Introduction

Frailty is a common clinical syndrome characterized by an underlying state of decline in reserve and function due to multisystem dysfunction [1, 2]. Frailty mainly manifests as the vulnerability to internal and external stress and the subsequent inability to restore to previous functional state. This means that even a small disturbance can render the older persons at risk of multiple adverse health outcomes, such as faster functional decline, prolonged hospitalizations, disability, higher health care-related expenses, and higher mortality rates [2,3,4,5]. Currently, there is no existing consensus regarding a standard definition of frailty. However, the frailty phenotype and deficits accumulation model has been extensively validated and widely used to conceptualize frailty. Fried et al. [5] characterized frailty as a purely physical condition of multisystem physiological dysregulation consisting of the presence of three or more of the following five components: weight loss, exhaustion, weakness, slow walking speed, and low physical activity. However, Rockwood et al. [6] defined frailty as predominantly an accumulation of deficits in various areas (symptoms, signs, functional impairment, and laboratory abnormalities). Beyond these two common definitions of frailty, several variations on the diagnostic criteria for frailty have also been developed [7]. Considering the dynamic nature of frailty and its development over time, many definitions also point out an identifiable intermediate stage between frail and non-frail known as prefrailty [8].

Studies have shown that the prevalence of pain in older adults increases with age [9]. Many older adults may have to spend most of their older age tackling the consequences of multiple chronic conditions. Among them, chronic pain is one of the most prevalent and burdensome in later life and it frequently leads to deleterious outcomes, including serious disability from reduced mobility, fall, depression, anxiety, sleep interference, isolation and sarcopenia [9,10,11]. Growing evidence suggests pain-related health consequences is linked to frailty onset and progression [12,13,14,15,16,17,18,19,20,21,22,23]. Chronic pain can be addressed through appropriate approaches, which represents one of the modifiable factors in improving frailty situation or reversing frailty status [9, 11, 24, 25]. The association between pain and frailty was not straightforward: some studies demonstrated that pain could act as a risk factor in increased frailty incidences [12,13,14,15,16,17,18,19,20,21,22,23], while other studies showed that pain is a consequence of frailty [24, 26, 27]. Since pain is a treatable condition, elucidating the association between pain and frailty can pave the way for the prevention, deceleration of progression, or even reversing the course of frailty among older people.

Therefore, the aims of our study were: (1) to perform a systematic review and meta-analysis of all studies regarding the prevalence of chronic pain and frailty and; (2) to perform a systematic review and meta-analysis of prospective studies regarding the longitudinal association between chronic pain and frailty among older persons.

Methods

The systematic review was reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Table S1) [28].

Data sources and search strategy

We first conducted a systematic literature search in Embase, Medline, Pubmed and Cochrane library via Ovid SP for observational studies from inception through the end of March 2020 without language restrictions. The keywords were chosen by examining other reviews on similar topics. The detailed search strategies are reported in Table S2. Moreover, references from the selected studies and other relevant reviews were also manually checked to determine their fit for potential candidates as selected studies.

Selection criteria

The titles and abstracts of all the selected articles in the initial search were screened independently by two reviewers (T. Lin and Y. Zhao). If either reviewer thought further evaluation was needed after the abstract screening, a full-text review was carried out against our selection criteria. Any discrepancy regarding the screening and selection of studies or the following extraction of data was resolved through consensus with a third independent reviewer (J. Yue).

Selection criteria were presented as follows: (1) cross-sectional and longitudinal studies that reported information on any of the above-mentioned aims were included; (2) studies reported the association between frailty and chronic pain in individuals aged 60 or older were included. Studies were excluded if: (1) individuals suffering from oncological, acute, or postoperative pain; (2) frailty was defined only with an indicator measurement (timed up-and-go test or gait speed); (3) they were case reports, letters, comments or editorials. When multiple studies used the same cohort, the study on the largest number of participants was selected.

Many cohort studies investigated the longitudinal relationship between frailty and chronic pain. And if the studies also reported frailty/pre-frailty prevalence in chronic pain or chronic pain prevalence in those with frailty/pre-frailty, they were also reported as cross-sectional and their relevant data were extracted.

Data extraction

The following items were extracted independently by two reviewers (T. Lin and X. Xia) from the eligible studies. A third reviewer (N. Ge) reviewed the data extraction, and any disagreement was resolved through consensus. The items included in the data extraction were as follows: the basic information of articles (the first author name, publication year, and cohort name), study design, location, cohort size, female proportion, mean age, follow-up period, the prevalence of frailty/pre-frailty in chronic pain and pain prevalence in frailty/prefrailty older adults, effect measures of interest, pain assessment method and frailty definition. Effect measures adjusted for confounders, such as age and gender, would be included with priority. When an article provided several adjusted models, the model that adjusted for the largest number of confounders was extracted. If the estimates of ORs concerning the association between frailty and chronic pain was not reported in the original study, the relevant data included in the article were used to calculate an unadjusted effect measure.

Quality assessment

The methodological quality of the studies was evaluated independently by the two authors (T. Lin and Y. Zhao) using the Newcastle–Ottawa Scale (NOS) [29]. For observational studies, this validated assessment tool utilizes nine multiple-choice items covering three main domains: the selection of the cohort, comparability of the groups, and quality of the outcomes. The scale scores ranged from 0 to 9 points. Score ≥7 was classified as high quality, 5–7 point as moderate quality, and 4 or less indicated low quality.

Statistical analysis

All statistical analyses were performed using the metan and metainf packages in the STATA/SE (version15.1, Stata Corp, College Station, TX, USA). Two-tailed P value < 0.05 was considered statistically significant. Considering the observational design of the included studies, and the methodological differences that might have contributed to a significant share of the variance within the measures of interest, we obtained the pooled estimates through random effect models and Mantel–Haenszel weighting. Heterogeneity across the studies was assessed using the I2 statistics (significant if I2 ≥ 50%) [30]. Subgroup analysis based on different population was conducted to explore the stratified prevalence of frailty and chronic pain. Sensitivity analysis was performed by omitting each study to check the impact of individual study on the overall results. To limit the impact of extremes or outliers, we also performed sensitivity analyses which excluded studies with small sample sizes (≤ 500 participants, considering that studies with larger sample sizes are more likely to represent the general population. Publication bias was assessed using a funnel plot and Egger’s test (linear regression method) [31].

Results

Literature search

Figure 1 shows the PRISMA flow diagram presenting the literature search as well as the number and reason for study exclusion. The initial search identified 844 records, and the manual review of the references yielded 2 eligible studies. 712 studies were retained after duplications were removed. After screening the titles and abstracts, 638 studies failed our selection criteria, leaving 74 studies for full-text review. Among them, 38 studies were excluded for the following reasons: (1). they did not investigate the aims of the review; (2). they did not provide an explicit definition of frailty or evaluated with a single measure; (3). the pain definition was unreported; (4). they were conference abstracts and there were no complete data. Ultimately, 36 articles were selected for the review and 24 studies were eligible to be assessed for methodological quality and perform the meta-analyses.

Fig. 1
figure 1

PRISMA flow chart for selection of papers for systematic review

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Study characteristics

The characteristics of the 24 included studies [12,13,14,15,16,17,18,19,20,21,22,23,24, 26, 32,33,34,35,36,37,38,39,40,41] were summarized in Table 1. The studies involved 39,370 older adults from 13 countries with six studies from North America, two from South America, eight from Europe, three from China, two from Australia and Japan. 22 studies involved community-dwelling older adults, one study [35] enrolled in nursing home individuals, and one study [40] included older adults with HIV. Frailty was defined based on the original or modified version of the Fried phenotype in 17 studies [13,14,15,16, 19, 21,22,23, 26, 32, 34,35,36,37,38, 40, 41], three studies [17, 18, 23] used the Frailty Index (the number of deficits used ranged from 33 to 51), and one study [12] used both methods, whereas another 4 studies used FRAIL scale (n = 2) [23, 39], SOF frailty index (n = 1) [20] and Kihon Checklist (n = 1) [33]. Pain was assessed using different methods among the included studies. Most of them applied a simple question for pain evaluation: “Have you experience chronic pain lasting for several months?” Only nine studies defined pain intensity on a scale, and another seven studies defined specific locations of pain (knee, hip or hand pain). The NOS scores were presented in Table S3.

Table 1 Characteristics of the observational studies on frailty and chronic pain among older persons
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Cross-sectional association between chronic pain and frailty

Table 1 summarized the cross-sectional prevalence data from all 24 studies [12,13,14,15,16,17,18,19,20,21,22,23,24, 26, 32,33,34,35,36,37,38,39,40,41] on the association between chronic pain and frailty. One study [34] provided specific results concerning the relationship between analgesic use and frailty in community-dwelling older people. For this study, only data on the duration of pain lasting at least 3 months were extracted for our purpose. Another study [40] evaluated frailty and its association with health-related quality of life in older people with HIV. For this study, only data on chronic bodily pain and frailty were extracted. The pooled prevalence in individuals with chronic pain was 18% (95% CI 14–23%; I2 = 98.7%) for frailty (derived from 23 studies; Fig. 2) and 43% (95% CI 36–51%; I2 = 98.2%) for prefrailty (derived from 16 studies; Fig. S1). The pooled prevalence of chronic pain was 50% (derived from 17 studies; Fig. 3) among individuals with frailty (95% CI 45–55%; I2 = 88.3%) and 37% (derived from 13 studies; Fig. S2) among those with prefrailty (95% CI 31–42%; I2 = 97.1%). As high heterogeneity was observed across the above meta-analyses, we limited the analyses to studies with at least 500 participants and the estimates and heterogeneity only changed minimally (data not shown). Additionally, a sensitivity analysis suggested that no individual study significantly affected the pooled prevalence of frailty in pain. We also conducted subgroup analyses based on different population settings to investigate the stratified prevalence of frailty/prefrailty in older persons with chronic pain and the prevalence of chronic pain among older adults with frailty/prefrailty. Results revealed that older persons from a nursing home or suffering from HIV were more susceptible to frailty or a combination of chronic pain. Results also revealed a lack of statistical significance existing between different sub-groups (Supplementary Fig. S3, 4, 5, and 6).

Fig. 2
figure 2

Prevalence of chronic pain participants with frailty

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Fig. 3
figure 3

Prevalence of frail participants with chronic pain

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Longitudinal association between chronic pain and frailty

Table 1 summarizes the 12 studies [12,13,14,15,16,17,18,19,20,21,22,23] (a total sample of 27,004 community-dwelling older persons) that evaluated the longitudinal association between chronic pain and the risks for frailty occurrence during the follow-up period. Ten studies [12,13,14, 16,17,18, 20,21,22,23] included in this review provided ORs with multiple confounders adjusted of frailty risks for pain. Two studies [15, 19] did not report relevant effect measures and unadjusted ORs were calculated according to study data. As shown in Fig. 4, non-frail participants who reported chronic pain were 1.85 (95% CI 1.49–2.28; I2 = 93.2%) times more likely to develop frailty after an average follow-up of 5.8 years compared to those who reported no chronic pain. This finding revealed that chronic pain at baseline is a risk factor for frailty incidence. As higher heterogeneity was observed across these studies, we performed a sensitivity analysis by omitting every single study and no statistical significance changed (Fig. S7). The asymmetric funnel plot (Fig. S8) and Egger’s test (P = 0.002) suggested the existence of publication bias or between-study heterogeneity.

Fig. 4
figure 4

Meta-analysis for the longitudinal association between baseline chronic pain and the risks for frailty occurrence

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One study [14] with all 1705 older men analyzed the longitudinal association between frailty status at baseline and the risk of chronic pain in the future. In multi-adjusted models, those with baseline frailty did not independently increase the risk of developing chronic (OR = 0.82; 95% CI 0.38–1.79) or intrusive pain (OR = 1.38; 95% CI 0.70–2.74). Conversely, this study established that the presence of chronic pain had an increased likelihood of developing frailty among community-dwelling older men (OR = 1.60; 95% CI 1.02–2.51), even after adjusting for potential confounders.

Discussion

This systematic review and meta-analysis revealed that 5 out of 10 frail older adults have chronic pain, while about 2 out of 11 of older persons with chronic pain are frail. 37% of older persons with pre-frailty have chronic pain and 43% of older people with chronic pain present a condition of pre-frailty. The longitudinal studies found that baseline chronic pain increased the likelihood of developing frailty among older adults. Furthermore, only one study has been conducted to determine whether frailty predicts chronic pain incidence while failed to find a significant association between these two conditions.

When older patients suffer from the comorbidity of frailty and chronic pain, the treatment strategies might change. There are two reasons: first, frailty is related to limited life expectancy [42]. The evidence suggested that the expected years of life for frail individuals at age 70 ranged from 0.4 to 5.5 years (female) and 0.1–1.8 years (male) [42]. Treatment plans for those older persons with chronic pain and physical frailty require not only the formulation of tailored therapeutic approaches for chronic pain but also the emphasis of interventions with multidisciplinary physical frailty management [43,44,45,46]. Otherwise, the efficacy and process of pain management may be adversely affected by physical frailty [44, 45]. Second, the pain management strategies based on the existing evidence may not be suitable to be generalized for frail older persons with chronic pain, since older people with frailty usually do not participate in the clinical trials. This is extremely important when considering the observation that 50% of frail individuals studied also have chronic pain and 18% of persons with chronic pain are frail. To date, there have been no clinical trials of treatments for chronic pain which also considered the effects of frailty. Additionally, there are no clear guidelines that make any specific recommendations concerning treatments of chronic pain in frail older persons [9, 46].

Chronic pain and frailty share several mechanisms including sedentary behaviors, malnutrition, and sleep impairment [2, 4, 9, 10]. Frailty is positively associated with sedentary behaviors [47]. Similarly, a sedentary lifestyle is a major contributor to muscle weakness, which in turn leads to further declines in activity levels and loss of muscle mass and strength, causing the development of sarcopenia [48]. Nevertheless, the fear-avoidance behavior in physical exercises leads to the formation of a sedentary lifestyle and the misleading common sense for treatment recommendations is to rest as much as possible, which can be a frequent problem among patients with chronic pain, gradually experiencing mobility impairments and slow gait speed [49, 50]. Both weight loss resulted from sarcopenia, and gait speed reductions are essential components for frailty [5]. In addition, it is well-known that unhealthy dietary behaviors can often be observed in patients with chronic pain [51]. In turn, emotional anxiety, depression, and social loneliness caused by chronic pain may lead to anorexia and even malnutrition [52]. These data emphasize the importance of considering frailty when making therapeutic regimens for chronic pain as well as the importance of developing tailored exercise programs and nutrition interventions for frail patients with chronic pain.

The meta-analysis of longitudinal studies showed a nearly two-fold increase in the likelihood of developing frailty in older adults affected by chronic pain compared with persons without after an average follow-up of 5.8 years. This observation is consistent with the results of a previous systematic review [53]. A possible explanation for our findings could be that chronic diseases, including chronic pain, are generally considered to be the determinants of frailty, and the adverse outcomes, such as disability and malnutrition, induced by chronic pain can result in frailty incidence [5]. It is estimated that 66% of older adults have at least two chronic conditions [54]. Thus, effective and tailored prevention strategies for comorbidity are crucial to reduce the overall disease burden.

Nonetheless, only one longitudinal study assessed the impact of frailty on the development of chronic pain, and no statistical significance was found. Lack of evidence does not mean a lack of significant association between these two conditions. Since there was only one cohort study included, we were unable to conduct a meta-analysis. This finding might be explained by the fact that frail individuals are associated with limited life expectancy and persons with frailty could be more likely to be lost in follow-up [42]. As a result, it is difficult to draw any firm conclusions about the causal association between baseline frailty and future chronic pain.

This study had several unique characteristics. It was the first systematic review and meta-analysis on the prevalence of frailty and prefrailty among older patients with chronic pain. Also, we conducted a comprehensive literature search and rigorous literature selection as well as methodological evaluation, providing a reliable review of the evidence concerning the association between frailty and chronic pain.

However, our study has some limitations. First, substantial heterogeneity was detected among the included studies, which could be explained by the lack of standard diagnostic methods for frailty and chronic pain and by the demographic discrepancies across studies. However, in the meta-analyses of observational studies, heterogeneity is often inevitable, and it does not necessarily invalidate the research results [55]. Second, only one longitudinal analyzed the association between frailty and the development of chronic pain, which limited the opportunity to conclude whether a causal association existed between frailty and chronic pain. Third, there are limited original studies examining the impact of chronic pain on cognitive, social, or psychological frailty. Therefore, more studies are needed to better understand the association between pain and types of frailty other than physical frailty.

Conclusion

We have found that non-frail older persons with chronic pain were more likely to experience physical frailty after an average follow-up of 5.8 years. We also found that frailty and prefrailty were common in older persons with chronic pain. Taken together, our findings suggest that early assessment and effective interventions of chronic pain may help reduce physical frailty and improve the quality of life. Future studies should explore the efficacy of different pain management strategies in reducing physical frailty and clarify the association of other types of frailty (cognitive, social and psychological) with chronic pain.