Transcript PHARMACOLOGICAL TREATMENT OF NEUROPATHIC PAIN …

Management of Neuropathic Pain
Mellar P Davis
MASCC ,June 2009
Pharmacological treatment of neurologic
pain relies on evidence from large
randomized controlled trials
Attal 2006
Dworkin 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 mechanism
gulf between empiricism and mechanistic
drug choices
Baron 2006
Woolf 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 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 2006
Farrar 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
TCA
SNRI
Alpha-2-delta ligands
Opioids
Topical lidocaine
Sodium channel blockers
• Monotonous (single drug)
Peripheral
neuropathic pain
yes
Postherpetic neuralgia no
and focal neuropathy
Lidocaine patch
yes
no
Gabapentin /
pregabalin
TCA
contraindication
TCA
contraindication
TCA
(SNRI)
yes
no
TCA
(SNRI)
Gabapentin /
pregabalin
Tramadol, oxycodone
‘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
1.4
TCAs-5HT/NE*
0
2
4
6
8
*Optimal dose achieved. SSRI, selective serotonin
reuptake inhibitor; TCA, tricyclic antidepressant.
Study by Sindrup and Jensen (1999)
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
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•
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•
Rationale-non-overlapping mechanism
Paucity of data
Polypharmacy, side effects
No data for central pain syndromes
Polypharmacy
• Gabapentin plus opioids
• Gabapentin plus venlafaxine
Gilron 2005
Hanna 2008
Simpson 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.
Score for Pain Intensity
Mean Daily Pain
7
6
5
4
3
2
1
0
Baseline
Placebo
Gabapentin
Morphine Combination
Dose (mg)
Maximal Tolerated Dose
2500
60
2000
50
40
1500
30
1000
20
500
10
0
Single agent combination
0
Single agent combination
Gabapentin
Morphine
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
Reaction Time (s)
20
16
10
8
4
0
Control
7.5
15
Desipramine
7.5
15
Rats pretreated
with Naltrindole
(1mg/kg)
Desipramine doses (mg/kg)
More Efficacious Drugs
• Lower side effect profiles
• New classes (CB2 receptor agonists,
anti-glia agents)
• More trials of combination therapy
• Rigorous studies of nonpharmacological measures
Hansson 2009
Non-TCA, SNRI Antidepressant:
Mirtazapine
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•
•
•
•
•
•
•
•
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
Withdrawal
duration (s)
20
10
0
Withdrawal
latency (s)
12
Vehicle
Amitriptylline 3 mgkg
Amitriptylline 10 mgkg
Amitriptylline 30 mgkg
Vehicle
Mirtazapine 3 mgkg
Mirtazapine 10 mgkg
Mirtazapine 30 mgkg
6
0
Base Base 30
1
2
60
90
Time (min)
120 180
Base Base 30
1
2
60
90
Time (min)
120 180
Combinations
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•
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•
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 2008
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
Effect on Mechanical Allodynia in PSNL
Mice
0.8
Control
Etodolac 10 mg/kg
Indomethacin 1 mg/kg
Celecoxib 30 mg/kg
PWT (g)
0.6
0.4
**
**
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. *P<0.05, **P<0.01 (vs. control, Steel test).
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
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
Increase in VAS (%)
500
400
*
Group 1
Group 2
Group 3
*
300
200
*
100
0
S1/BL
S2/BL
S3/BL
*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.
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.
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
Effect (%)
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
pg/mg Protein
1200
Saline
Chronic Morphine
Saline / Incision
Chronic Morphine / Incision
IL-1
900
600
300
0
pg/mg Protein
600
TNF
450
300
150
0
2h
24h
Time after Incision
72h
Paw Withdrawal
Threshold (g)
2.0
Saline prior to incision
MSO4 prior to incision
1.0
0.0
Baseline
-
+
-
+
PTX
Alternative Medications
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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 2003
Goodin 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)
SF-36 subscales
Younger (n = 37) Older (n = 37)
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
General health (0-100)
Age groups differ at *P<0.05. Higher SF-36 subscale score
represents better functioning (e.g. less pain, better health).
Younger Adults
DNIC +
(n=24)
DNIC (n=13)
Older Adults
DNIC +
(n=11)
DNIC (n=26)
100
90
80
70
60
50
Younger Older
BP*
Younger Older
PF*
Younger Older
PR
Younger Older
GH
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
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
DNIC
a
In vivo
catastrophizing
B*
c’
SF-MPQ pain
ratings
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
Pain intensity
(VAS 0-100)
100
Non-Religious condition
Religious condition
80
60
40
Non-Religious
group
Religious group
50
Pain intensity
(VAS 0-100)
40
Non-Religious condition
Religious condition
30
20
10
0
-10
-20
-30
Non-Religious
group
Religious group
Summary
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Tools
Standard treatment
Limitations and treatment resistance
Combinations
OIH
Diffuse noxious inhibitory control
Catastrophizing
Religious convictions and imagery
Alternative therapies