 1992
18
IMI
vs
MIA
vs Placebo
Variable
60
Yes
IMI>Placebo
MIA = Placebo
Sindrup SH,
et al. 1992
15
CIT
vs
IMI
vs Placebo
40 Yes IMI>CIT>Placebo

21. NNTs for Anticonvulsants vs
Antidepressants in DPNP
• 12 trials of 9 antidepressants (including SSRIs)
• 4 trials of anticonvulsants (phenytoin, carbamazepine, GBP)
• NNT antidepressants = 3.4
• NNT anticonvulsants = 2.7
SSRI = selective serotonin reuptake inhibitor.
Collins SL, et al. J Pain Symptom Manage. 2000;20:449-458.

22. Consensus Treatment Guidelines for DPNP
Agent Type
Reason for
Recommendation
Agent Names
First tier >2 RCTs in DPNP
• Duloxetine • Pregabalin
• Oxycodone CR • TCAs
Second tier
1 RCT in DPNP >1 RCT
neuropathic pain
• GBP • Tramadol
• Lamotrigine • VEN XR
CR = controlled-release. RCT = randomized controlled trial.
Modified from: Argoff CE, et al. Mayo Clin Proc. 2006;81:S12-S25.

23. First Tier: Duloxetine
• SNRI
• FDA-approved for DPNP
– 3 RCTs: 60-120 mg/day
– N=1139; 12 weeks
– Positive studies
FDA = US Food and Drug Administration.

24. Study Duration Treatment Groups N
Duloxetine
60 mg/day
Duloxetine
120 mg/day
Goldstein DJ, et al.1* 12 weeks
20, 60, 120 mg/day vs
placebo
457 P<0.001** P<0.001**
Wernicke JF, et al.2* 12 weeks + 1
week taper
60, 120 mg/day vs
placebo
334 P<0.001** P<0.001**
Raskin J, et al.3* 12 weeks + 1
week taper
60, 120 mg/day vs
placebo
348 P<0.001** P<0.001**
Duloxetine: Clinical Trials in DPNP
Study Duration Treatment Groups N
1-year, open-label safety studies –
extension of studies 1, 2, and 34* 52 weeks 120 mg vs routine care 867
6-month, open-label safety study5 28 weeks 60 mg BID vs 120 mg QD 449
*Patients with mood disorders excluded.
**Duloxetine vs placebo on primary endpoint: 24-hour average pain severity in 12 weeks.
†Duloxetine is not indicated for long-term treatment in DPNP; the efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.
1. Goldstein DJ, et al. Pain. 2005;116:109-118. 2. Wernicke JF, et al. Neurology. 2006;67:1411-1420. 3.Raskin J, et al. Pain Med. 2005;6:346-356.
4. Hardy T, et al. Diabetes Care. 2007;30:21-26. 5. Raskin J, et al. Pain Med. 2006;7:373-385.
Long-term Safety Studies†
Short-term Efficacy and Safety Studies

25. Adverse Events: Duloxetine
• Anorexia
• Asthenia
• Constipation
• Cough
• Decreased appetite
• Diarrhea
• Dizziness
• Dry mouth
• Dyspepsia
• Erectile dysfunction
• Fatigue
• Headache
• Hyperhidrosis
• Insomnia
• Loose stool
• Muscle cramp
• Myalgia
• Nasopharyngitis
• Nausea
• Pharyngolaryngeal pain
• Pollakiuria
• Pyrexia
• Somnolence
• Tremor
• Vomiting
Observed in at least 3% of patients
Gremillion SW, et al, eds. Drug Facts And Comparisons® Pocket Version 2010. St. Louis, MO: Wolters Kluwer; 2010.

26. First Tier: Pregabalin
• α2-δ calcium channel modulator
• FDA-approved for DPNP
• 3 RCTs:
– 75 mg/day and 150 mg/day; same as placebo
– 300 mg/day and 600 mg/day; good efficacy
Lesser H, et al. Neurology. 2004;63:2104-2110. Richter RW, et al. J Pain. 2005;6:253-260. Rosenstock J, et al. Pain. 2004;110:628-638.

27. Adverse Events: Pregabalin
Most common reactions that
lead to discontinuation
• Dizziness
• Somnolence
• Asthenia
• Ataxia
• Blurred vision
• Confusion
• Incoordination
• Peripheral edema
• Abnormal thinking
Most common reactions in
controlled clinical trials
• Blurred vision
• Dizziness
• Dry mouth
• Edema
• Somnolence
• Abnormal thinking
• Weight gain
Gremillion SW, et al, eds. Drug Facts And Comparisons® Pocket Version 2010. St. Louis, MO: Wolters Kluwer; 2010.

28. First Tier: TCAs
• Amitriptyline has been studied the most extensively
– Limitations due to anticholinergic adverse effects
• Constipation and pseudodementia
– Potential cardiac conduction abnormalities1
• Nortriptyline and desipramine
– Better adverse effect profiles
– High doses cause anticholinergic side effects
• Affects cardiac conduction
– Desipramine is an alternative if patient has an amitriptyline
intolerance2
1. Max MB, et al. Pain. 1991;45:3-9. 2. Duby JJ, et al. Am J Health Syst Pharm. 2004;61:160-173.

29. TCAs: Mechanisms
• Relief of pain through serotonin (5-HT) and norepinephrine (NE)
reuptake blockade1
• Blockade of -adrenergic receptors2
• Sodium and potassium channel modulation
• Modulation of monoamine neurotransmitters
• NMDA receptor antagonism?
NMDA = N-methyl-D-aspartate
1. Lawson K. Expert Opin Investig Drugs. 2002;11:1437-1445. 2. Sindrup SH, Jensen TS. Pain. 1999;83:389-400.

30. TCAs: Adverse Events
• Commonly reported AEs
(generally anticholinergic)
– Blurred vision
– Cognitive changes
– Constipation
– Dry mouth
– Orthostatic hypotension
– Sedation
– Sexual dysfunction
– Tachycardia
– Urinary retention
– Weight gain
Most AEs
desipramine
nortriptyline
imipramine
doxepin
amitriptyline
Fewest
AEs
AEs = adverse events

31. Postherpetic
Neuralgia

32. Efficacy of Pregabalin in PHN
*≥50% and ≥30% reduction from baseline. †P≥0.001 vs placebo. ‡600 mg/day arm stratified according to CLcr. Patients either CLcr >30 and ≤60
mL/min received 300 mg/day; patients with CLcr >60 mL/min received 600 mg/day.
CLcr = creatinine clearance.
van Seventer, RV et al. Curr Med Res Opin. 2006;22:375-384.
Patients(%)
10
20
30
40
50
60 Responders (≥50%*)
Placebo
(n=93)
Responders (≥30%*)
0
150
(n=87)
300
(n=98)
600‡
(n=98)
600‡
(n=98)
Placebo
(n=93)
150
(n=87)
300
(n=98)
Pregabalin dose (mg/day) Pregabalin dose (mg/day)
†
†††
†
Proportion of Responders to Treatment

33. Pregabalin Improves Sleep
Disturbance in Patients with PHN
*P≤0.01 vs placebo.†600 mg/day arm stratified according to CLcr patients with CLcr >30 and ≤60mL/min received 300 mg/day pregabalin;
patients with CLcr >60 mL/min received 600 mg/day.
van Seventer R, et al. Curr Med Res Opin. 2006;22:375-384.
WeeklyMeanSleep
InterferenceScore
*
1
2
3
4
5
6
0 Endpoint
Treatment (Weeks)
Mean Weekly Pain-related Sleep-interference in PHN at All Doses
1 2 4 7 11 131210
Placebo (n=93)
Pregabalin 150 mg/day (n=87)
Pregabalin 300 mg/day (n=98)
Pregabalin 600† mg/day (n=88)
**********
*
*
*
* *
*
*
* *
*
* *
* *
****
* * *
*** * * *
*
**
*
98653

34. Efficacy of Gabapentin in PHN
RespondersatEndpoint(%)
25
30
35
40
45
50
PBO
0
Study 1
*P<0.01
**P<0.001
Study 2
GBP
3600 mg/day
GBP
1800 mg/day
GBP
2400mg/day
PBO
12%
*
**
**
20
15
10
5
29%
14%
32%
34%
Proportion of Responders (Patients with ≥50% Reduction in
Pain Score) at Endpoint Controlled PHN Studies
Neurontin [package insert]. New York, New York: Pfizer Inc; 2009.

35. Conclusions
• Irrespective of the neuropathic pain condition under treatment, the
central pathways involved in these conditions remain the same;
hence, the use of antidepressants and anticonvulsants that modulate
pathways in patients with chronic pain will be very effective.