Why pain matters
Blair H. Smith
Generation Scotland 10th Anniversary Symposium, 6th May 2016
1
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
Total in
Scotland
267,015
(NRS mid-2014 population
estimates)
1,150
1,446
1,086
29,119
20,799
14,973
18,272
16,111
57,062
18,604
42,692
32,414
5,722
7,561
“Severe” (intense, disabling) chronic pain – 5.6% of adults (Smith et al, 2001)
Other key facts
• Age:
– 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 Prescription Items
•
•
•
6,000,000
5,000,000
Total of >3.7M prescriptions in 2003
Increase to 5.9M prescriptions in 2012
Increase of 63% in 10 years
WEAK
STRONG
4,000,000
3,000,000
2,000,000
1,000,000
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
0
Total Number of DDDs
120,000,000
•
•
•
Total of ~75M DDDs in 2003
Increase to ~124M DDDs in 2012
Increase of 65% in 10 years
100,000,000
80,000,000
60,000,000
40,000,000
20,000,000
0
2012: 18% of the Scottish population were
prescribed an opioid
2014/15: Gross ingredient cost for all analgesics
= £70.8M (excludes adjuvants and topicals)
WEAK
STRONG
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%)
CPG 1
CPG 2
CPG 3
CPG 4
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
IV
III
IV
IV
IV
III
III
Hocking et al. Eur J Pain 2012
III
III
II
I
I
IV
Heritability of chronic pain
Severe chronic
pain
Heritability (h2; %)
60
Any chronic pain
50
40
30
20
10
0
Adjustment
All + shared
household
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). 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
OR 95%CI
(adjusted for age [and gender])
Model 2: predicting any chronic pain
Model 2: Predicting widespread moderate
intensity pain
4.0
4.0
3.0
3.0
2.0
2.0
1.0
1.0
High Obese Ever Age
TC:HDL
smoker
ratio
Female
gender
N = 8,093
High Obese Ever Age
TC:HDL
smoker
ratio
Female
gender
Chronic pain and cardiovascular risk
Low HDL cholesterol
n
OR
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
95%CI
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.
CARDIOVASCULAR DISEASE
• 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