Complex regional pain syndrome (CRPS) is an incompletely understood sequela of orthopaedic trauma in which the predominant feature is pain that is out of proportion to the degree of the inciting injury. Multiple terms have been used to describe CRPS in the past, including reflex sympathetic dystrophy (RSD), Sudeck’s atrophy, and causalgia.

Similarly, different classification systems have been used to characterize CRPS, and the diagnostic criteria continue to evolve. The result is a marked heterogeneity in the scientific literature that makes clear interpretation of the clinical presentation, effective treatment methods, and functional outcomes of CRPS difficult.

Although much of the data regarding CRPS are murky, some information is generally accepted. Specifically, CRPS is characterized by a constellation of signs and symptoms that include the following:

• pain (hyperalgesia, and/or allodynia in a nondermatomal distribution)
• vasomotor instability, with resultant changes in the color and/or temperature of the affected limb
• movement abnormalities (decreased range of motion, motor weakness, tremor, or dystonia)
• swelling and/or asymmetry in the sweating pattern of the affected limb

In addition, trophic changes in the hair, nails, or skin may be observed (Fig. 1). Importantly, the diagnosis of CRPS is only made when no other diagnosis can explain the combination of clinical findings. An antecedent injury such as a fracture, sprain, crush injury, or surgery is identified in most patients. The upper limbs are affected more frequently than the lower limbs.

Although the diagnosis of CRPS is typically made clinically, diagnostic imaging—including radiographs, bone scans, and MRI—may be helpful. Findings typical of CRPS include periarticular osteopenia seen on plain radiographs and increased radionuclide uptake of the affected region on 3-phase bone scintigraphy.

Pathophysiology
The pathophysiology of CRPS is poorly understood, but multiple factors likely play a role. Proposed etiologies include an atypical, exaggerated local inflammatory response to musculoskeletal trauma and neurologic dysfunction, possibly as the result of nerve damage. Because the underlying cause of CRPS has not been firmly delineated, myriad treatment modalities have been employed with variable levels of clinical success.

Treatment options typically include physical therapy (aimed at regaining and/or maintaining range of motion and muscle strength, as well as symptom control through desensitization), pharmacotherapy (ranging from simple analgesics to anticonvulsants, narcotic pain relievers, and diphosphonate therapy), and more invasive interventions including spinal cord stimulation, sympathetic blockade, sympathectomy, and limb amputation.

A recent analysis of the efficacy of various treatments for CRPS revealed that physical therapy and pharmacotherapy with diphosphonates are generally effective. More invasive interventions such as regional sympathetic blockade and sympathectomy are not supported by strong evidence.

The ideal situation would be to prevent CRPS from developing. Some data support the use of vitamin C supplements for patients being treated for wrist fracture to prevent the subsequent development of CRPS.

Incidence and prevalence differences
CRPS is markedly more common in females than in males, with a relative risk estimated by some authors to be as high as 4:1. A recent study at the Mayo Clinic found that the overall incidence of CRPS per 100,000 person years was 5.46 (8.57 among females and 2.16 among males). Similarly, the prevalence of CRPS in this patient population was significantly higher among females at 35.33 per 100,000 person years compared to 5.06 per 100,000 person years in males.

A study from the Netherlands reported an overall higher incidence of CRPS in the general Dutch population (26.2 cases per 100,000 person years) than that found in the Mayo Clinic study, but again, females were disproportionately affected with an incidence rate of 40.4 in females and 11.9 in males, and with a reported relative risk of 3.4.

Interestingly, incidence rates for CRPS increase with age in both sexes, spiking dramatically in females older than 50 years. From these data the Dutch researchers hypothesized a “hormonal etiology” to CRPS, noting that most patients with CRPS were postmenarchal females.

Presentation differences
Although a well-defined sexual dimorphism in the incidence and prevalence of CRPS exists, males and females have similar clinical presentations. Both the Dutch and the Mayo Clinic studies reported similar mean age of onset—46.9 years in one and 52.7 years in the other. In both studies, onset in females occurred later than in males.

Additionally, a sex-based dimorphism in terms of symptom duration for CRPS has not been found, with the Mayo Clinic group reporting a similar mean duration of symptoms for males and females. Finally, no study has documented a difference in pattern of presentation of CRPS between the sexes.

Differences in management, outcomes
No significant difference between the sexes in terms of clinical outcomes has been found, with one study reporting symptom resolution in 74 percent of patients, irrespective of sex. When investigated independently, sex was not significantly associated with clinical outcome in patients with CRPS.

That said, the literature on CRPS has many limitations. Because CRPS is a rare and heterogeneous disorder, few scientific studies are able to generate enough power to determine whether a particular treatment modality is efficacious for any patient, regardless of sex. As a result, almost no researchers look specifically at sex as an independent variable when investigating the role that pharmacotherapy, physical therapy, or surgery may play in the treatment of patients with CRPS.

Conclusion
CRPS is a rare, poorly understood sequela of orthopaedic trauma. Its incidence and prevalence are significantly higher in females than in males, although the presentation of CRPS does not seem to differ significantly between the sexes nor do the treatment responses and clinical outcomes. Most patients achieve resolution of symptoms at an average of one year from onset.

Sex-specific physiologic differences that predispose females to the development of chronic pain disorders—including CRPS, fibromyalgia, temporomandibular disorders, and osteoarthritis of the knee—have not been fully elucidated, although the influence of sex hormones (estrogen status) has been hypothesized to play a role. Identifying sex as an independent variable in the study of patients with CRPS may yield valuable insight into the etiology, pathophysiology, and, ultimately, the treatment of this syndrome.

Erica Giles, BSc, is a medical student, and Cordelia W. Carter, MD, is a member of the AAOS Women’s Health Issues Advisory Board.

Bottom Line

• CRPS is a rare, poorly understood sequela of orthopaedic trauma.
• The incidence and prevalence of CRPS are significantly higher in females.
• Age and pattern of presentation of CRPS are similar between the sexes, with mean age of onset occurring in the fifth and sixth decades of life.
• Various treatments exist for CRPS, including physical therapy and pharmacotherapy.
• Data on sex-related differences in response to treatment and clinical outcomes for patients with CRPS are meager.

Putting sex in your orthopaedic practice
This quarterly column from the AAOS Women’s Health Issues Advisory Board and the Ruth Jackson Orthopaedic Society provides important information for your practice about issues related to sex (determined by our chromosomes) and gender (how we present ourselves as male or female, which can be influenced by environment, families and peers, and social institutions). It is our mission to promote the philosophy that male and female patients experience and react to musculoskeletal conditions differently; when it comes to patient care, surgeons should not have a one-size-fits-all mentality.

References

1. Field J: Complex regional pain syndrome: A review. J Hand Surg (Eur) 2013;38(6): 616-626.
2. Veldman PH, Reynen HM, Arntz IE, Goris RJ: Signs and symptoms of reflex sympathetic dystrophy: Prospective study of 829 patients. Lancet 1993,342(8878):1012-1016.
3. Maihöfner C, Seifert F, Markovic K: Complex regional pain syndromes: New pathophysiological concepts and therapies. Eur J Neurology, 2010;17(5):649-660.
4. Cossins L, Okell RW, Cameron H, Simpson B, Poole HM, Goebel A: Treatment of complex regional pain syndrome in adults: A systematic review of randomized controlled trials published from June 2000 to February 2012. Eur J Pain 2013;17(2):158-173.
5. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW: Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am 2007;89(7):1424-1431.
6. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA: Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county. A population-based study. Pain 2003;103(1-2):199-207.
7. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC: The incidence of complex regional pain syndrome: A population-based study. Pain 2007;129(1-2):12-20.
8. Castro-Sánchez AM, Matarán-Peñarrocha GA, López-Rodríguez MM, Lara-Palomo IC, Arendt-Nielsen L, Fernández-de-las-Peñas C: Gender differences in pain severity, disability, depression, and widespread pressure pain sensitivity in patients with fibromyalgia syndrome without comorbid conditions.” Pain Med 2012;13(12):1639-1647.
9. Schmid-Schwap M, Bristela M, Kundi M, Piehslinger E: Sex-specific differences in patients with temporomandibular disorders. J Orofac Pain 2013;27(1):42-50.
10. Sluka KA, Berkley KJ, O’Connor MI, et al: Neural and psychosocial contributions to sex differences in knee osteoarthritic pain. Biol Sex Differ 2012;3(1):26. doi:10.1186/2042-6410-3-26.
11. Bartley EJ, Fillingim RB. Sex differences in pain: A brief review of clinical and experimental findings. Br J Anaesth 2013;111(1):52-58.