NEUROPATHIC PAIN PHENOTYPING BY INTERNATIONAL CONSENSUS

Peter Kamerman (for the NeuroPPIC Group)University of the Witwatersrand, South Africa

NeuroPPIC

5th International Congress of Neuropathic Pain, Nice, France, 2015

Houle et al., 2010

Genotype to phenotypeGenotype-phenotype-environment interaction

Slide courtesy of Blair Smith (University of Dundee, UK)

Genetic association studiesPopulation-based genetic studies of (neuropathic) pain

SCIENTIFICUnderstanding pain mechanisms and vulnerabilityDiscovering new genes, or testing candidates from animal

studies

CLINICAL Understand G:E interactionsTargeted prevention and prognosis New taxonomies of painNew drug targetsTargeting existing treatments based on likely response

Lanktree et al., 2010

Genetic association studiesMajor procedural confounders

Measurement error

Study heterogeneity

Lanktree et al., 2010

Genetic association studiesMajor procedural confounders

Measurement error

Study heterogeneity

‘Genetic science’ ‘Phenotyping science’

Lanktree et al., 2010

Genetic association studiesMajor procedural confounders

Measurement error

Study heterogeneity

‘Genetic science’ ‘Phenotyping science’

Phenotyping for neuropathic pain

Phenotyping for neuropathic painWhere do we start?

“No whole-genome association study has been conducted yet for neuropathic pain. The problems are formidable:• How to phenotype patients in a standardized way to

eliminate spurious associations,• Which controls to use, and• How large the cohorts need to be to retain sensitivity

but eliminate false positive results….”

Costigan et al, Annu Rev Neurosci, 2009

Slide courtesy of Blair Smith (University of Dundee, UK)

Phenotyping for neuropathic painBenefits of an agreed phenotype

FACILITATES:Interpretation

Collaboration / meta-analyses

Reproducibility

Phenotyping for neuropathic painCharacteristics of the ‘ideal’ phenotype

VALID:Accurate

Precise

FEASIBLE:Simple to implement

Cost-effective

ETHICAL

Phenotyping for neuropathic painCharacteristics of the ‘ideal’ phenotype

HIGH VALIDITY LOW FEASIBILITY

LOW VALIDITY HIGH FEASIBILITY

Phenotyping for neuropathic painCharacteristics of the ‘ideal’ phenotype

CONSISTENT + CUSTOMIZABLE

Slide courtesy of Blair Smith (University of Dundee, UK)

Entry-level phenotyping(high feasibility / low validity)

Deep phenotyping(high validity / low feasibility)

Large / very large sample

Small sample

NeuroPPICNeuropathic pain phenotyping by international consensus

THREE-STAGE PROCESS:

Systematic review: Identify and compare phenotypes used in genetic studies of non-cancer neuropathic pain in adults;

Delphi survey: Obtain expert consensus on phenotype components to determine ‘caseness’;

Consensus meeting: To develop a consensus statement on an approach to phenotyping to identify an ‘entry level’ phenotype.

van Hecke et al., 2015

NeuroPPIC: Systematic review

AIMTo identify and compare phenotypes used in genetic studies of non-cancer neuropathic pain in adults. SEARCH (January 1966 to April 2014) MEDLINE;EMBASE;SCOPUS;Science Direct;ISI Web of Science;CINAHL

INCLUSION:Genetic association,Non-cancer neuropathic pain states, Adults

Unique records recovered

3 372

PRISMA flowchart

van Hecke et al., 2015

NeuroPPIC: Systematic review

AIMTo identify and compare phenotypes used in genetic studies of non-cancer neuropathic pain in adults. EXCLUSION:Not neuropathic pain;Unclear pain state;Cancer-related;Children

Unique records recovered

3 372

Records excluded(title / abstract)

3 319

Full-text articles assessed for eligibility

53

PRISMA flowchart

van Hecke et al., 2015

NeuroPPIC: Systematic review

AIMTo identify and compare phenotypes used in genetic studies of non-cancer neuropathic pain in adults. EXCLUSION:Not neuropathic pain;Unclear pain state;Cancer-related;Children

Unique records recovered

3 372

Records excluded(title / abstract)

3 319

Studies included

21

Full-text articles assessed for eligibility

53

Records excluded(full text)

31

PRISMA flowchart

van Hecke et al., 2015

NeuroPPIC: Systematic reviewDiverse populations groups

Population

Nordic/European African-AmericanAfrican

Hispanic-American Israeli-JewishAsian

van Hecke et al., 2015

NeuroPPIC: Systematic reviewDiverse causes of neuropathic pain

Disease

Post-herpetic neuralgia Diabetic polyneuropathy Discogenic sciatica

Persistent post-surgical pain(lumbar discectomy, inguinal hernia, mastectomy)

HIV polyneuropathyOther aetiologies

Multiple sclerosisPhantom limb / Stump pain

van Hecke et al., 2015

NeuroPPIC: Systematic reviewDiverse control groups

Control

Healthy volunteers National reference cohorts

Diseased

van Hecke et al., 2015

NeuroPPIC: Systematic reviewDiverse phenotyping methods

Study

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Clinical examination l l l l l l l l l l l l l l l l

Pain rating scale l l l l l l l l l l l l l l

History l l l l l l l l l l l

Radiological imaging l l l l l l l l l l

NeP questionnaire l l l l l l

QST l l l l l

NCS l l

IENFD l l

Inflammatory markers l l

Body chart l

Psychological measures l

van Hecke et al., 2015

NeuroPPIC: Systematic reviewTwo studies with ‘build-in’ replication cohorts

van Hecke et al., 2015

NeuroPPIC: Systematic reviewLack of reproducibility

COMTrs4680

GCH1rs3783641

rs10483639rs8007267

KCNS1rs734784

OPRM1rs1799971

van Hecke et al., 2015

NeuroPPIC: Systematic reviewSummary

HIGH HETEROGENEITY

Population studied

Diseases studied

Control groups

Phenotyping methods

LACK OF REPLICATION

NeuroPPIC: Delphi surveyNeuroPPIC

van Hecke et al., 2015

AIMObtain expert consensus on phenotype components to determine ‘caseness’

ROUND 1• Invited 28 experts • 20 (71%) completed Round 1• 17 (85%) agreed to participate in subsequent rounds

ROUND 2• Results of Round 1 distributed with Round 2 invitations• 16 (94%) completed Round 2

ROUND 3• Results of Round 1 & 2 distributed with Round 3 invitations• 15 (88%) completed Round 3

NeuroPPIC: Delphi surveyDiagnostic certainty

Definite Probable Possible

Clinical signs, symptoms, body chart, history

Probable

Assessments Diagnostic certaintyMost common

Symptoms, body chart, history Possible

Other tests, clinical signs,symptoms, body chart, history

Definite

Number of responses in Round 3(percentages shown in blocks)

van Hecke et al., 2015

NeuroPPIC: Delphi surveySummary

Good consensus:That diagnostic certainty increases as more assessment domains are used.

Less consensus:On what the various assessment domains should include

From a list of 14 symptoms consensus was reached on:o “hot / burning”o “pain evoked by light touch”

From a list of 12 clinical signs, consensus was reached on:o “dynamic mechanical allodynia”o “altered sensitivity to punctate mechanical stimuli”

van Hecke et al., 2015

NeuroPPIC: Consensus meeting

AIMTo develop a consensus statement on an approach to phenotyping to identify an ‘entry level’ phenotype.

CONSENSUS MEETING

Date & venue: 12 to 13 June 2014, Versailles, France

Delegates: 18 experts (neurology, anaesthesiology, pain medicine, palliative care, primary care, basic neuroscience, and genetics)

Meeting aims and format

van Hecke et al., 2015

NeuroPPIC: Consensus meeting

• The basis of establishing neuropathic pain ‘caseness’ for genetic studies.

• To provide a framework to:o Guide study designo Facilitate unambiguous appraisal of findings

• Allow the addition of more in-depth measures for higher level phenotyping

Goals of the ‘Entry-level’ phenotype

van Hecke et al., 2015

NeuroPPIC: Consensus meeting

Symptom assessment using neuropathic pain screening tools

• The symptom component of at least one validated screening tool

• Screening tools should have been validated in:

o The language and culture of the target population(s)

o The condition(s) under investigation

‘Entry-level’ phenotype – ‘possible neuropathic pain’

van Hecke et al., 2015

NeuroPPIC: Consensus meeting

Symptom assessment using neuropathic pain screening tools

Anatomical distribution

• A body chart or checklist

‘Entry-level’ phenotype – ‘possible neuropathic pain’

van Hecke et al., 2015

NeuroPPIC: Consensus meeting

Symptom assessment using neuropathic pain screening tools

Anatomical distribution

History

• Pain duration

• Pain intensity over the last 24 hours

• The presence of any previously diagnosed chronic pain syndromes

• Demographic information

‘Entry-level’ phenotype – ‘possible neuropathic pain’

van Hecke et al., 2015

NeuroPPICConclusion

• The field is characterized by high levels of heterogeneity

• Heterogeneity reduces:o Interpretation

o Collaboration / meta-analyses

o Reproducibility

• NeuroPPIC sought to reduce the heterogeneity

NeuroPPICConclusion

CONSISTENT + CUSTOMIZABLE

Entry-level phenotyping(high feasibility / low validity)

Deep phenotyping(high validity / low feasibility)

NeuroPPIC phenotype• Symptoms• Distribution• History

Large / very large sample

Small sample

NeuroPPICConclusion

CONSISTENT + CUSTOMIZABLE

Entry-level phenotyping(high feasibility / low validity)

Deep phenotyping(high validity / low feasibility)

NeuroPPIC phenotype• Symptoms• Distribution• History

Large / very large sample

Small sample

Add-on:• What is feasible• What is required

NeuroPPIC Group:• Blair H Smith (UK) [Chair]* • Oliver van Hecke (UK)*• Nadine Attal (France)• Ralf Baron (Germany)• Gyda Bjornsdottir (Iceland)• David L Bennett (UK)• Michael I Bennett (UK)• Didier Bouhassira (France)• Luda Diatchenko (Canada)• Roy Freeman (USA)• Rainer Freynhagen (Germany)• Maija Haanpää (Finalnd)• Troels S Jensen (Denmark)• Srinivasa N Raja (USA)• Andrew SC Rice (UK)• Ze’ev Seltzer (Canada)• Thorgeir E. Thorgeirsson (Iceland)• David Yarnitsky (Israel)

Acknowledgements

Funding:

• Neuropathic Pain Special Interest Group (NeuPSIG), International Association for the Study of Pain

Special thanks to:• Harriet Wordsworth (UK)• Delphi survey respondents