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 cm 2 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/place bo Capsaicin application Blood sampling at the end ~ 50 min ~30 min AM AMAM TactilePunctate 6s stimuli x15 VAS pain and unpleasantness 1s stimuli x18; 512 mN VAS intensity after each poke (0-100) VAS unpleasantness time (mins) after drug Other scans OAMOOOO M: Mood scale A: State anxiety O: 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 * * * p <0.05n=24 Sedation score (/10) 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 <0.05n=24 * ** * VAS time (mins) in scanner

Allodynia 20/24 subjects demonstrated dynamic mechanical allodynia (pain and/or unpleasantness) to the brush stimulus after capsaicin on screening 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 ** ** p <0.01n=24 VAS

Imaging

Pain in the cortex

Brain response to mechanical hyperalgesia Mean Activation Map Placebo Z= Lee et al, J Neuroscience 2008 Contrast Placebo v Ibuprofen R LR L n=24, Mixed effects, Z=2.3 p<0.05 Pl>Ib: Ib>Pl: R LR L R L R L

Gabapentin effect on cortical activation Ibuprofen > Gabapentin n=24, Mixed effects, Z=2.3 p<0.05 Ib>Gb: Gb>Ib: Z= Pl>Gb: Gb>Pl: Placebo > Gabapentin

Gabapentin effect on brainstem activation Region of interest Analysis n=24, Mixed Effects, Z=2.3, p<0.05 Midbrain reticular formation Brainstem atlas Midbrain field of view Nucleus Cuneiformis Placebo > Gabapentin Ibuprofen > Gabapentin Lee et al, J Neuroscience 2008 RL

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

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= Z= Z=

Psychophysics- Expectation of pain relief No overall effect of visit on pain expectation or confidence

Mood/Anxiety in scanner Tranquility/Sociability Sedation

Ongoing pain over progressive visits DMA over progressive visits Post capsaicin punctateΔ magnitude Post – Pre capsaicin