Is suffering from chronic pain causing cardiovascular death?

This editorial refers to ‘Widespread pain is a risk factor for cardiovascular mortality: results from the Framingham Heart Study’†, by J. Tesarz et al., on page 1609. Pain is such an uncomfortable feeling that even a tiny amount of it is enough to ruin every enjoyment. Will Rogers Chronic pain and depression are the two most prevalent conditions worldwide (Global Study, 2013), and they substantially impact public health. Widespread pain (WSP) is considered by the ICF (International Classification of Functioning, Disability, and Health) to be a primary pain syndrome, and affects >1 in 10 adults, with higher incidence in females.1 , 2 WSP is defined as a pain condition with concurrent axial pain, pain of the upper and lower segments, as well as left- and right-sided pain.3 , 4 Studies have shown that pain and cardiovascular disease (CVD) often co-exist, which is not surprising given the obvious autonomic activation present in pain patients.5 This is due to an intertwined neuronal modulation between baroreceptors and nociceptive signals.6 It is also of note that genetic predisposition may exist in patients with WSP and the development of CVD.7 , 8 Interestingly, in addition to the negative impact of WSP on individual patients and its socio-economic burden on society, the literature supports a link between pain and elevated rates of mortality. Multiple studies have illustrated increased rates of cardiovascular death in WSP patients.9 , 10 A systematic literature review by Fayaz et al., showed that there is a statistically significant association between chronic pain and mortality from cardiovascular diseases.9 However, due to confounding variables, the literature remains rather inconsistent. Another systematic review of the literature showed increased mortality in patients with chronic pain syndrome which was mainly attributed to cancer.11 However, the Mini-Finland Health Survey study did not corroborate this observation.10 As such, exploration of whether there are increased cardiovascular death rates in patients with chronic pain necessitates longitudinal population studies. The prospective meta-analysis utilizing data from the longitudinal multi-generational Framingham Heart Study (FHS) by Tesarz et al. in this issue of the European Heart Journal aims to address the current knowledge gap about the effect(s) of WSP on fatal and non-fatal cardiovascular events.12 The goal of the current study is to further delineate all-cause mortality in those with and without WSP and to elucidate the underlying mortality mechanism (overall, cardiovascular, or cancer related). The study includes 4689 subjects from the FHS further categorized into those with WSP (678) and without WSP (4011), as defined by a pain questionnaire utilized from 1990 to 1994, during a 15-year follow-up period. During the study period, 202 persons with WSP and 1144 in the no-WSP group died. Several parameters were investigated and results were adjusted for age and gender. Investigators found that all-cause mortality was 16% higher in WSP subjects. The WSP group also had an increased hazard ratio (HR) for CVD death [HR adjusted by age and gender = 1.46, 95% confidence interval (CI)1.10–1.94] but not for cancer mortality (HR = 0.69, 95% CI 0.38–1.27). Investigators found no relationship between medications (narcotics, sleeping aids, antidepressants, and anxiolytics) and cardiovascular mortality. Interestingly, narcotics were related to higher overall (HR = 2.79, 95% CI 1.81–4.31) and cancer-related death (HR = 5.36, 95% CI 2.52–11.4), but not to CVD-related death (HR = 1.24, 95% CI 0.38–4.02). Ultimately, the study concluded that increased risk of CVD-related death and all-cause mortality in WSP patients is independent of age, gender, physical activity, medication use, and cardiovascular risk factors. Careful examination of the methods and results of this study identifies some limitations. First, the pain assessment and definition of WSP differ from those used in previous studies. In essence, due to the controversial nature of the definitions, the authors fail to define the terms precisely in the manuscript. Assessment of joint pain in the FHS did not include temporal aspects of pain (acute vs. chronic), its severity, or the underlying pathophysiology (i.e. degeneration, rheumatic disease, post-trauma, etc.). Also, fibromyalgia, which could be seen as an important form of chronic WSP, is not explicitly used as a disease entity in the study. This is clinically relevant because research has shown that women suffering from the former have higher cardiovascular risks, but this is due to lack of physical activity.13 However, a systemic review by Chamizo did not find increased morbidity in this patient population due to CVD or infections.14 Furthermore, a study by Wolfe et al. found that mortality in this population was not necessarily increased, but there was a higher risk of death due to suicide and accidents.2 Additionally, potentially confounding variables including psychological factors, socio-economic status (income, education), and lifestyle were not included in the analysis, as the impact of those variables on CVD-related mortality is unclear. The modest increase in all-cause mortality (16%) vs. the pronounced increase in CVD death (46%) in the WSP group may also be due to cause of death redistribution rather than high CVD death. Moreover, mortality in those with WSP, adjusted for age and gender, had a P-value of 0.051, indicating a trend rather than actual statistical significance. The FHS is the cornerstone of epidemiological studies in defining CVD risk factors and their effects on survival. Nonetheless, results must be interpreted with extreme caution in generalizing the findings of the FHS across different populations. Much remains to be discovered about the effects of non-traditional cardiovascular risk factors and their long-term impact on morbidity and mortality. Recent studies from a large international registry have shown that psychological stimuli that induce a stress response are associated with a neurohormonal cascade of events which can produce catastrophic cardiovascular outcomes such as myocardial infarction.15 It is entirely plausible that in, for example, inflammatory diseases (i.e. rheumatoid arthritis), chronic pain could act as a physical stressor, activating molecular pathways responsible for adverse impact on the cardiovascular system. Therefore, a subanalysis of this study of patients with active rheumatoid arthritis and the utilization of inflammatory biomarkers to determine disease activity would have better elucidated the correlation of pain vs. inflammation and CVD. Therefore, it is not far fetched that not only well-known risk factors including coronary artery disease, hypertension, and diabetes, but also downstream pathophysiological processes associated with chronic pain states including WSP could substantially impact cardiovascular function. While the findings remain controversial, the study by Tesarz et al. advances our knowledge particularly on WSP and its cardiovascular impact.12 Leveraging on a large population-based cohort with particularly detailed documentation, the study identifies an association between WSP and mortality, in particular CVD death. Although the effect of WSP is not strong in an absolute sense, a large number of patients suffer from WSP, which could nonetheless result in a significant increase in CVD. While this association could be due to co-existing confounders in patients with WSP, future research should explore biological pathways activated in chronic pain syndromes which can adversely impact cardiovascular health. As such, while current society guidelines do not consider non-traditional variables such as emotional stressors and/or WSP as cardiovascular risk factors, future studies designed to include these factors may provide new evidence-based guidelines and suggest whether therapies for WSP could ameliorate cardiovascular risk. Conflict of interest: none declared.