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Management of Neuropathic Pain
Mellar P Davis MASCC ,June 2009
Pharmacological treatment of neurologic pain relies on evidence from large randomized controlled trials
Attal 2006Dworkin 2007
Despite advances in research and clinical trials, a considerable number of individuals do not get relief
NNT- 3-5 for most drugs
Response is defined as a “30-50% reduction in pain severity
empiric drug trials – “trial and error”choices based on mechanismgulf between empiricism and mechanisticdrug choices
Baron 2006Woolf 1998
It is unclear which laboratory pain responses are most strongly associated with the experience of pain in daily life
Edwards 2003
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 2009Mercadante 2009
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
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 2006Baron 2006Farrar 2001Farrar 2001
Pain Relief
• Not “all or none” but continuous• Balance of pain relief, medication
burden, side effects, QOL, function• Artifact to use binomial outcomes
Dosage
• Tolerable dose vs therapeutic dose (serum levels vs empiric recommendations)
• Combinations may reduce the tolerable dose
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
Treatment Paradigm
• Drug classes proven by RCT
TCASNRIAlpha-2-delta ligandsOpioidsTopical lidocaineSodium channel blockers
• Monotonous (single drug)
Peripheral neuropathic pain
Postherpetic neuralgia and focal neuropathy
Lidocaine patch
yes no
yes
no
TCA contraindication
Gabapentin / pregabalin
yes
Tramadol, oxycodone
TCA contraindication
TCA(SNRI)
noTCA
(SNRI)Gabapentin / pregabalin
‘Numbers Need to Treat’ Calculated for Various Drug Classes in the Treatment of Painful Neuropathy
*Optimal dose achieved. SSRI, selective serotonin *Optimal dose achieved. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.reuptake inhibitor; TCA, tricyclic antidepressant.
Study by Sindrup and Jensen (1999)Study by Sindrup and Jensen (1999)
0 2 4 6 8
SSRIs
Gabapentin
TCAs-NE
TCAs-5HT/NE
TCAs-5HT/NE* 1.4
2
3.4
3.7
6.7
Pharmacoresistance• Pharmacorotation fails to produce
response or produces intolerable side effects
• Lowers QOL, increases symptoms• Expensive
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
Combination Therapy
• Rationale-non-overlapping mechanism• Paucity of data• Polypharmacy, side effects• No data for central pain syndromes
Polypharmacy
• Gabapentin plus opioids
• Gabapentin plus venlafaxine
Gilron 2005Hanna 2008Simpson 2001
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.
Mean Daily Pain
Baseline
Scor
e fo
r Pai
n In
tens
ity
Placebo Gabapentin Morphine Combination0
2
1
3
5
4
7
6
Maximal Tolerated Dose
Gabapentin MorphineSingle agent combination Single agent combination
Dos
e (m
g)
0
500
1000
1500
2000
2500
0
60
50
40
30
20
10
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
Desipramine doses (mg/kg)
Control 7.5 15 7.5 150
4
8
10
16
20
Rea
ctio
n Ti
me
(s)
Rats pretreated with Naltrindole
(1mg/kg)
Desipramine
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 2009Hansson 2009
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 2008Sahin 2008
Evsoy 2008Evsoy 2008Kim 2008Kim 2008Hannan 2007Hannan 2007
With
draw
al
dura
tion
(s)
With
draw
al
late
ncy
(s)
Time (min)
0
6
12
0
10
20
VehicleAmitriptylline 3 mgkgAmitriptylline 10 mgkgAmitriptylline 30 mgkg
Base 1
Base 2
30 60 90 120 180
Time (min)
VehicleMirtazapine 3 mgkgMirtazapine 10 mgkgMirtazapine 30 mgkg
Base 2
30 60 90 120 180Base 1
Combinations
• NSAIDs plus alpha-2-delta ligand• Opioid plus minocycline (anti-glia)• CB2 agonist plus opioid (anti-glia)• (+) opioid antagonists (anti-glia)• etodolac
Glia and Opioids: Minocycline
• Attenuates morphine induced respiratory depression
• Reduces conditioned place preference• Potentiate morphine analgesia• Blocks morphine induced upregulation of
Cox-1
Hutchinson 2008Hutchinson 2008
Etodolac Attenuates Mechanical Allodynia in a Mouse Model of
Neuropathic Pain
Naoki Inoue, Sunao Ito, Koyuki Tajima, Masaki NogawaYosuke Takahashi, Takahiro Sasagawa,
Akio Nakamura, and Takashi Kyoi
Effect on Mechanical Allodynia in PSNL Mice
Each symbol represents the mean PWT for 10 mice. Drugs were administered orally once a day for two weeks from seven days after PSNL. *P<0.05, **P<0.01 (vs. control, Steel test).
ControlEtodolac 10 mg/kgIndomethacin 1 mg/kgCelecoxib 30 mg/kg
Time after administrationDay 7 Day 14 Day 21
Day 0 Pre 1h4h
0.0
0.2
0.4
0.6
0.8PW
T (g
)
*** **
** ** **
**
Pre 1h4h
Pre 1h4h
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 2009Chen 2009
Altered Quantitative Sensory Testing Outcome in Subjects with Opioid
Therapy
Lucy Chen, Charlene Malarick, Lindsey Seefeld,Shuxing Wang, Mary Houghton,Jianren Mao
Exacerbated Temporal Summation of the Second Pain in Group 3 Subjects
*P<0.05, 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 (47°C) stimuli.
Incr
ease
in V
AS
(%)
S1/BL S2/BL S3/BL0
100
200
300
400
500
*
*
*Group 1Group 2Group 3
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
Antihyperalgesia Analgesia Ratio
Buprenorphine i.v.
Buprenorphine s.i.
Fentanyl i.v.
Alfentanil i.v.
S-ketamine i.v.
2.6 (0.8-3.8)
1.9 (-0.1-8.1)
0.6 (-0.3-2.2)
0.3 (-0.3-0.5)
5.5 (3.1-6.1)
Effect (%)100 75 50 25 0 25 50
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
SalineChronic MorphineSaline / IncisionChronic Morphine / Incision
0
pg/m
g P
rote
in
300
600
900
1200IL-1
0
pg/m
g P
rote
in
150
300
450
600TNF
Time after Incision2h 24h 72h
0.0
Paw
With
draw
al
Thre
shol
d (g
)
PTX
Baseline - +
1.0
2.0 Saline prior to incisionMSO4 prior to incision
- +
Alternative Medications
• Melatonin• S-adenosyl methionine• L-carnitine• Vitamin D
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)
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
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 2003Edwards 2003Goodin 2009Goodin 2009
Individual Differences in Diffuse Noxious Inhibitory Control (DNIC): Association with Clinical Variables
Robert R. Edwards, Timothy J Ness, Douglas A Weigent,
Roger B Fillingim
Scores on SF-36 Subscales (mean ± SD)
Age groups differ at *P<0.05. Higher SF-36 subscale score represents better functioning (e.g. less pain, better health).
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
50
60
70
80
90
100
Younger Older Younger Older Younger Older Younger Older
BP* PF* PR GH
Younger Adults Older AdultsDNIC +(n=24)
DNIC -(n=13)
DNIC +(n=11)
DNIC -(n=26)
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 2009Campbell 2009Weissman-Fogel 2008Weissman-Fogel 2008George 2008George 2008
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
In vivo catastrophizing
SF-MPQ pain ratings
DNIC
a B*
c’
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
An fMRI Study Measuring Analgesia Enhanced by Religion as a Belief
System
Katja Wiech, Miguel Farias, Guy Kahane,Nicholas Shackel, Wiebke Tiede, Irene Tracey
Pai
n in
tens
ity
(VA
S 0
-100
)
Religious groupNon-Religious group
40
60
80
100Non-Religious conditionReligious condition
Pai
n in
tens
ity
(VA
S 0
-100
)
Religious groupNon-Religious group
-30
0
20
50Non-Religious conditionReligious condition
-20
-10
10
30
40
Summary
• Tools• Standard treatment• Limitations and treatment resistance• Combinations• OIH • Diffuse noxious inhibitory control• Catastrophizing• Religious convictions and imagery• Alternative therapies