1. Introduction

Chronic pain (CP), defined as pain lasting more than 3 months, represents a major global burden for years lived with disability and the associated economic impact due to health resources used and work absenteeism.128 As an example, nonspecific low back pain (LBP) is the largest single cause of years lived with disability globally,49 accounting for 11% of the entire disability burden from all diseases. In 2017, LBP was estimated to cost the UK up to 116 million lost workdays and approximately £12.3 billion through direct health care costs, production losses, and informal care https://www.gov.uk/government/publications/chronic-pain-in-adults-2017.

Pain has long been considered solely as a symptom, and it is only recently that CP has been recognised by the World Health Organization International Classification of Diseases (ICD)-11121 as a long-term condition in its own right.

Chronic pain prevalence increases with age as predisposing conditions such as obesity, arthritis, diabetes mellitus, and malignancy become more common.41 A recent meta-analysis of population-based epidemiological studies worldwide reported a pooled CP prevalence estimate of 31%,111 with an equivalent figure from UK studies of 43.5%,41 similar to data arising from UK Biobank (UKB, 42.9%).75 Of those reporting CP, a subset conservatively estimated at 20%20 have disabling CP that substantially interferes with activities of daily living. Similarly, there is an overlapping population who express a substantial need for health care. Such individuals are often characterised by comorbid depression, fear, cognitive dysfunction, avoidance of movement, and poor coping skills.15 From a public health perspective, the challenge is to prevent the progression of mild or transient pain to CP which becomes severe.14

The development and severity of CP involve a complex interaction between genetic, environmental, and clinical factors in vulnerable individuals.126 Chronic pain is heritable: Twin72,78,110 and extended family61 studies have provided estimates of 30% to 76%. Mutations in specific genes (most of which encode ion channels) cause rare (Mendelian) pain conditions in humans.12 This includes the disorder inherited erythromelalgia (characterized by pain and erythema of the extremities exacerbated by warming), which is caused by autosomal dominant and highly penetrant gain of function mutations in the gene SCN9A encoding the voltage-gated sodium channel NaV1.7.13 Human pain complex trait genetics (especially when combined with rich phenotypic data, biosamples, and large-scale brain imaging cohorts34) has the potential to revolutionise our understanding of CP pathogenesis, risk factors, and the determinants of treatment responses. Current significant challenges and limitations to this approach relate to (1) a lack of precision in CP phenotyping with respect to the duration, location, intensity, and quality of pain as well as the temporal relationship to predisposing factors and comorbidities such as anxiety and depression and (2) the size of the existing CP cohorts which are limited and, therefore, studies are relatively underpowered. Key to overcoming these challenges is large consortia with a harmonised approach to pain phenotyping and nationwide biorepositories with a wide range of genetic and nongenetic data. There is now an increasing international effort to harmonise data collection which is likely to further inform clinical practice. One example is “INTEGRATE-Pain”. This is a joint initiative between the US National Institute of Health (NIH) and Innovative Medicines Initiative-PainCare which is developing consensus on overarching core outcome domain sets for clinical pain trials and clinical pain research (https://www.comet-initiative.org/Studies/Details/2083). Newer cohorts now available to study CP include DOLORisk,93 and this has informed the approach taken by current studies such as the rephenotyped UKB Chronic Pain (UKB CP) Cohort and PAINSTORM.

This review introduces these cohorts, provides an overview of their main outputs, and outlines the key lessons learned.

2. UK Biobank (chronic pain cohort)

The scope of UKB, which comprises 500,000 volunteers enrolled between 2006 and 2010 at ages 40 to 69 from across the UK, provides a unique opportunity to examine the epidemiology and genetics of CP in a prospective population cohort. A brief assessment of CP was completed by all participants at booking (https://biobank.ndph.ox.ac.uk/showcase/field.cgi?id=6159) although it did not include validated questionnaires enabling categorisation of CP of diverse aetiologies. Using that initial data, we have previously demonstrated that the prevalence of CP and most regional (ie, site specific) musculoskeletal pains in UKB are similar to that found in other pain epidemiological studies. Our findings also reproduce known relationships from a range of socioeconomic and psychological factors.75,90

To address the lack of specificity when categorising CP, a UK academic consortium of clinicians and pain researchers, many of whom have experience of working with UKB75,86,130,133 and with a range of synergistic expertise in epidemiology, genomics, psychology, neuroimaging, and pain management, developed a UKB CP phenotyping survey (2017–2018). The pain phenotyping survey (https://biobank.ctsu.ox.ac.uk/crystal/ukb/docs/pain_questionnaire.pdf) was designed by a group of experts (including the authors B.H.S., D.W., and D.L.H.B.) and based on a series of validated questionnaires in routine use (Table 1), which were fully aligned with the CP cohorts described in this paper. These focused on the most prevalent causes of CP and associated comorbidities and risk factors.

Table 1 - Questionnaires used in DOLORisk, PAINSTORM, and UK Biobank. Category Questionnaire DOLORisk PAINSTORM UK Biobank Reference Core Extended Core Extended Demographics Age, gender, years in education, working status, weight, and height X X X X X Ethnicity X X X Household income X Characterisation of pain Presence and duration of pain X X X X X Family history Family history of chronic pain X X Pain medication Currently taking pain medication X X X X Brief Pain Inventory—usefulness of medication X X Cleeland and Ryan30 Adherence to medication X X Pain relief strategies other than medication X Pain severity Chronic pain grade X X X X Von Korf et al.127 Brief Pain Inventory—pain severity X Only the item on “pain on average” X X Cleeland and Ryan30 Pain quality DN4 Questionnaire X X X X X Bouhassira et al.18 DN4 Examination X X Neuropathic Pain Symptom Inventory X X Bouhassira et al.17 PainDETECT X Freynhagen et al.47 Pain location List of locations X X X X Body map X X Pain interference PROMIS Pain Interference 8a X Amtmann et al.3 PROMIS Ability to Participate in Social Roles and Activities 8a Hahn et al.54 Pain-related worrying Pain Catastrophizing Scale X X X X Sullivan et al.113 Health status and psychological assessment EQ-5D-5L X X X X X Herdman et al.60 Patient Health Questionnaire-9 X Kroenke et al.67 PROMIS Depression 4a 8a 4a 8a Pilkonis et al.95 PROMIS Anxiety 4a 8a 4a 8a PROMIS Sleep Disturbance 4a 8a 4a 8a Buysse et al.23 PROMIS Fatigue 8a 8a Lai et al.69 Fatigue Severity Scale X Krupp et al.68 PROMIS Emotional Support 4a 4a 4a 4a Hahn et al.54 PROMIS Instrumental Support 4a 4a 4a 4a Trauma X X X X Ten-item Personality Inventory X X X X Gosling et al.51 International Personality Item Pool (Emotional Stability) X Goldberg50 State Optimism Measure (SOM-7) X Millstein et al.87 Disease-specific (diabetic neuropathy) Michigan Neuropathy Screening Instrument X X Feldman et al.42 Lifestyle Smoking X X X X Campbell et al.24 Alcohol X X X X International Physical Activity Questionnaire X X Craig et al.33 Bespoke questions Financial situation and impact on pain management X Description of pain in the participant's own words X Other chronic pain conditions Fibromyalgia X Wolfe et al.131 Headache and migraine X Lipton et al.71

DN4, Douleur Neuropathique en 4 Questions; EQ-5D-5L, EuroQol-5 dimensions-5 levels; PROMIS, Patient-Reported Outcomes Measurement Information System.

The CP phenotyping survey was then sent to ∼335,000 UKB participants who consented to recontact, had an email address, and were still actively participating as of May 2019 (ie, not deceased or withdrawn). The survey was (partially or fully) completed by ∼167,000 individuals (a response rate of 49.8%). Approximately 148,000 individuals either reported no CP (∼72,000), or CP (pain or discomfort that had been present for more than 3 months) and fully completed the Douleur Neuropathique en 4 (DN4) questionnaire (∼76,000; 51.1%). The data were released in early 2021 and are available to bona fide researchers worldwide. The UKB CP cohort has the added values of: (1) being by far the largest phenotyped CP cohort generated to date worldwide; (2) linkage to longitudinal GP records for >95% of respondents by 2024; (3) access to all the other rich datasets obtained by previous (and subsequent) UKB questionnaires completed by these individuals for imaging, depression, anxiety, cognition, multimorbidity, deprivation, etc; (4) the CP survey will be repeated in summer 2024 and extended to provide detailed outcome and treatment data on those with CP, thus allowing the identification over the intervening 5 years of those with newly reported CP; and (5) being of sufficient size and detail to allow data-derived categorisation of CP symptoms and risk factors.

The CP data demonstrate that 75% of subjects with CP reported pain having lasted for more than a year and about a third for more than 5 years. Using the Brief Pain Inventory (BPI) questionnaire, approximately 25% of subjects with CP reported severe or moderate pain whereas 20% reported severe or moderate interference in their activities of daily living. Over half of subjects with CP reported back or neck pain, over 40% had pain in one or more joints (the commonest being knee, then hip, hands, and feet), whereas 10% reported pain all over the body. The commonest self-reported CP diagnoses were osteoarthritis affecting one or more joints, followed by migraine, nerve damage or neuropathy, carpal tunnel, pelvic pain, and rheumatoid arthritis. Using the DN4 questionnaire, the prevalence of “possible” neuropathic pain (NeuP) was 9.2%, making up 18.1% of those with CP. Our recent analysis7 of those with NeuP demonstrated that this was significantly associated with worse health-related quality of life, having a manual or personal service type occupation and younger age compared with those without CP. As expected, NeuP was associated with diabetes and neuropathy but also with other pains (pelvic, postsurgical, and migraine) and musculoskeletal disorders (rheumatoid arthritis, osteoarthritis, and fibromyalgia). In addition, NeuP was associated with pain in the limbs and greater pain intensity and higher body mass index (BMI) compared with those with nonneuropathic pain.

2.1. Caveats/limitations (1) Non-White ethnic backgrounds were rare in UKB (2.2%); 1.6% were from Black, Asian, and Minority ethnicities; 0.6% were mixed ethnicity; and the remaining 97.8% were White. This compares with 18.3% non-White in England and Wales in the 2021 Census.35 In the 2011 Census, which is closer to when the UKB cohort was recruited, 14% were non-White in England and Wales36 and 4% were non-White in Scotland28 (2022 census not yet available). (2) There was an overrepresentation of participants who were female, of younger age, who had lower BMI, and who were less socially deprived in the group that completed the 2019 pain phenotyping questionnaire compared with the rest of the UKB cohort who did not. The overrepresentation of participants of younger age and who were less socially deprived could potentially be due to the fact that the questionnaire was only available online. (3) The definition of NeuP relies on a self-completed screening tool, which does not meet the grading system for “probable” or “definite” NeuP. These necessitate clinical examination which is clearly not feasible in a large population survey. 2.2. Outputs

Because of the large sample size and range of data available compared with other cohorts, UKB allows associations to be quantified with greater precision and across different levels of demographics. As the data from the CP phenotyping survey was only released in early 2021, the results of studies using these data are only just beginning to emerge. Up to this point, studies have used the CP data that were collected at baseline recruitment. This has limited studies to specific single or multipain sites, without consideration for underlying aetiology. An extensive but nonexhaustive list of pain studies conducted either wholly or partially using UKB is provided in Table 2. These are intended to provide an overview of the kind of analyses that are possible using the cohort.

Table 2 - Publications on (chronic) pain using the UK Biobank cohort. Study Pain phenotype Design Finding Allen et al.1 AP and CP CS Social exclusion and loneliness are associated with pain Atkins et al.5 CP CS Low cardiovascular disease score individuals had less chronic pain Beasley et al.8 CWP CS Relationship between alcohol consumption and reporting of CWP Beasley et al.9 CWP MR Protective effect of alcohol on CWP is not supported Benavides et al.10 CP Genetic association rs1045642 (ABCB1) effect on response to chronic pain treatment with nortriptyline or morphine combo Bortsov et al.16 BP (acute and chronic) GWAS 13 GWS loci for chronic BP, none for acute BP. SNP heritability 4.6% for chronic BP and 0.8% for acute BP Broberg et al.21 General pain and multisite CP MR Bidirectional causal relationship between insomnia and pain Carvalho et al.25 Musculoskeletal pain CS and longitudinal T2D is associated cross-sectionally and longitudinally with shoulder or neck, knee, or hip pain and longitudinally with neck or shoulder pain Carvalho et al.26 Musculoskeletal pain CS Metformin is protective of back, knee, neck or shoulder, and multisite pain Cassidy et al.27 Drugs prescribed for CP CS Opiate and NP medications taken with cardiometabolic medications associated with obesity, increased waist circumference, and hypertension compared with cardiometabolic medications alone Chen et al.29 Musculoskeletal pain Longitudinal Higher number of pain sites associated with risk of all-cause mortality Cox et al.32 Opioid cessation/CBP GWAS PRS for opioid cessation significantly associated with chronic back pain, being a former drinker, and being a former smoker Faber et al.37 Hip pain CS Cam morphology is associated with hip pain Faber et al.38 Hip pain CS Radiographic hip osteoarthritis, total osteocyte area, joint space narrowing and acetabular, and superior and inferior femoral osteophyte areas were all associated with hip pain Faber et al.39 Hip pain CS Osteophytes and joint space narrowing are associated with hip pain Farrell et al.40 CP GWAS/PhWAS Shared genetic signature across 8 chronic pain types and 1492 biopsychosocial traits. 488 traits with causal association with CP Freidin et al.45 BP GWAS 3 loci associated with BP. Pleiotropic effects of genetic risk factors for BP, height, and intervertebral disk problems. Genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking Freidin et al.46 Chronic BP GWAS 2 and 7 GWS loci associated with chronic BP in males and females, respectively Green et al.53 Frozen shoulder GWAS/MR 5 GWS loci associated with frozen shoulder. Diabetes but not obesity is a causal risk factor for frozen shoulder Hanlon et al.55 CWP CS Physical, sexual, and emotional childhood maltreatment and neglect associated with CWP Hastie et al.56 CP and CWP Longitudinal CP and CWP associated with hospital admission for COVID-19. CWP but not CP associated with COVID-19 mortality Jin et al.62 Oral inflammatory diseases (including mouth ulcer, painful gums, and toothache) GWAS meta-analysis 31, 4, and 4 GWS loci associated with mouth ulcer, painful gums, and toothache. 2 novel GWS loci associated with painful gums and toothache Johnston et al.63 Multisite CP GWAS/MR SNP heritability of 10.2%. 39 GWS loci associated with multisite CP. Genetic correlation with psychiatric, autoimmune, and anthropometric traits. Causal effect of multisite CP on MDD Johnston et al.64 Multisite CP GWAS 5 and 10 GWS loci associated with multisite chronic pain in men and women, respectively. Sex-specific gene associations and expression in dorsal root ganglion. Sex-specific association of multisite CP with MDD. Genetic correlation with a range of psychiatric and mood phenotypes Kasher et al.65 CBP CS/MR RA, OP, CRP, BMI, age, and gender associated with CBP. Genetic correlation between CBP and RA and CRP and BMI. CRP causally predicts CBP. Pleiotropy seems to explain relationship between CBP and RA/OP Khoury et al.66 Single and multisite CP GWAS 23 GWS loci associated with multisite CP (none with single site CP) and 9 replicated in HUNT cohort. Axonogenesis in brain tissues is a major contributing pathway Larvin et al.70 Painful gums Longitudinal Higher incidence of CVD and depression in painful gums compared with healthy controls. Increased risk of baseline → CVD → censor and baseline → metabolic → censor disease trajectory in painful gums. The former trajectory has increased the risk of mortality Lobo et al.73 Chronic multisite musculoskeletal pain CS/genetic association Interaction between FKBP5 rs3800373 risk variant and right hippocampal volume associated with chronic multisite musculoskeletal pain. This is mediated by severity of childhood trauma Macfarlane et al.75 ‘Any pain’, CP, and musculoskeletal pain CS Estimates of ‘any pain’, CP, and site-specific musculoskeletal pain prevalence similar between UK Biobank and MUSICIAN/NCDS cohorts Macfarlane et al.76 CWP Longitudinal/meta-analysis CWP associated with excess all-cause mortality as well as excess cancer, cardiovascular, and respiratory-related deaths Macfarlane et al.77 Opioid use CS/longitudinal 5.5% of UK Biobank regularly using opioids. Opioid use is most common in groups of low socioeconomic status. Weak and strong opioids were associated with excess mortality Macfarlane et al.74 (Chronic) Facial pain CS Overall prevalence of facial pain was 1.9%, of which 48% was chronic. Facial pain was more common in women, smokers and associated with psychological distress, low socioeconomic status, low alcohol consumption, and all types of regional pain McIntosh et al.81 CP CS/genetic association PRS for MDD associated with CP in UK Biobank McQueenie et al.83 CP/CWP CS Chronic pain is extremely common across a wide range of LTCs including migraine/headache, IBS, mental health conditions, and diseases of the digestive system. People with ≥4 LTCs 3 and 20 times more likely to have CP and CWP, respectively Meng et al.84 Knee pain GWAS 2 GWS loci (GDF5 and COL27A1) associated with knee pain Meng et al.85 Headache, facial, neck/shoulder, back, stomach/abdominal, hip and knee pain, and pain all over the body Genetic association Positive genetic correlation between all pain phenotypes and depressive symptoms, MDD, and neuroticism, except hip and knee pain Meng et al.86 Neck and shoulder pain GWAS 3 GWS loci associated with neck or shoulder pain. 2 loci (FOXP2 and LINC01572) weakly replicated in an independent cohort. Genetic correlation between neck or shoulder pain and depression, insomnia, and neuroticism Muralidharan et al.88 Multisite CP Longitudinal/genetic association Significant negative correlation between the number of chronic pain sites and age at death in men, but not women. TP53 significantly associated with the number of chronic pain sites in women but not men Nicholl et al.89 Multisite CP CS Individuals who report CP and multisite CP are more likely to have MDD and BD. Relationship between extent of CP and risk of MDD and BD Nicholl et al.90 CP CS CP is more common, and depression is less common in Black and Asian ethnic groups compared with White. Association between presence and extent of CP and depression strongest in minority ethnic groups Pan et al.91 Multisite musculoskeletal pain (hip, knee, back, and neck/shoulder pain) CS Greater number of painful sites consistently associated with poorer physical working capacity and low intensity physical activity compared with moderate or vigorous physical activity Parisien et al.92 Acute back pain CS Elevated risk of acute back pain persistence in subjects taking NSAIDs Patasova et al.94