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