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PHARMARCOLOGICAL FUNCTIONAL MRI FOR NEUROPATHIC PAIN: EVALUATING ANALGESIC
EFFICACY
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
Woolf, Pain 2011
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
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
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)
~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
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
Psychophysics
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.
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
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
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
Imaging
Pain in the cortex
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
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
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
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
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
Acknowledgments
Professor Irene Tracey
Dr Vishvarani Wanigasekera
Stuart Wilson
Dr Michael Lee
Oxford Pain Imaging Neuroscience Group
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
Mean functional maps- DMA
Placebo
Ibuprofen
Gabapentin
Z=2.3
7.1
Z=2.3
6.7
Z=2.3
6.1
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
Mood/Anxiety in scannerTranquility/Sociability
Sedation
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