Introduction
Painful diabetic peripheral neuropathy (painful DPN) affects up to 25% of individuals with diabetes and is a leading factor that prompts those with DPN to seek medical advice [
1,
2]. Painful DPN presents with a range of neuropathic symptoms, including burning, deep aching, pins and needles and electric shock like pains, resulting in moderate to severe unremitting lower-limb pain in over 70% of cases [
3,
4]. These unpleasant symptoms have a profound effect on sufferers’ lives, leading to insomnia [
4], poor quality of life [
4,
5], unemployment [
6] and depression [
6,
7]. Unfortunately, current treatments for painful DPN are only partially effective at best, providing 50% pain relief in less than 50% of affected individuals [
8]. Moreover, individuals with painful DPN have significant healthcare resource utilisation costs [
9]. A recent study from the USA found that annual direct medical costs for painful DPN were over double those for painless DPN, and over four times those for diabetes alone [
9]. There is therefore a good rationale for a better understanding of the risk factors for this disease as it might give insight into new treatment and prevention strategies.
The risk factors for DPN have been extensively studied in high-quality prospective studies [
10,
11]. In the EURODIAB study that followed 1172 participants with type 1 diabetes who did not have DPN at baseline, the incidence of DPN was found to be 23.5% over 7.3±0.6 years [
11]. The risk factors for incident DPN included duration of diabetes, elevated HbA
1c, obesity, smoking, elevated triglycerides, elevated urinary AER and hypertension. Conversely, there is no consensus on the risk factors of painful DPN, although a number of factors have been proposed, including age, obesity, duration of diabetes and female sex [
3,
5,
12‐
22]. However, all the studies investigating the risk factors for painful DPN are cross-sectional and therefore not as robust as those examining the risk factors for DPN. The EURODIAB Prospective Diabetes Complications Cohort thus represents a unique opportunity to investigate the risk factors for painful DPN in a prospective study.
Discussion
Chronic painful DPN can be extremely distressing and is a leading cause of morbidity and healthcare utilisation [
1,
3‐
7,
9]. Furthermore, its pathophysiology remains undetermined and current treatments provide sub-optimal pain relief [
8,
26]. Therefore, there is a clear rationale for identifying risk factors for painful DPN. Despite this, few well-designed studies have looked at the incidence and risk factors for painful DPN and in particular there have been no prospective studies. Thus, the EURODIAB Prospective Diabetes Complication Study, one of the largest multi-centre prospective diabetes studies, provides a unique opportunity. The prevalence of painful DPN in a cohort of 3250 individuals (mean age 30.7 years) at baseline was 7.2%. After excluding participants with DPN at baseline, 276 (23.5%) developed DPN after 7.3 years, and of these 14.9% had incident painful DPN. In this European study, there was a striking preponderance for the development of painful DPN in female participants, providing the strongest evidence so far for female sex being a major risk factor for painful DPN. Furthermore, there was less evidence of nephropathy at baseline, measured by albuminuria, in participants with incident painful compared with painless DPN. This suggests that the development of painful DPN may not be driven by simple cardiometabolic factors but may be influenced by psychological, social, cultural, genetic and other factors [
2,
7,
22]. Although there have been cross-sectional studies this is the first prospective study to show that female sex is a risk factor for painful DPN.
Key risk factors for DPN, including poor glycaemic control and markers of large vessel disease, such as hypertension, smoking, increased triglycerides, obesity and raised cholesterol have already been reported in the same cohort of participants [
11]. Similar findings have since been confirmed more recently [
10] in type 2 diabetes. In contrast, the risk factors for painful DPN are less well known [
2]. However, a number of cross-sectional studies have found increasing age [
12,
14,
15,
19], duration of diabetes [
12,
15,
19,
27], obesity [
12‐
14,
16,
27] and severity of neuropathy [
5,
16‐
18] to be risk factors for painful DPN. Female sex has also been highlighted as a potential risk factor for painful DPN in recent studies [
3,
15,
17,
19‐
21,
27,
28]. Nevertheless, it has been highlighted that prospective epidemiological studies are needed to confirm that female sex is a risk factor for painful DPN [
29]. Our study meets this need and proves the findings from cross-sectional studies, including a large cohort study in England (
N=15,692) that found women had a 50% increased adjusted risk for painful DPN compared with men [
3]. More recently, Truini et al consecutively enrolled 816 diabetes patients and found that 13% had painful DPN, with female sex as the only identifiable risk factor (
p=0.03 vs painless DPN) [
20]. Another recent study also demonstrated that female participants with diabetes reported a higher frequency and intensity of pain despite milder nerve injury [
29]; however, other studies [
3,
19] that assessed pain severity did not find a significant relationship with female sex. It is noteworthy that all these previous studies were cross-sectional and that our large and well-conducted European study definitively demonstrates a causal link between female sex and painful DPN.
There is now a considerable body of literature that suggests there is a difference between men and women in the prevalence of chronic pain [
30]. Population-based research has consistently demonstrated a greater prevalence of chronic pain conditions, including neuropathic pain, among women relative to men [
31‐
33]. However, the mechanisms underlying sex differences in chronic pain are incompletely understood. Sex hormones are known to contribute to sexual differentiation of the nervous system and are hypothesised to be involved in pain modulation [
34]. Fluctuations in oestrogen levels may contribute to increased pain sensitivity in women whereas testosterone in men may promote pain relief. Sex hormones also appear to interact with the neuroimmune system to alter sensory neuron activity. Recent animal model data indicate different innate and adaptive immune system responses to neuropathic pain models between males and females [
35]. The involvement of microglia and T cells in mediating pain hypersensitivity appears to be sexually dimorphic, whereas macrophages, primary sensory neurons and spinal dorsal horn neurons are involved in a sex-independent manner [
35]. A recent review concluded that the use of transcriptomic analysis for studying neuropathic pain could be an unbiased, effective strategy to identify molecular mechanisms and better therapeutic targets in men and women [
35]. Moreover, significant sex-specific cerebral differences have been demonstrated not only in neuropathic pain but also in chronic pain. In women, key regions of the brain responsible for detection and processing of nociception (e.g. primary somatosensory cortex, insular cortex, anterior cingulate cortex and thalamus) have been found to have altered structure and function, and response to experimental pain [
36]. Furthermore, it is possible that sex differences in pain are not entirely of a biological basis as several psychosocial and cultural factors have also been proposed, including sociocultural differences in gender roles, higher levels of catastrophising and altered coping strategies [
30,
33]. Clearly the pathophysiological basis of sex differences in pain requires urgent attention, as this could have a considerable impact upon the prevention and treatment of neuropathic pain in women. Moreover, although several studies have demonstrated a higher prevalence of painful DPN in women, it is not known whether there are specific sex differences in the pathophysiology of painful DPN [
37]. Clearly, well-designed mechanistic research in well-characterised (phenotyped) individuals is required to investigate this further.
In this study, incident painful DPN was not related to clinical or metabolic factors but it was associated with a lower baseline prevalence of diabetic nephropathy [
11]. We know that DPN (painless) is driven by glycaemic control and traditional risk factors for CVD [
11]. We also know that the development of nephropathy is similarly driven by cardiometabolic factors [
38], hence the increased baseline prevalence of albuminuria in those that develop painless DPN. The lack of relationship between cardiometabolic factors and the incidence of painful DPN suggests that the development of neuropathic pain appears to be more complex and may not be entirely explained by cardiometabolic factors. After all, pain is well recognised to be influenced by cultural, environmental and psychosocial factors in addition to potential factors including peripheral structural/molecular biomarkers [
37], central nervous system pain processing [
37], genetics [
22] and sex [
20].
Our study provides the only prospective incidence data for painful DPN. In this cohort of young individuals with type 1 diabetes (mean age 30.7 years), we found the incidence of painful DPN to be 14.9% in those with confirmed DPN after 7 years of follow-up. Additionally, the baseline prevalence of painful DPN in our study was 25.2%. This is relatively similar to the prevalence reported by studies conducted in individuals with type 1 diabetes and type 2 diabetes [
3], and type 2 diabetes [
1,
5]. However, the reported prevalence rates for painful DPN varies greatly among studies (5.8–54.8%) [
1,
3,
5,
12,
13]. The predominant reason for this is the differences in case definition and diagnostic techniques used among studies, although population differences may also contribute. A strength of our study is the robust detection of painful DPN, using the presence of common neuropathic pain symptoms in the presence of confirmed DPN using neurophysiological tests [
39]. We therefore believe that our incidence and prevalence data are valid.
The great strengths of this study are that it is a large, prospective study with several years of follow-up and that participants underwent comprehensive neuropathy and diabetes evaluation. Moreover, the study was performed in participants with type 1 diabetes, who were younger with potentially fewer confounding factors than people with type 2 diabetes. However, it may have some limitations. This study is an analysis of the EURODIAB cohort, with the participant follow-up completed in 1999. Since then, there have been improvements in neurological and pain phenotyping (e.g. calf skin biopsy [intra-epidermal nerve fibre density] and modern detailed quantitative sensory testing) that were not available when the study was designed. Additionally, participants unrepresentative of local European ethnic groups were not recruited into the study, which may have an impact on generalisability of the study findings. Moreover, neuropathic pain severity was not assessed in this epidemiological study. However, we believe the results are valid, due to the study being well-designed and representing the only prospective study to identify risk factors of painful DPN.
In conclusion, this largest-ever prospective study of painful DPN in type 1 diabetes, including over 1100 individuals followed for 7 years, has shown the strongest evidence that women are more at risk of developing painful DPN. Incident painful DPN was not related to metabolic variables (glycaemic control, hyperlipidaemia, etc.) or advanced microvascular disease but was associated with lower incidence of albuminuria. The findings of this study will provide greater awareness that female patients are at risk of developing painful DPN in clinical practice.
EURODIAB Prospective Complications Study investigators
In addition to the authors, the following investigators participated in the EURODIAB Prospective Complications Study: B. Karamanos, A. Kofinis and K. Petrou (Hippokration Hospital, Athens, Greece); F. Giorgino, G. Picca, A. Angarano, G. De Pergola, L. Laviola and R. Giorgino (Endocrinologia e Malattie Metaboliche, DETO, Università Degli Studi di Bari, Bari, Italy); M. Songini, A. Casu, M. Pedron, S. Pintus and M. Fossarello (Ospedale San Michele, Cagliari, Italy); J. B. Ferriss, G. Grealy and D. O. Keefe (Cork Regional Hospital, Cork, Ireland); M. Toeller and C. Arden (Heinrich-Heine University, Dusseldorf, Germany); R. Rottiers, C. Tuyttens and H. Priem (University Hospital of Gent, Belgium); P. Ebeling, M. Kylliäinen and V. A. Koivisto (University Hospital of Helsinki, Finland); B. Idzior-Walus, J. Sieradzki and K. Cyganek (Jagiellonian University, Krakow, Poland); H. H. P. J. Lemkes and M. Krans (Leiden University Medical Centre, the Netherlands); J. Nunes-Correa, M. C. Rogado, L. Gardete-Correia, M. C. Cardoso, A. Silva, J. Boavida and M. Machado Sa Marques (Portuguese Diabetic Association, Lisbon, Portugal); G. Michel, R. Wirion and S. Cardillo (Centre Hospitalier, Luxembourg); G. Pozza, R. Mangili and V. Asnaghi (Ospedale San Raffaele, Milan, Italy); E. Standl, B. Schaffler, H. Brand and A. Harms (City Hospital Schwabing, Munich, Germany); B. Soussan, O. Verier-Mine, P. Fallas and M. C. Fallas (Centre Hospitalier de Valenciennes, France); J. H. Fuller, J. Holloway, L. Asbury and D. J. Betteridge (University College, London, UK); G. Cathelineau, A. Bouallouche and B. Villatte Cathelineau (Hospital Saint-Louis, Paris, France); F. Santeusanio, G. Rosi, V. D'Alessandro, C. Cagini, P. Bottini and P. Reboldi (Instituto di Patologia Medica, Policlinico, Perugia, Italy); R. Navalesi, G. Penno, S. Bandinelli, R. Miccoli and M. Nannipieri (Dipartimento di Endocrinologia e Metabolismo, Pisa, Italy); G. Ghirlanda, C. Saponara, P. Cotroneo, A. Manto and A. Minnella (Università Cattolica del Sacro Cuore, Rome, Italy); J. D. Ward, S. Tesfaye, S. Eaton and C. Mody (Royal Hallamshire Hospital, Sheffield, UK); M. Borra, P. Cavallo Perin, S. Giunti, G. Grassi, G. F. Pagano, M. Porta, R. Sivieri, F. Vitelli and D. Ferrari (Dipartimento di Medicina Interna, Università di Torino and ASO CTO-CRF Maria Adelaide, Turin, Italy); N. Papazoglou and C. Manes (General Hospital of Thessaloniki, Greece); M. Muggeo and M. Iagulli (V Cattedra di Malattie del Metabolismo, Verona, Italy); K. Irsigler and H. Abrahamian (Hospital Vienna Lainz, Austria); S. Walford, J. Sinclair, S. Hughes, V. McLelland and J. Ward (New Cross Hospital, Wolverhampton, UK); G. Roglic, Z. Metelko, Z. R. Pepeonik and Z. Babic (Vuk Vrhovac Institute for Diabetes, Zagreb, Croatia); and C. Ionescu-Tirgoviste, A. Coszma and C. Guja (Clinic of Diabetes, Nutrition & Metabolic Diseases, Bucharest, Romania).
Co-ordinating centre J. H. Fuller, N. Chaturvedi, J. Holloway, D. Webb, L. Asbury, M. Shipley and S. J. Livingstone, University College London, London, UK.
Central laboratories G.-C. Viberti, R. Swaminathan, P. Lumb, A. Collins and S. Sankaralingham, Guy’s and St Thomas Hospital, London, UK.
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