Determinants of complex regional pain syndrome type I in patients with scaphoid waist fracture- a multicenter prospective observational study

Complex regional pain syndrome type I is a chronic pain condition, which characterized by spontaneous abnormal pain intensity and duration. In two population-based studies performed in North America [1] and Europe [2], the incidence of CRPS I was 5.5 and 26.2 per 100,000 person-years, respectively. The common symptoms of CRPS I include abnormal sensation, vasomotor edema changes, and motor dysfunction [3]. The clinical signs include four categories: the evidence of sensory; vasomotor; edema and trophic. The diagnosis of CRPS I involves the presence of at least two clinical signs included in the four categories and at least three symptoms in its four categories [4]. Previous studies [5] reported that trauma was the most common events of CRPS I and the athletes can be easily affected by CRPS I because of exposure to traumatic or overuse injuries [6]. The causes of CRPS I are unclear. Evans et.al [4] reported that an excess of afferential input related to the damaged tissue could start a chain of activation involving sympathetic neurons. The activity of sympathetic postganglionic fibers could produce spasms of the arteries and therefore ischemia with increased capillary filtration pressure, edema and swelling. Generally speaking, comprehensive approach maybe more suitable for CRPS I, including pharmacological therapy, physical therapy, therapeutic exercise, and neurorehabilitation, psychological and educational interventions [4]. The timing of the pharmacological intervention is important for treatment outcomes. Prednisolone might be useful for the treatment of CRPS and vitamin C could work as a preventive strategy [7].

According to the authors’ clinical experience, CRPS I may develop after scaphoid fractures, which was also be reported in previous studies [8‐10]. Distal radius fracture was the most common induced event of CRPS I and it was also the most commonly encountered associated injury of scaphoid fracture [11]. However, few studies have focused on the incidence of CRPS I in scaphoid fractures patients, most articles mainly focus on the wrist fracture, which was includes multiple fracture types [10]. In addition, exploring the risk factors for CRPS I is important, which helps clinicians establish prevention measures and alleviate the discomfort of patients.

The aim of the study was to assess the incidence of CRPS I in patients with scaphoid waist fractures and to explore the associated factors.

A total of 743 participants were screened for eligibility, of whom 190 (33.6%) patients were excluded. 553 participants were recruited in this study. A total of 493 (89%) patients, including 295 male and 198 female patients, completed the 1-year follow-up. The mean age was 50.3 ± 4.2 years. The mean time interval from injury to conservative treatment was 3 days. The average time between injury and the onset of CRPS I was 6.7 ± 2.1 weeks. In this study, the results of the Budapest criteria demonstrated that 87 (20%) patients presented with CRPS I.

The demographic and clinical characteristics are summarized in Tables 1 and 2. The factors associated with CRPS I were gender (p = 0.031), type of trauma (p = 0.035), diabetes mellitus (p = 0.005), pain condition before treatment (p = 0.001), anxiety (p < 0.001), SF-12 mental points (p < 0.001), and PRWE pain points (p = 0.003). These parameters were included in multivariable logistic analysis to identify the independently associated factors of developing CRPS I in scaphoid waist fracture. Female sex (OR: 1.669; 95% CI: 1.189–2.338), diabetes mellitus (OR: 3.206; 95% CI: 2.284–4.492), severe pain condition before treatment (VAS more than 4 cm) (OR: 27.966; 95% CI: 2.323–6.151) were independently associated with CRPS I (Table 3).

Scaphoid fracture is a frequent and common carpal fracture and accounts for 2 to 7% of all fractures [13]. Young people are the most affected population [13]. However, chronic pain conditions may occur after the treatment, which could potentially disable patients for an extended time. Chronic pain conditions may be caused by some surgical factors, such as nonunion and malunion, but in most chronic pain cases no obvious cause can be found. The presence of CRPS I is one of the major underlying causes of chronic pain conditions [25].

In total, 438 patients were recruited consecutively and completed the 1-year follow-up. The incidence of CRPS I in this study was 20%, which is lower than that in distal radius fracture patients (32.2%) [26]. The disparity of diagnostic criteria could partly explain this difference. Veldman criteria and Budapest Diagnostic Criteria were used in the two studies. The incidence of CRPS1 is greatly affected by the diagnostic criteria of CRPS1.The results of Annemerle Beerthuizen et al. [10] indicate that Budapest criteria are recommended in future studies on CRPS1. In fact, diagnosing CRPS I remains challenging in the absence of a uniform criterion standard. Another possible explanation of this lower incidence is the difference in fracture types. Our studies only included scaphoid waist fracture patients. Previous studies [10] have reported that intra-articular fracture patients seem to have a higher chance of developing CRPS1.

In our study, no significant difference was observed in wrist function of two groups, which could be partly explained by the characteristics of the disease. CRPS is a syndrome characterized by a continuing regional pain which is seemingly disproportionate in time or severity to the trauma events [4]. In this study, the statistically significant results of anxiety and mental aspect of SF12 were observed. High preoperative anxiety levels have been verified as a predictive index of the CRPS I following total knee arthroplasty [27]. Female sex, diabetes mellitus, and severe pain condition before treatment were independent risk factors for the development of CRPS I. Female sex has been identified as the risk factors for CRPS I by many studies [28‐31]. Previous studies reported that CRPS I seems to be more prevalent in women, and the incidence of women was of 2–4 times that of men [28‐31]. Women, especially postmenopausal women, have low vitamin D levels. Vitamin D deficiency is related to neuropathic pain. Sang-Uk Lee et al. [32] reported that the reason why the women’s incidence of CRPS I is higher than men’s may be that neuropathic pain is associated with the low vitamin D levels frequently found in post-menopausal women. Yesil et al. [33] reported that rheumatoid arthritis patients with serum vitamin D levels below 20 ng/mL exhibit an increased prevalence of neuropathic pain compared with patients with vitamin D values 30 ng/mL or over (5.8:1). Therefore, early screening of pain conditions is vital for female patients.

In our study, diabetes mellitus was independently associated with CRPS I. Many studies have reported that diabetes mellitus is highly related to CRPS occurrence [34, 35]. Pro-inflammatory cytokines, including interleukin -1β, interleukin-6 and tumor necrosis factor-alpha, play an important role in the relationship of diabetes mellitus and CRPS I. Skin biopsy results show that the expression of pro-inflammatory cytokines was significantly higher in the upper extremities of CRPS-affected patients than in those of the unaffected patients [36, 37]. Pro-inflammatory cytokines which was derived from fat cells could lead to the resistance to insulin, while excessive fat cells promote the synthesis and secretion of pro-inflammatory cytokines [38]. In addition, Jong Ho Choi et al. [39] verified that higher HbA1c could be related to higher CRPS prevalence and that uncontrolled blood glucose could increase CRPS occurrence. Among the treatment of CRPS, it has always been a controversial issue whether physical therapy has a role for improving the clinical condition [40]. Diabetes mellitus was the risk factor of CRPS I. Our team believed that appropriate physical therapy can produce certain positive role in the prevention of CRPS I by decreasing the blood glucose [38].

In our study, a severe pain condition before treatment was also a risk factor for the development of CRPS I, which was almost identical to previous studies [10, 41] as reported by Barbara et al. [41] that reported that basal pain sensitivity and modulation vary widely in different patients. The sensitization of the nervous system could partly explain this phenomenon [42, 43]. Therefore, the baseline pain condition of fractures deserves more attention.

There are some potential limitations that should be considered. First, the assessment of psychological conditions (anxiety and depression) is controversial because the HADS is a screening tool rather than a clinical diagnostic tool. Second, convenient sampling was used as the sampling method in this study, which could result in a large random error in the estimated prevalence ratio. Third, the small sample size could reduce the generalizability of this study.

Patients suffering from scaphoid waist fracture may be at a higher risk of CRPS I, especially in women with diabetes mellitus who report severe pain before treatment. Early screening and regular follow up evaluation are recommended in these patients.