Generation Scotland 10th Anniversary Symposium, 6th May 2016 Why pain matters Blair H. Smith Generation Scotland 10th Anniversary Symposium, 6th May 2016

Pain: “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” IASP, 1986

Chronic pain: “Pain that persists beyond normal tissue healing time [3 months]”IASP, 1986

Pain in Europe study Breivik et al 2006 Duration of pain Prevalence of chronic pain among 46,394 adults (>18 years) in 15 European countries and Israel  “19% of 46,434 respondents willing to participate had suffered pain for ≥6 months, had experienced pain in the last month and several times during the last week. Their pain intensity was ≥5 on a 10-point NRS”

Global Burden of Disease Study 2013 CLBP the single greatest cause of disability, by far (146m YLDs) MDD 2nd greatest cause (51m YLDs) 4 of the top ten causes of YLDs were chronic pain conditions, globally and in Scotland Other important causes of YLDs are associated with chronic pain (e.g. diabetes, HIV) Lancet 2015

“Severe” chronic pain in Scotland 1,446 42,692 18,272 14,973 20,799 29,119 1,150 16,111 57,062 18,604 7,561 5,722 32,414 1,086 “Severe” (intense, disabling) chronic pain – 5.6% of adults (Smith et al, 2001) Total in Scotland 267,015 (NRS mid-2014 population estimates)

Other key facts Age: Health inequalities Mortality Productivity Prevalence increases with age Severity increases with age Health inequalities Commoner in areas of high deprivation “Severe” chronic pain particularly associated with indicators of deprivation (education, housing, employment) Mortality 10-year mortality increased (x1.4 for any pain; x1.8 for “severe” chronic pain) – particularly heart and respiratory disease Productivity 60% of working-aged with “severe” chronic pain are unable to work

NHS impact 4.6 million GP appointments/year for chronic pain in UK (≡793 fulltime GPs) 3 times likelier to be admitted to hospital >10,000 new appointments/year at specialist pain services in Scotland Rising analgesic prescribing costs and adverse effects

Opioids in Scotland 2003-2012 Total of >3.7M prescriptions in 2003 Increase to 5.9M prescriptions in 2012 Increase of 63% in 10 years Total of ~75M DDDs in 2003 Increase to ~124M DDDs in 2012 Increase of 65% in 10 years Drugs for diabetes, and inhaled steroids were the only BNF chapters to cost more. Lidocaine plasters = £4.55M 2012: 18% of the Scottish population were prescribed an opioid 2014/15: Gross ingredient cost for all analgesics = £70.8M (excludes adjuvants and topicals)

Gabapentin prescribing, Scotland 2001-2013 Gross ingredient cost/year (2014/15): Gabapentin - £6.9M Pregabalin - £30.4M

GS: Chronic pain phenotype Pain currently? [YES/NO] n = 10,736 (44.7%) Pain lasting longer than 3 months? [YES/NO] n = 8,350 (34.8%) Sites of pain (checklist) Site of main pain (same checklist) Chronic pain grade (CPG) questionnaire CPG 1: Low intensity, low disability (n = 4,001; 54.1%) CPG 2: High intensity, low disability (n = 2,128; 28.7) CPG 3: High disability, moderately limiting (n = 6,386; 8.6%) CPG 4: High disability, severely limiting (n = 631; 8.5%)

Opioid prescribing in GS:SFHS [Unpublished data. Summary: Significant association between presence and severity of chronic pain, and receipt of opioid prescription. >50% of those reporting severe chronic pain did not receive an opioid in the 6 months before or after chronic pain phenotyping for GS:SFHS Most of them did not receive any analgesic prescription in this time. Conclusion: opioids, where prescribed, are generally prescribed appropriately; however, there is a suggestion of under-treatment of chronic pain.]

SIGN Guidelines “Management of Chronic Pain” In the nonspecialist setting Sections on Assessment and planning of case Supported self management Pharmacological therapies Psychology based interventions Physical therapies Complementary therapies Dietary therapies Provision of information Publication date 12th December 2013

GS:SFHS. ‘Extreme’ Families IV III III IV II I Hocking et al. Eur J Pain 2012

Heritability of chronic pain Severe chronic pain Any chronic pain 60 50 40 Heritability (h2; %) 30 20 10 Age Sex BMI All + shared household Income Unadjusted Occupation Physical activity Adjustment Hocking et al (2012) Eur J Pain

GWAS on Chronic Pain using 9,000 Generation Scotland samples (GCTA) Further analysis in progress using all data – W. Meng

Meta-analysis: Pfizer-23andMe (n=30,000) and GS:SFHS (n=5,000) Meta-analysis: Pfizer-23andMe (n=30,000) and GS:SFHS (n=5,000). Meng W, Hayward C, Hocking L, Smith BH, GS. Full report delivered to Pfizer, October 2015. Further analysis in progress (n=60,000)

Chronic pain and co-morbidities N = 1.75M Guthrie et al, 2012

GS:SFHS - Chronic pain and CVD risk Goodson et al, 2013 Model 2: predicting any chronic pain 1.0 3.0 2.0 High TC:HDL ratio Obese Ever smoker Age Female gender 4.0 Model 2: Predicting widespread moderate intensity pain 4.0 3.0 (adjusted for age [and gender]) OR 95%CI 2.0 1.0 High Obese Ever Age Female gender TC:HDL smoker ratio N = 8,093

Chronic pain and cardiovascular risk   Low HDL cholesterol n OR 95%CI No pain (reference) 8119 1.00 Low pain intensity 1-3 2418 1.01 0.85, 1.20 Moderate pain intensity 4-6 2084 1.28 1.23, 1.52 High pain intensity 7-10 707 1.59 1.23, 2.05 Goodson et al, 2013

Chronic pain as a co-morbidity with depression and/or angina GS:SFHS Van Hecke et al (submitted) [Unpublished data. Summary: Individuals with one or more of these conditions (chronic pain, major depressive disorder, angina) were at much higher odds of also having the other conditions.]

GS: Co-morbidity in sibling pairs [Unpublished data. Summary: Siblings of individuals with any one of the conditions (chronic pain, major depressive disorder, angina) were at higher risk of having either of the other, even after adjustment for the presence of the index condition. This suggests a genetic basis for co-morbidity.] van Hecke et al (under review)

Genome-wide analyses [Unpublished data] GS:SFHS. Chronic pain, genetic heritability quantified, with an additional contribution from shared environment, measured by presence/absence in spouses. GS:SFHS. Chronic pain correlated with MDD genetic contribution to covariance >50% Polygenic risk scores: PGRS for chronic pain predicted chronic pain in GS:SFHS PGRS for MDD predicted chronic pain in GS:SFHS PGRS for chronic pain did not predict MDD in GS:SFHS McIntosh et al (under review)

GENETIC BASIS FOR MULTI-MORBIDITY BETWEEN CHRONIC PAIN, DEPRESSION AND CARDIOVASCULAR DISEASE Risk factors can be genetic and/or environmental. Risk factors can be unique to a single disorder, shared between two disorders, or common to all three. The combination of unique and shared risk factors determines which of the disorders an individual will manifest. Greater generalisability by having phenotypes ascertained in different ways in different cohorts. UK Collaboration involving GS, UKB, TwinsUK, 23andMe: “HEART-ACHE”

DOLORisk EU Horizon 2020 Programme (€6M) To identify risk factors for development and exacerbation of neuropathic pain Environmental Genetic Neurophysiological Molecular DOLORisk DUNDEE Longitudinal study of two large cohorts (Generation Scotland and GoDARTS, n = 33,000), re-phenotyped for neuropathic pain Genetic and environmental factors and interactions Predictive modelling

What is the genetic architecture of chronic pain?

Generation Smith