Management of Neuropathic Pain

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Management of Neuropathic Pain

• Mellar P Davis
• MASCC ,June 2009

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Pharmacological treatment of neurologic pain
relies on evidence from large randomized
controlled trials

• Attal 2006
• Dworkin 2007

3

• Despite advances in research and clinical
  trials, a considerable number of individuals do
  not get relief
• NNT- 3-5 for most drugs

4

• Response is defined as a 30-50 reduction in
  pain severity
• empiric drug trials trial and error
• choices based on mechanism
• gulf between empiricism and mechanistic
• drug choices
• Baron 2006
• Woolf 1998

5

• It is unclear which laboratory pain responses are
  most strongly associated with the experience of
  pain in daily life
• Edwards 2003

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Tools for Neuropathic Pain

• Neuropathic pain questionnaire, Leeds assessment
  of neuropathic signs and symptoms Neuropathic
  Pain Symptom Inventory
• Definite NP, possible NP, unlikely NP
• Definite NP had greater pain intensity
• Definite NP had greater opioid escalation index

Mercadante 2009
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• Differences Between Peripheral and Central
  Neuropathic Pain
• Less evidence for central pain syndromes
• Differences in drug classes (cannabinoids)
• Central pain syndromes do not respond to
  peripheral blocks or ablative procedures
• Motor cortex stimulation

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Pain Relief

• 30-50 pain relief may not correlate with
  Patient Global Impression of change (PGIC)
• Analgesia vs. function
• Differential response on the several pain
  mechanisms found in a single individual
• Allodynia
• Burning C fiber pain
• Spontaneous pain

Baron 2006 Farrar 2001
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Pain Relief

• Not all or none but continuous
• Balance of pain relief, medication burden, side
  effects, QOL, function
• Artifact to use binomial outcomes

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Dosage

• Tolerable dose vs therapeutic dose (serum levels
  vs empiric recommendations)
• Combinations may reduce the tolerable dose

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Duration

• Maximum tolerable dose and duration of time to
  see maximum benefit
• Pharmacodynamic optimal time for response is
  largely unknown
• Maintenance period of 3 weeks, longer if
  suggested by RCTs
• Drug specific
• Poorly related to drug half-life
• Challenge in neuropathic pain

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Treatment Paradigm

• Drug classes proven by RCT
• TCA
• SNRI
• Alpha-2-delta ligands
• Opioids
• Topical lidocaine
• Sodium channel blockers
• Monotonous (single drug)

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Peripheral neuropathic pain
yes
Postherpetic neuralgia and focal neuropathy
no
Lidocaine patch
TCA contraindication
yes
no
Gabapentin / pregabalin
TCA (SNRI)
TCA contraindication
yes
no
TCA (SNRI)
Gabapentin / pregabalin
Tramadol, oxycodone
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Numbers Need to Treat Calculated for Various
Drug Classes in the Treatment of Painful
Neuropathy
SSRIs
6.7
Gabapentin
3.7
TCAs-NE
3.4
TCAs-5HT/NE
2
TCAs-5HT/NE
1.4
0
2
4
6
8
Optimal dose achieved. SSRI, selective serotonin
reuptake inhibitor TCA, tricyclic antidepressant.
Study by Sindrup and Jensen (1999)
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• Pharmacoresistance
• Pharmacorotation fails to produce response or
  produces intolerable side effects
• Lowers QOL, increases symptoms
• Expensive

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Definition of Pharmacoresistance

• A neuropathic pain condition is resistant to
  pharmacotherapy when mono or a rational
  combination treatment using drugs proved
  efficacious in RCTs fails in inducing useful pain
  relief from the patients/physicians point of view
  after an appropriate duration of treatment with
  adequate dosage or if intolerable side effects
  occur
• Hansson 2009

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Combination Therapy

• Rationale-non-overlapping mechanism
• Paucity of data
• Polypharmacy, side effects
• No data for central pain syndromes

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Polypharmacy

• Gabapentin plus opioids
• Gabapentin plus venlafaxine
• Gilron 2005
• Hanna 2008
• Simpson 2001

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Morphine, Gabapentin, or Their Combination for
Neuropathic Pain

• Ian Gilron, M.D., Joan M. Bailey, R.N.,
  M.Ed.,Dongsheng Tu, PhD., Ronald R. Holden,
  Ph.D., Donald F. Weaver, M.D., Ph.D., and Robyn
  L. Houlden, M.D.

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Mean Daily Pain
7
6
5
4
Score for Pain Intensity
3
2
1
0
Baseline
Placebo
Gabapentin
Morphine
Combination
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Maximal Tolerated Dose
2500
60
50
2000
40
1500
Dose (mg)
30
1000
20
500
10
0
0
Single agent combination
Single agent combination
Gabapentin
Morphine
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The Involvement of Endogenous Opioid Mechanisms
in the Antinociceptive Effects Induced by
Antidepressant Drugs, Desipramine and
Trimipramine

• Yusuf Özturk, Süleyman Aydin,
• Rana Beis, Tuba Herekman-Demir

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20
16
10
Reaction Time (s)
8
4
0
Control
7.5
15
7.5
15
Rats pretreated with Naltrindole (1mg/kg)
Desipramine
Desipramine doses (mg/kg)
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More Efficacious Drugs

• Lower side effect profiles
• New classes (CB2 receptor agonists, anti-glia
  agents)
• More trials of combination therapy
• Rigorous studies of non-pharmacological measures

Hansson 2009
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Non-TCA, SNRI Antidepressant Mirtazapine

• Therapeutic with initial dose
• Pain control
• Sleep, anxiety and appetite improvement
• Fewer drug interactions
• No QTc effects, hypertension
• Anti-emetic
• Tolerance to sedation
• ? Tolerable in very advanced cancer
• Combined with SNRI

Sahin 2008 Evsoy 2008 Kim 2008 Hannan 2007
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Withdrawal duration (s)
10
0
Vehicle Amitriptylline 3 mgkg
Vehicle Mirtazapine 3 mgkg
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Amitriptylline 10 mgkg Amitriptylline 30 mgkg
Mirtazapine 10 mgkg Mirtazapine 30 mgkg
Withdrawal latency (s)
6
0
Base 1
Base 2
30
60
90
120
180
Base 2
30
60
90
120
180
Base 1
Time (min)
Time (min)
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Combinations

• NSAIDs plus alpha-2-delta ligand
• Opioid plus minocycline (anti-glia)
• CB2 agonist plus opioid (anti-glia)
• () opioid antagonists (anti-glia)
• etodolac

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Glia and Opioids Minocycline

• Attenuates morphine induced respiratory
  depression
• Reduces conditioned place preference
• Potentiate morphine analgesia
• Blocks morphine induced upregulation of Cox-1

Hutchinson 2008
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Etodolac Attenuates Mechanical Allodynia in a
Mouse Model of Neuropathic Pain

• Naoki Inoue, Sunao Ito, Koyuki Tajima, Masaki
  Nogawa
• Yosuke Takahashi, Takahiro Sasagawa,
• Akio Nakamura, and Takashi Kyoi

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Effect on Mechanical Allodynia in PSNL Mice
0.8
Control Etodolac 10 mg/kg Indomethacin 1
mg/kg Celecoxib 30 mg/kg
0.6
0.4
PWT (g)




0.2



0.0
Day 0
Pre 1h 4h
Pre 1h 4h
Pre 1h 4h
Day 7
Day 14
Day 21
Time after administration
Each symbol represents the mean PWT for 10 mice.
Drugs were administered orally once a day for two
weeks from seven days after PSNL. Plt0.05,
Plt0.01 (vs. control, Steel test).
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Opioid Induced Hyperalgesia

• Quantitative sensory testing
• Reduced heat pain thresholds
• Exacerbated temporal summation of a second pain
• Dose effect
• Opioid tolerance
• Narrow therapeutic window

Chen 2009
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Altered Quantitative Sensory Testing Outcome in
Subjects with Opioid Therapy

• Lucy Chen, Charlene Malarick, Lindsey Seefeld,
• Shuxing Wang, Mary Houghton,Jianren Mao

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Exacerbated Temporal Summation of the Second Pain
in Group 3 Subjects
500

Group 1 Group 2 Group 3
400

300

Increase in VAS ()
200
100
0
S1/BL
S2/BL
S3/BL
Plt0.05, as compared with group 1 and group 2
subjects. S1/BK, S2/BL, S3/BL the percent
increase in VAS (visual analogue scale) score in
response to the second, third, and fourth
stimulation over that of the first stimulation in
a train of four noxious heat (47C) stimuli.
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Different Profiles of Buprenorphine Induced
Analgesia and Antihyperalgesia in a Human Pain
Model

• Wolfgang Koppert, Harald Ihmsen, Nicole Körber,
  Andreas Wehrfritz, Reinhard Sittl, Martin
  Schmelz, Jürgen Schüttler

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Antihyperalgesia
Analgesia
Ratio
Buprenorphine i.v.
2.6 (0.8-3.8)
Buprenorphine s.i.
1.9 (-0.1-8.1)
Fentanyl i.v.
0.6 (-0.3-2.2)
Alfentanil i.v.
0.3 (-0.3-0.5)
S-ketamine i.v.
5.5 (3.1-6.1)
100
75
50
25
0
25
50
Effect ()
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Chronic Morphine Administration Enhances
Nociceptive Sensitivity and Local Cytokine
Production After Incision

• DeYong Liang, Xiaoyou Shi, Yanli Qiao, Martin S
  Angst,
• David C. Yeomans, and J David Clark

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Saline Chronic Morphine Saline / Incision Chronic
Morphine / Incision
1200
IL-1?
900
pg/mg Protein
600
300
0
600
TNF?
450
pg/mg Protein
300
150
0
2h
24h
72h
Time after Incision
40
2.0
Saline prior to incision MSO4 prior to incision
Paw Withdrawal Threshold (g)
1.0
0.0
Baseline
-

-

PTX
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Alternative Medications

• Melatonin
• S-adenosyl methionine
• L-carnitine
• Vitamin D

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Neuropathic Pain Seed or Soil

• Individuals differ widely in their ability to
  moderate pain
• Range from substantial inhibition to substantial
  facilatation
• Diffuse noxious inhibitory controls (DNIC)

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Diffuse Noxious Inhibitory Control

• Ability to modulate phasic pain when experiencing
  chronic pain
• Supraspinal generated inhibition of spinal wide
  dynamic range neuron
• Reduced in fibromyalgia, temporomandibular
  disorder, irritable bowel syndrome

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Diffuse Noxious Inhibitory Control

• Reduced with age
• Influenced by certain domains of quality of life
• ? premorbid background to neuropathic pain
  syndrome
• ? Improved by non-pharmacologic approaches to
  pain
• ? Altering pain catastrophizing

Edwards 2003 Goodin 2009
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Individual Differences in Diffuse Noxious
Inhibitory Control (DNIC) Association with
Clinical Variables

• Robert R. Edwards, Timothy J Ness,
• Douglas A Weigent,
• Roger B Fillingim

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Scores on SF-36 Subscales (mean SD)
SF-36 subscales Younger (n 37) Older (n
37) General health (0-100) 79.1 13.8 77.6
18.2 Physical functioning (0-100) 93.2
19.2 84.6 15.4 Physical role (0-100) 95.3
15.4 81.1 31.7 Bodily pain (0-100) 76.2
16.5 73.7 16.1
Age groups differ at Plt0.05. Higher SF-36
subscale score represents better functioning
(e.g. less pain, better health).
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Younger Adults
Older Adults
DNIC (n24)
DNIC - (n13)
DNIC (n11)
DNIC - (n26)
100
90
80
70
60
50
Younger
Older
Younger
Older
Younger
Older
Younger
Older
BP
PF
PR
GH
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Catastrophizing

• Interferes with the endogenous opioid system
• Distraction which mobilizes the endogenous opioid
  system is less effective in high catastrophizing
  individuals
• Catastrophizing produces a pro-inflammatory
  response
• Interact with pain genotype (COMT) as a predictor
  for high pain sensitivity

Campbell 2009 Weissman-Fogel 2008 George 2008
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Associations Between Catastrophizing and
Endogenous Pain Inhibitory Processes Sex
Differences

• Burel R Goodin, Lynanne Mcguire, Mark Allshouse,
• Laura Stapleton, Jennifer A Haythornthwaite, Noel
  Burns,
• Lacy A Mayes, and Robert R Edwards

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DNIC
a
B
In vivo catastrophizing
SF-MPQ pain ratings
c
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Religion, Spirituality and Chronic Pain

• Organized religion reduced chronic pain
• Spirituality without affiliated regular worship
  attendance increased chronic pain prevalence
• Individuals with chronic pain are more likely to
  use prayer, spiritual support for coping

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An fMRI Study Measuring Analgesia Enhanced by
Religion as a Belief System

• Katja Wiech, Miguel Farias, Guy Kahane,
• Nicholas Shackel, Wiebke Tiede, Irene Tracey

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100
Non-Religious condition Religious condition
80
Pain intensity (VAS 0-100)
60
40
Religious group
Non-Religious group
56
50
Non-Religious condition Religious condition
40
30
20
Pain intensity (VAS 0-100)
10
0
-10
-20
-30
Religious group
Non-Religious group
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Summary

• Tools
• Standard treatment
• Limitations and treatment resistance
• Combinations
• OIH
• Diffuse noxious inhibitory control
• Catastrophizing
• Religious convictions and imagery
• Alternative therapies