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

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

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

6. 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”

7. 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

8. “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)

9. 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

10. 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

11. Opioids in Scotland
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)

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

13. 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%)

15. 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.]

16. 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

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

18. 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

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

20. 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 Further analysis in progress (n=60,000)

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

22. 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

23. 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

24. 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.]

25. 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)

26. 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)

27. 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”

28. 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

29. What is the genetic architecture of chronic pain?

30. Generation Smith