Risk Factors to Persistent Pain Following Musculoskeletal Injuries: A Systematic Literature Review

Background: Musculoskeletal (MSK) injury is one of the major causes of persistent pain. Objective: This systematic literature review explored the factors that lead to persistent pain following a MSK injury in the general population, including athletes. Methods: A primary literature search of five electronic databases was performed to identify cohort, prospective, and longitudinal trials. Studies of adults who diagnosed with a MSK injury, such as sprains, strains or trauma, were included. Results: Eighteen studies involving 5372 participants were included in this review. Participants’ ages ranged from 18–95 years. Most of the included studies were of prospective longitudinal design. Participants had a variety of MSK injuries (traumatic and non-traumatic) causing persistent pain. Multiple factors were identified as influencing the development of persistent pain following a MSK injury, including high pain intensity at baseline, post-traumatic stress syndrome, presence of medical comorbidities, and fear of movement. Scarcity of existing literature and the heterogeneity of the studies made meta-analysis not possible. Conclusions: This systematic review highlighted factors that might help predict persistent pain and disability following MSK injury in the general population, including athletes. Identification of these factors may help clinicians and other health care providers prevent the development of persistent pain following a MSK injury.


Introduction
Musculoskeletal (MSK) pain conditions are very common and are one of the top 20 causes for years lived with disabilities globally [1]. MSK injuries are one of the major causes of persistent pain leading to disabilities and high disease burden [2]. Persistent pain after MSK injury is not only common in the general population but also in athletes, leading to disability and time lost from sports activities [3]. Persistent pain is defined as pain that persists for three to six months following onset, according to the International Association for the Study of Pain [4]. It has been reported that only a small percentage of people will be free of pain following MSK trauma [5]. For that reason, the development of persistent pain following MSK injuries in the general population has been the subject of a number of studies [5][6][7], with one study finding that up to 48% develop chronic pain after traumatic MSK injuries, and a combination of social and medical risk factors identified in the development of chronic pain [5].
In sport-related MSK injuries, a recent scoping review explored the psychological, social, and contextual factors across recovery stages following a sport-related knee injury, finding a broad spectrum of psychological, social, and contextual factors that influenced recovery [8]. It was suggested in this review that athletes who suffered a sport-related knee injury experienced fear/anxiety as well as other barriers to recovery, most predominantly at the return to sport. It was also suggested that psychological, social, and contextual factors influencing recovery were dynamic over the stages of recovery. Central sensitization and psychosocial variables have also been considered to be explanatory factors for persistent pain after MSK injury [9,10].
The limited success seen for the management of persistent pain following MSK injuries in the general population underscores the need for strategies to prevent the development of persistent pain. In order to do this, it is important to understand the factors that contribute to the transition from acute to chronic pain following MSK injury. Therefore, the current systematic review explored the factors that lead to persistent pain following acute MSK injury in the general population. This will be the first step towards focusing on preventing persistent pain and shifting the focus towards prevention of chronicity following musculoskeletal injuries. The study findings may help identify modifiable factors to help prevent chronicity following MSK injury. Additionally, the current systematic review investigated the intrinsic factors (i.e., anatomical and psychological) and extrinsic factors (i.e., social and environmental) that predict the transition from acute to persistent pain state in individuals following MSK injury.

Materials and Methods
The search strategy was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [11].

Search Strategy
A primary literature search of five electronic databases was performed to extract data from prospective and retrospective cohort studies. The search strategy was prepared by an information specialist from the Erasmus Medical Centre in Rotterdam, The Netherlands. Electronic databases, including MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, ProQuest, and Web of Science, were searched from their inception to June 2020. The reference lists of eligible studies and relevant systematic reviews were screened for additional articles. In addition, experts in the field were contacted to identify unpublished studies and corresponding authors from the included articles were, when necessary, consulted in order to clarify any missing data.

Selection Criteria
To systematically select studies, inclusion and exclusion criteria were developed a priori and were applied in three stages. In stage one, identified studies were exported into Covidence, an online systematic review-management platform, where two investigators (O.A. and P.A.) independently reviewed the titles and abstracts against predefined criteria. In stage two, relevant full text articles were retrieved and independently reviewed by two investigators (O.A. and P.A.) to determine their eligibility. The final stage involved screening the included full text studies to exclude unrelated studies. In the event where agreement could not be reached, a third investigator (H.S.) was consulted.
The literature search was conducted using the following criteria: (1) population: adults who had sustained a MSK injury, (2) types of studies: observational studies (retrospective, prospective, cross-sectional, and longitudinal studies), and (3) outcome of interest: pain following injury. Reviews, case reports, and studies that examined the epidemiology, examination, and treatment were excluded. No restriction was placed on language or date of publication. Adults over 18 years who had been diagnosed with injuries such as sprains, strains, or trauma through impact or fall were included. Individuals who presented at baseline with chronic pain or pain as a result of surgery or non-MSK injury were excluded. Studies were included when they examined outcomes associated with the measurement of pain and the factors associated with the development of acute to chronic pain.

Data Extraction
A data-extraction form was developed for the purposes of this review. Data extraction included the following information: (1) study characteristics (authors, year of publication, and study design); (2) participant characteristics (number of participants at enrollment and follow-up, demographic information, and injury characteristics); (3) risk factors identified; (4) outcomes measured; (5) estimates of risk factors and persistent pain (e.g., odd radios (ORs)); and (6) authors' conclusions. Kappa statistics were used to assess agreement between the two investigators on inclusion at each stage of the review.

Quality Assessment
The methodological quality of each included study was assessed using the Quality in Prognosis (QUIP) checklist, which comprises six important domains (i.e., participation, prognostic factor measurement, attrition, outcome measurement, confounding measurement, and analysis and reporting) for assessing validity and risk of bias in prognostic studies [12][13][14]. Therefore, the current systematic review used the QUIP checklist to assess risk of bias in the included studies. Two independent investigators (O.A. and P.A.) evaluated the included studies based on these criteria [13]. The checklist items were evaluated independently as either 'Identified' (1 point) or 'Not identified' (0 point) by investigators and then discussed to reach consensus. If an agreement between the two investigators could not be met, a third investigator (HS) was consulted. The points from the QUIP checklist were totaled, and studies were considered as having low risk of bias if they were found to be of high quality (score ≥ 17/22) and high risk of bias if they were found to be of low quality (score ≤ 16/22), with this near the 80% quality cut-off point [14].

Study Selection and Characteristics
Out of 4022 identified studies, six duplicates were removed ( Figure 1). Out of the remaining 4016 studies, 3942 studies were excluded during title and abstract screening. Out of 74 full-text studies, 56 studies did not meet the inclusion criteria. Finally, a total of 18 studies involving 5372 participants were included in this systematic review. Two independent investigators (O.A. and P.A.) examined the relevant articles and short-listed as per a priori risk-of-bias criteria. Table 1 presents study characteristics, such as authors' names, country of study, study design, and sample size. Included studies originated from Australia [15][16][17][18], United States [19][20][21], Canada [22,23], Denmark [24], Germany [25], The Netherlands [26,27], Sweden [28,29], Spain [30], and United Kingdom [31,32]. Participants' ages ranged from 18-92 years. Most of the included studies used a prospective longitudinal design, only one study was cross-sectional in nature [15]. Participants in the included studies had various of MSK injuries (traumatic and non-traumatic MSK) that led to persistent pain. Minimum and maximum follow-up periods were one week [26] and five years [21], respectively. Most of the included studies measured pain intensity using a numerical rating scale (NRS) [16,17,24,26,27], while three studies used a visual analogue scale [18,30,31]. Sample sizes of the included studies ranged between 66 [21] and 1290 [18]. (NRS) [16,17,24,26,27], while three studies used a visual analogue scale [18,30,31]. Sample sizes of the included studies ranged between 66 [21] and 1290 [18].  Table 2 presents the quality scores from each of the included trials. The risk-of-bias assessment, conducted by the two investigators, was found to be reliable (kappa coefficient = 0.85). Risk of bias was assessed separately for the six QUIP factors. More than 70% of included studies had a low risk of bias for most of the QUIP. Five studies had a high risk of bias for factor 2 and six studies for factor 5. Four studies had a moderate risk of bias for factor 2. Figure 2 presents the assessors' judgments about the risk of bias for each QUIP factor presented as percentages across all included studies. Studies were considered with low quality if most criteria were not met, or significant flaws relating to key aspects of study design were evident. Five studies with low quality [15,20,25,30,31] were not included in the narrative synthesis of the results.   Table 2 presents the quality scores from each of the included trials. The risk-of-bias assessment, conducted by the two investigators, was found to be reliable (kappa coefficient = 0.85). Risk of bias was assessed separately for the six QUIP factors. More than 70% of included studies had a low risk of bias for most of the QUIP. Five studies had a high risk of bias for factor 2 and six studies for factor 5. Four studies had a moderate risk of bias for factor 2. Figure 2 presents the assessors' judgments about the risk of bias for each QUIP factor presented as percentages across all included studies. Studies were considered with low quality if most criteria were not met, or significant flaws relating to key aspects of study design were evident. Five studies with low quality [15,20,25,30,31] were not included in the narrative synthesis of the results.  Overall +++ +++ ++ ++ +++ ++ + ++ + +++ ++ +++ ++ +++ ++ + + + H: High bias; M: Medium Bias; and L: Low Bias. High quality (+++): Majority of criteria met, little or no risk of bias. Results unlikely to be changed by further research. Acceptable (++): Most criteria met. Some flaws in the study with an associated risk of bias, Conclusions may change in the light of further studies. Low quality (+): Either most criteria not met, or significant flaws relating to key aspects of study design.

Risk Factors for Persistent Pain
Multiple risk factors for developing persistent pain following MSK injury were identified. However, due to the between-study heterogenicity and the limited number of studies examining each risk factor, it was not possible to run a meta-analysis of the results. Therefore, a narrative synthesis of results was conducted. Table 3 presents details of risk factors contributing to persistent pain following MSK injuries as identified through this systematic review.

Risk Factors for Persistent Pain
Multiple risk factors for developing persistent pain following MSK injury were identified. However, due to the between-study heterogenicity and the limited number of studies examining each risk factor, it was not possible to run a meta-analysis of the results. Therefore, a narrative synthesis of results was conducted. Table 3 presents details of risk factors contributing to persistent pain following MSK injuries as identified through this systematic review.
Age was found to be a significant risk factor for developing chronic pain after MSK injury in a study by Pierik, IJzerman et al. [26].
Initial pain severity was reported as a risk factor for the development of chronic pain in three studies [16,17,19]. Pain at the time of discharge from hospital after traumatic MSK injury predicted the development of chronic pain in one study [28]. The severity of the MSK injury was found to predict the course of pain in MSK injuries [26].
One study reported that the presence of comorbidities predicted chronic pain after MSK injury [28]. In this study, comorbidities were defined as having three or more chronic medical conditions (e.g., diabetes, and hypertension). A low level of physical activity was reported to be a predictor of chronic pain in MSK injuries in two studies [21,28]. One study demonstrated that the level of education and eligibility for compensation following MSK injury may act as risk factors for the development of chronic pain [21].
The presence of post-traumatic stress disorder was shown to be a risk factor for developing chronic pain following MSK injury in one study [25]. One study reported that fear avoidance and catastrophizing may be risk factors for chronic pain [27]. In a sample of patients after distal radius fractures, Ref. [26] reported that depression was a significant risk factor for slowing recovery after the injury. Fear of movement and fear of (re)injury Pain acceptance Patients with support from significant others and lower levels of fear of movement and better outcome predictions were associated with better outcomes at the 1 year follow-up than those without. The deleterious effects of neuropathic pain were seen in the 32% of young trauma patients who had symptoms of neuropathic pain 4 months after injury. The pain interfered significantly with their daily living, employment, mood, sleep, and enjoyment of life. Self-reported pre-injury, pain-related disability, and moderate or severe pain at discharge from the acute hospital were found to be independent predictors of moderate or severe pain at 6 months post-injury.

Discussion
This systematic review explored the factors that contribute to persistent pain following acute MSK injury in the general population. Many of the included studies identified persistent pain following MSK injury. Similarly, Rosenbloom et al. [2] reviewed 11 studies and they concluded high prevalence of persistent pain following traumatic musculoskeletal injury. The results highlighted several modifiable and non-modifiable risk factors leading to chronicity in patients who experienced a MSK injury. The results of this study contribute to the body of knowledge on factors leading to persistent pain following MSK injuries that will help guiding prevention strategies to reduce the burden of these conditions.
Comparing our results to previous research, many of the studies included in this review identified persistent pain following MSK injury [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Personal factors such as age, which is considered to be a non-modifiable factor, have reported association with persistent pain. Most of the studies included in the current review reported that the prevalence of persistent pain following MSK injury was more common in those of middle age. In contrast, a previous review identified older age as one of the predicting factors for persistent pain following MSK injury [2]. The reason for this is not clear because heterogeneity in the study design and methodology precludes direct comparison. For instance, four included studies in this review had reported persistent pain following musculoskeletal injuries in more than 60% of female patients. Likewise, a previous study reported high risk of chronic pain following trauma in female patients [34].
Our finding that persistent pain after MSK injury was associated with a group of modifiable factors, including high intensity of pain, pain-catastrophizing, fear-avoidance beliefs, and post-traumatic stress symptoms, is similar to that of a previous review which identified predictive factors including initial pain, anxiety and depression, fear-avoidance, and patient perception for persistent pain [2]. Another study reported high risk of persistent pain in patient with high levels of general anxiety and post-traumatic stress symptoms [22]. Moreover, several studies had reported a positive relationship between post-traumatic stress symptoms and chronic pain [35][36][37][38].
Other modifiable risk factors identified in the current review for developing persistent pain after MSK injury included total abbreviated injury score, initial pain severity, and initial pain control attitudes, which concur with previous studies. Similarly, other studies reported several risk factors of pain progression in traumatic patients [3,39]. Some of the factors are present at the time of admission (e.g., injury pattern and type, anxiety and depression), some are present during hospitalization (e.g., pain intensity, type of surgery, treatment strategies, and hospital-stay duration), while others are present at the time of discharge (e.g., anxiety and depression, post-traumatic stress symptoms, and pain catastrophizing) [2,3,40,41].
None of the studies included in this review investigated or reported risk factors for persistent pain following a sport MSK injury. Therefore, there is a need for more research to understand the transition from acute to chronic pain following sports MSK injury, preferentially applying a broad biopsychosocial perspective and sport-related perspectives for identifying potential risk factors. This will inform health and medical programs at all levels (preventive, primary, secondary, and tertiary) in order to reduce disability following MSK injuries.
The current review had several strengths as well as limitations. Strengths included the screening of five electronic databases by two independent investigators, the search strategy which was prepared by a specialized and independent information specialist, the risk-of-bias assessment performed by two independent investigators, the high interrater reliability of the risk-of-bias assessment, the compliance with the international standards for conducting and reporting systematic literature reviews (i.e., the PRISMA guidelines) and the detailed and thorough data processing. Hence, all efforts were undertaken to optimize the internal and external validity of the study findings, yet some study limitations should be mentioned. First, heterogeneity in the included studies prevented the ability to directly compare various factors causing persistent pain following MSK injury. Second, most of the included studies in this review were cross-sectional in nature, preventing the ability to conduct a cause-and-effect analysis. Finally, a relatively small number of studies (n = 11) were included in this review due to the scarcity of studies that fulfil the inclusion criteria. Therefore, more studies using larger and more homogenous study populations are warranted to further identify various predictors of persistent pain following MSK injury in the adult general population.

Conclusions
There are multiple factors causing persistent pain following MSK injury in the general population. These factors include high intensity of pain, pain-catastrophizing, fearavoidance beliefs, depression, presence of comorbidities, and post-traumatic stress symptoms. Clinicians and other health care providers may focus on preventing persistent pain and shifting the focus towards prevention of chronicity following an injury.