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Neuropathic Pain

Marie Fallon

St Columba’s Hospice Chair of Palliative Medicine

University of Edinburgh

PRC Trondheim

attentionLimbic System

PAG

Parabrachial

Thalamus

CortexFear, anxiety, sleep, punishmentautonomic changes

Location& intensity

Descending controls allow top down processesto enhance pain-link mood, sleep and pain

VPL

PAG = periaqueductal gray

Lamina I

RVM

Lamina V

Spinal changes

Dorsal Columns

Peripheralmechanisms

and spinal inputs

Motor activation/autonomic

PAG = periaqueductal gray

RVM = rostroventromedial medulla

VPL = thalamic nucleus ventroposterior lateralis

C fibres

A-beta fibres

Peripheral changesSpontaneous pain

Ectopic discharges

? Initiated by cytokine effects

Specific Na+ channel blockers

Altered Na+

channel subtypes

Dorsal root gangliaNeurotransmitter changes

Spinal cord changesAmplification of response• “Anatomical”: silent synapses• Chemical: changes in receptors• Electrical: central sensitisation

Increased afferent volley

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A-beta fibres

C fibres

Central sensitization

NMDA receptor– wind up

Different pains, different mechanisms

Nociceptive pain

Pain caused by an

Neuropathic pain

Pain initiated or caused b i l i

Pain caused by an inflammatory or non-

inflammatory response to a noxious stimulus

Tissue damage

by a primary lesion or disease in the peripheral

or central nervous system

Nerve distribution

Generalized pain

No tissue or nerve damage

Cancer pain:extra layer, e.g. cytokines and other tumour-related factors

Noradrenaline and 5HT

NMDA antagonists

Ion channels

Na channels – go

K h l b kK channels – brakes

Ca channels – release of neurotransmitters

Calcium channels Potassium channels Sodium channels

Treatment

– Antidepressants• Amitriptyline, Duloxetine

– AnticonvulsantsP b li G b ti

• Treatment is challenging

• Often limited by side effects

• No predictors of• Pregabalin, Gabapentin

– Opioids

– NMDA Antagonists• Ketamine

– Topical• Lidocaine,Capsaicin 8%

patches

No predictors of response, largely empirical approach

• Potential of linking somatosensory profile with underlying neurobiology and treatment response

Finnerup et al, Pain 118 (2005) 289-305

Maier et al Pain 2010, Tan et al BMJ (2010) 340, 707-709

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BUT MOST INTENSELY PURSUED NEW STRATEGIES ARE WITH THE TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNELS Nature Reviews 2010 Wolff

http://www.mdc-berlin.de/en/research/research_teams/temperature_detection_and_thermoregulation/Research/Research_Project_3/index.html

TRPM8 – cool analgesia?• Expressed on subset of small primary afferent

nerve fibres• Up-regulated after nerve injury• Topical application of TRPM8 agonists (icilin)

in animal modelsin animal models

Behavioural evidence of thermal and mechanical analgesia

Proudfoot at al, Current Biol. 2006; 6;1591‐1605

Mechanism of TRPM8 analgesia

Fleetwood-Walker

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Topical menthol: Bench to bedside

An example of a novel clinical intervention using TRP channel knowledge and clinical

biomarkers

• Chemotherapy-induced peripheral neuropathy (CIPN) is common.

• 60,000 patients/year in UK, receive potentially neurotoxic chemotherapy.

• CIPN affects up to 96%

• 50% require dose reduction or early cessation of treatment

• Platinums, taxanes, vinca alkaloids,proteosome pinhibitors

• Mechanisms poorly understood

• No effective treatment available

• 1 year on, 35-50% patients still have symptoms

• Individual predictors of CIPN not currently available

• Significant implications for palliative care

Chronic

Chemotherapy induced peripheral neuropathy

• Glove and stocking distribution• Predominantly Sensory

– Numbness– Pins and needles / tingling / pain / burning– Hyperalgesia

(increased response to normally painful stimulus)– AllodyniaAllodynia

(pain in response to innocuous stimulus)

• Proprioception difficulties• Functional impairment

– Fine motor tasks• Fastening buttons / jewellery / keyboard

– Carrying coffee cups– Walking– Driving

• 35% still have symptoms 1 year after adjuvant chemotherapy (Storey et al, Ann. Oncol 2010;21(8):1657-61)

Proof-of-concept study:Topical menthol and neuropathic pain

• Aims–Assess efficacy and safety of 6 weeks of

topical 1% menthol for neuropathic pain (Brief Pain Inventory)

–Determine associations between changes in pain andpain and

– Other subjective patient rated outcomes» Psychological distress» Catastrophising

– Objective assessments» Quantitative Sensory Testing » Physical function

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Chemotherapy induced peripheral neuropathy patients

• Patients with neuropathic pain – (post- treatment chemotherapy induced neuropathy

subgroup)– Eligible if BPI average score of ≥ 4– n=29 – Median age 63 years (range 46 to 76)– Female = 52% (n=15)– Median 16 months since last chemo (range 2 to 35)

• Oxaliplatin (n=21)• Cisplatin (n=3)• Bortezomib (n=2)• Taxanes (n=2)• Carboplatin (n=1)

– All had CTC grade 2/3 neurosensory toxicity– Approx 2/3 had tried medication for neuropathic pain

Proof-of-concept study:Topical menthol and neuropathic pain

• Methods– Open label study

– Applied topical menthol creamApplied topical menthol cream • to affected areas and skin overlying

corresponding dorsal root ganglia

• Twice daily for 6 weeks

Subjective and Objective assessments

• Assessed at baseline, 2 and 6 weeks– Questionnaire

• Brief Pain Inventory• Hospital Anxiety and Depression Scale • Pain Catastrophising Scale• Pain Catastrophising Scale • Leeds Assessment of Neuropathic Symptoms and Signs

– ‘Bedside’ Quantitative Sensory Testing • Mechanical detection threshold• Mechanical pain threshold• Allodynia (calibrated brush)• Wind up ratio

– Physical function (gait and hand dexterity)

• Exploratory analysis

Calibrated brushCalibrated brush Dynamic allodynia

MechanicalPin prickPin prick

Mechanical Sensation/ pain thresholds

Von Frey HairsVon Frey Hairs

A beta fibres

A beta fibres

A d lt fib

Mechanical stimuli (dorsal web space between 1st and 2nd digit of right hand & foot)

METHODS - Quantitative Sensory Testing

Mechanical hypo/hyperalgesiaWind up

Rolltemp

Cool Cool

WarmWarm

Thermal hypo/hyperalgesia

A delta fibres

A delta and C fibres

Thermal stimuli (also distal portion of arm and leg)

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METHODSPhysical function assessments

Gaitrite electronic walkway

(walking velocity + cadence)

Slotted grooved peg board

(hand dexterity)

Pain improved after 6 weeks of topical menthol

Mean total pain

score (BPI)

p = 0.002

p = 0.002

BASELINE 2 WEEKS 6 WEEKS

• 6 (6/29) dropped out after 2 weeks – 2 had exacerbations of pain

– 3 did not like the cream

– 1 developed brain metastases

• 83% (19/23) had improved pain scores

• 52% (12/23) had ≥30% decrease in mean total BPI (clinically relevant)

Pain improved after 6 weeks and also …..

• Subjective measures– Less psychological distress

(HADS 9 vs. 8.5, p= 0.042)– Less catastrophising

( PCS 14.5 vs. 10, p= 0.004) – No change in

Leeds Assessment of Neuropathic Signs

P=0.014

Peg board time

• Leeds Assessment of Neuropathic Signs and Symptoms Scale

• Objective measures– Faster hand dexterity

( 101 vs. 92 seconds, p=0.014)– Hand numbness improved

(mechanical detection thresholds decreased)

(1.10 vs. 0.32 grammes, p=0.011)– Increased walking velocity (trend only)

( 79.5 vs 89 metres/sec 0.110)

Abnormal sensory areas decreased and moved distally

(for brush, warm, cool stimuli)baseline 6 weeks

Example of one patient:

abnormal sensory areas to warm

Right side assessed only

Median values for all patientsto warm

stimulus

p

Arm: 70% vs. 24%, p=0.004

Leg:90% vs. 56%p=0.011

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Correlations with change (decrease) in pain scores between baseline and 6

weeks

• Strong correlation with improved– Dominant hand dexterity (Correlation Coeff = 0.636, p = 0.011)

– walking velocity ( .. .. = - 0.743, p = 0.009)

– Walking cadence ( .. .. = - 0.766, p = 0.006)

• Moderate correlation with improved– Psychological distress (HADS) (Correlation Coeff. = 0.442, p = 0.039)

– Foot mech. detection threshold ( .. .. = 0.453, p = 0.034)

(less numbness)

– Foot mech. pain thresholds ( .. .. = 0.453, p = 0.034)

(less numbness)

– Wind-up ratio ( .. .. = 0.534, p = 0.009)

(got less)

Menthol - the future

Potentially very exciting:

• Subjective improvements

R d d i– Reduced pain

– Reduced psych distress

– Reduced catastrophising

• Objective improvements

– improved physical function

– Improved quantitative sensory tests

Future• Further work on TRP channels

• Cytokine blockade

• Linking optimum therapy with somatosensory profile, other characteristics of individual patients

• Understanding role of current agents

Thanks to• THE PATIENTS

• University of Edinburgh TRP Research Team

• Edinburgh Cancer Centre Colorectal Oncology Team– Dr Catriona McLean

– Dr Lesley Colvin– Prof S Fleetwood-Walker– Dr Rory Mitchell– Dr Dawn Storey– Dr Angela Scott

– Dr Sally Clive– Dr Lesley Dawson – Dr Ewan Brown– Dr Hamish Phillips– Joyce Livingstone– Anna Clarkson– Susan Mckean– Gillian Knowles

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Acute oxaliplatin induced peripheral neuropathy

• Oxaliplatin-based chemotherapy = standard treatment for colorectal cancer

• Peripheral neuropathy = dose limiting toxicityA t ( l ithi h d )– Acute (resolves within hours or days)

• 94% of patients (Storey et al, Ann. Oncol 2010;21(8):1657-61)

• Cold related dysaesthesia – peri-oral areas– Hands/ feet

• Pseudolaryngospasm• Muscle fasciculations / myotonia / tetanic spasms

– affecting face and limbs

– Cumulative/chronic (usually resolves in months/years)

Menthol did not suit everyone

• 6 patients dropped out after 2 weeks (6/29)– 2 had worse pain

• Not clear why

• oxaliplatin neuropathy– 4 months and 3 years duration

• 1 = heavy alcohol intake …. Other neuropathy mechanism??– (other = Tea total)

• Different TRPM8 action in some patients??

• Resolved to baseline levels within a few weeks of stopping cream

– 3 did not like the cream

• 2 female, 1 male

(older men a bit more reluctant to apply cream in general)

[1 = progressive disease (brain mets)]

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TRP channels-the future• Menthol-Potentially very exciting

– Topical (not another tablet)– Cheap– But may worsen pain in some cases??

• Anti-tumour activity? TRPM8 expressed on prostate bladder colorectal breast lung– TRPM8 expressed on prostate, bladder, colorectal, breast, lung carcinomas and melanoma.

– Interest in TRPM8 agonists for cancer treatment

• Unanswered questions– Placebo response?– Duration of response?– Dose?– Need randomised controlled trial

Chronic oxaliplatin induced peripheral neuropathy

• Glove and stocking distribution• Predominantly Sensory

– Numbness– Pins and needles / tingling / pain / burning– Hyperalgesia (inc response to normally painful

stimulus)– Allodynia (pain in response to innocuous y (p p

stimulus)

• Proprioception difficulties• Functional impairment

– Fine motor tasks• Fastening buttons / jewellery / keyboard

– Carrying coffee cups– Walking– Driving

• 35% still have symptoms 1 year after adjuvant treatment (Storey et al, Ann. Oncol 2010;21(8):1657-61)

Difficult to predict whose pain scores would change

• Only baseline predictors were mechanical detection thresholds – HandsHands

(correl coeff. = 0.534, p= 0.027)

– Feet (correl coeff. = 0.511, p=0.036)

• But heavily influenced by

1 patient so not reliable

Treatment duration

baseline 2 weeks 6 weeks (12 wks) (24 wks)

n still on menthol 21 21 17 10 5

n stopped menthol after this - 4 7 5 -

Primary endpoint

Reason for stoppingPain gone / improved and plateaued - - 2 4

No benefit - - 3 -

Pain worse - 2 1 1

Did not like cream - 2 - -

Non compliant (withdrawn by investigator) - - 1 -

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Chemotherapy induced peripheral neuropathy

• Common dose- limiting chemotherapy toxicity– Platinums – Taxanes– Vinca Alkaloids– Proteosome inhibitors

d– newer drugs• Can affect up to 98% of patients depending on the drug

– Acute (resolves within days)– Chronic (resolves within months…..supposedly)

• Prevents patients getting the life saving/prolonging treatment they need

• Leaves survivors with long term debilitating symptoms• Complicates symptom control in advancing disease

http://www.pharmeste.com/home.asp?op=interna&id=2

The Spinal Cord(1st central synapse)

Amino AcidsInhibitoryExcitatory

GlutamateGlutamate

AMPAAMPA

NMDANMDA

MetabotropicMetabotropic

GABAGABA

GlycineGlycine

C fibres

A-beta fibres

pp

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TRP family of ion channels

•• Thermal sensationThermal sensation–– TRPV1TRPV1--44

–– TRPA1TRPA1TRPA1TRPA1

––TRPM8: cooling sensationTRPM8: cooling sensation•• Temp (Temp (1818--2424°°CC ))

•• MintMint

•• Menthol and related compoundsMenthol and related compounds

TRPM8 – cool analgesia?

•• Expressed on subset of small primary Expressed on subset of small primary afferentsafferents

•• UpUp--regulated after nerve injuryregulated after nerve injurypp g j yg j y•• Topical application of TRPM8 agonistsTopical application of TRPM8 agonists

Behavioural evidence of thermal Behavioural evidence of thermal and mechanical analgesiaand mechanical analgesia

Proudfoot at al, 2006

Cooling analgesia• Menthol (mint) and related products used in traditional

medicines as analgesics

• Mechanism previously not known

• TRP family of ion channels (found in sensory neurons)

– Transient Receptor Potential (TRP) ion channels (transducers) transform stimuli into action potentialsp

– Revolutionised understanding of cutaneous temperature detection• TRPV1, TRPA1 (noxious heat and cold (<5 C )….etc

–TRPM8: moderate cooling sensation• Temp (18-24°C )

• Activated by menthol (mint) and related compounds

Pain pathway

Dorsal root gangliaNeurotransmitter changes

Brain

• Dynamic system• Modulation at each level

Noxious stimulus

Peripheral

Increased afferent volley

Spinal cord

Further amplification

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Peripheral afferent changes: chemical

•Thermal sensation:

Primary afferent phenotype changes

Thermal MechanicalChemical

Retrograde transport blocked/ altered

Thermal sensation:•TRPV1•TRPA1

•TRPM8

Proudfoot,C. Current Biology (2006), 1591-1605

•Growth factors•Cytokines•Peptides

0 51

1.52

2.53

3.54

4.55 Least pain

Average pain

Worst pain

General activity

Brief Pain Inventory

Effects of topical menthol

00.5

Colvin,Johnstone,Mitchell,Fleetwood-Walker,Fallon (JCO, Sept 2008)

QST: Rapid improvement esp in mechanical responses

HADs: reduced from 22 to 14 at 2 weeks

Subsequently able to tolerate further chemotherapy