PHARMARCOLOGICAL FUNCTIONAL MRI FOR NEUROPATHIC PAIN: EVALUATING ANALGESIC EFFICACY.
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Transcript of PHARMARCOLOGICAL FUNCTIONAL MRI FOR NEUROPATHIC PAIN: EVALUATING ANALGESIC EFFICACY.
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PHARMARCOLOGICAL FUNCTIONAL MRI FOR NEUROPATHIC PAIN: EVALUATING ANALGESIC
EFFICACY
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Neuropathic pain
• “Pain caused by a lesion or disease of the somatosensory nervous system” IASP 2011
• Peripheral neuropathy common postsurgically, in polyneuropathies, as complications of HIV, diabetes, stroke, MS and other sources of neural damage
• Key symptom is persistent pain hypersensitivity leading to spontaneous pain, hyperalgesia and allodynia
• Peripheral and central sensitisation are the two mechanisms of post-injury pain hypersensitivity
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Woolf, Pain 2011
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Study rationale• Pre clinical efficacy of analgesics does not always translate as
efficacy in patients.
• Capsaicin induced hyperalgesia (via central sensitisation) as a surrogate model of neuropathic pain
• Neuropathic pain features present with topical capsaicin:– Spontaneous pain; Mechanical hyperalgesia; Dynamic mechanical Allodynia
• Animal and human data supports the specific importance of descending brainstem activity in the maintenance of spinal excitability
• In healthy human, midbrain activity – is a specific marker of CS induced by capsaicin – Induced by capsaicin has been shown to be reduced by gabapentin
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Hypothesis
• Gabapentin is effective in attenuating capsaicin induced hyperalgesia while ibuprofen is not
• Drug modulation by Gabapentin can be picked up at an earlier stage in a small cohort using fMRI than is manifest psychophysically
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Method• 24 healthy subjects (11 male)
• 3 way cross over study; double blind; drug visit order randomised
• Using – Gabapentin 1200mg (effective in neuropathic pain)– Ibuprofen 600mg (ineffective in neuropathic pain)– Placebo
• Topical capsaicin 1% cream (applied on 4x4 cm2 area on lower leg)
• Functional scans while eliciting mechanical hyperalgesia (>3cm from site of application)
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~60 mins
Study paradigm
Brief medical screening & Urine test
Sensory testing before scanning
Scanning with intermittent sensory testing
~60 mins
Study drug/placebo
Capsaicin application
Blood sampling at the end
~ 50 min~30 min
AM
AM AM
Tactile Punctate
6s stimuli x15VAS pain andunpleasantness
1s stimuli x18; 512 mNVAS intensity after each poke (0-100)VAS unpleasantness
time (mins) after drug
Other scans150 160 170
180
OAM OOOO
M: Mood scaleA: State anxietyO: Ongoing pain
fMRI
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Analysis
• Psychophysics– SPSS– Group ANOVA for ongoing pain– Paired t-tests for evoked pain & mood/anxiety
• Functional scans– Automated analysis tools (FMRIB Software Library)– Group activation means– Paired t-test contrasts
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Psychophysics
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Mood/Sedation scores
Placebo Ibuprofen Gabapentin0
0.51
1.52
2.53
3.54
4.55
Mental Sedation
Physical Sedation
* *
* p <0.05 n=24
Sed
atio
n s
core
(/1
0)
• Gabapentin induced an increase in the mental sedation score when compared to ibuprofen (p=0.02) and placebo (p= 0.03)
• But not in physical sedation or any other psychological parameters.
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Ongoing pain
3x5 ANOVA (visits v timepoints)• Main effect of drug on ongoing pain
• [Gb v Ib]: corr p=0.01• [Gb v Pl]: corr p=0.46
• Main effect of time, significant at timepoints 3 & 4• No interaction effects
* p <0.05 n=24
*
* *
*
VAS
0 10 20 30 400
5
10
15
20
25
30
35
Placebo
Ibuprofen
Gabapentin
time (mins) in scanner
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Allodynia
20/24 subjects demonstrated dynamic mechanical allodynia (pain and/or unpleasantness)to the brush stimulus after capsaicin on screening
Placebo Ibuprofen Gabapentin0
2
4
6
8
10
12
14
16
18
20
Intensity
Unpleasantness
VAS
n=20
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Secondary punctate hyperalgesia
• Gabapentin causes significant fall in punctate intensity when compared with Placebo but not when compared with Ibuprofen
• There is no difference in punctate unpleasantness between the compounds
**
Placebo Ibuprofen Gabapentin0
10
20
30
40
50
60
** p <0.01 n=24
VAS
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Imaging
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Pain in the cortex
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Brain response to mechanical hyperalgesia
Mean ActivationMap
PlaceboZ=2.3
6.9
Lee et al, J Neuroscience 2008
ContrastPlacebo v Ibuprofen
R L R L
n=24, Mixed effects, Z=2.3 p<0.05
Pl>Ib:
Ib>Pl:
R L R L
R LR L
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Gabapentin effect on cortical activationIbuprofen > Gabapentin
n=24, Mixed effects, Z=2.3 p<0.05
Ib>Gb:
Gb>Ib:
Z=2.3
3.9
Pl>Gb:
Gb>Pl:
Placebo > Gabapentin
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Gabapentin effect on brainstem activation
Region of interest Analysisn=24, Mixed Effects, Z=2.3, p<0.05
Midbrain reticular formation
Brainstem atlasMidbrain field of view
NucleusCuneiformis
Placebo > Gabapentin Ibuprofen > Gabapentin
Lee et al, J Neuroscience 2008
R L
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Conclusions• In a model of central sensitisation, gabapentin causes
decreased subject-reported secondary punctate hyperalgesia than placebo, but not when compared to ibuprofen
• Gabapentin significantly decreases brain activity to secondary mechanical hyperalgesia in the midbrain (nucleus cuneiformis) when compared to ibuprofen or placebo
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Some implications for future work
• fMRI may be more sensitive than subjective reports for evaluating drug efficacy
• Gabapentin may provide its early analgesic action by modulating activity in the brainstem descending pain modulatory pathway
• Gabapentin may be effective in prophylactic treatment of neuropathic pain by inhibiting development of central sensitisation
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Acknowledgments
Professor Irene Tracey
Dr Vishvarani Wanigasekera
Stuart Wilson
Dr Michael Lee
Oxford Pain Imaging Neuroscience Group
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Placebo Ibuprofen Gabapentin0
5
10
15
20
25
30
35
40
Δ magnitude Post – Pre capsaicin
• Gabapentin causes significant fall in pain intensity delta (post-pre capsaicin) when compared to Placebo and Ib (p=0.017)
• There is no difference in the delta of poke unpleasantness between the compounds
**
*
Gabapentin effect on development of hyperalgesia
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Mean functional maps- DMA
Placebo
Ibuprofen
Gabapentin
Z=2.3
7.1
Z=2.3
6.7
Z=2.3
6.1
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Psychophysics- Expectation of pain relief
Placebo Ibuprofen Gabapentin0
10
20
30
EXPECTATION
Placebo Ibuprofen Gabapentin20
30
40
CONFIDENCE
No overall effect of visit on pain expectationor confidence
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Mood/Anxiety in scannerTranquility/Sociability
Sedation
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START Pre-Poke Pre ASL Pre RSN END0
5
10
15
20
25
30
35
40
Visit 2/3/4 PlaceboVisit 5 Caps_scanVisit 1 - Screen
Ongoing pain over progressive visits
Visit 1 screen Placebo Visit 5 Caps scan0
5
10
15
20
25
30
Intensity Unpleasantness
DMA over progressive visits
Visit 1 screen Placebo Visit 5 Caps scan0
10
20
30
40
50
60
Visit 1 screen Placebo Visit 5 Caps scan0
5
10
15
20
25
30
35
40Post capsaicin punctate Δ magnitude Post – Pre capsaicin