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Review article

Complex regional pain syndrome: literature review as a guide for the practicing clinician

Emilija Dubljanin Raspopović1,2, Goran Tulić2,3, Una Nedeljković1,2, Nela Ilić1,2, Milica Aleksić1, Marko Kadija2,3, Sanja Tomanović Vujadinović1,2
  • University Clinical Center of Serbia, Center for Physical Medicine and Rehabilitation, Belgrade, Serbia
  • University of Belgrade, Faculty of Medicine, Belgrade, Serbia
  • University Clinical Center of Serbia, Clinic for Orthopedic Surgery and Traumatology, Belgrade, Serbia

ABSTRACT

Complex regional pain syndrome (CRPS) is a chronic complex disorder that significantly affects the quality of life of the people suffering from it. This syndrome affects the extremities after trauma or nerve injury. Hyperalgesia and allodynia of the extremities often accompany this condition. Diagnosing and treating this disease is very complex. The Budapest criteria are currently the most widely accepted diagnostic criteria. Early diagnosis and treatment are essential for a favorable outcome in CRPS. Therapeutic modalities available for the treatment of CRPS include physical therapy, pharmacotherapy, and interventional techniques. Additional high-quality studies are needed to determine the best therapeutic option.


INTRODUCTION

Complex regional pain syndrome (CRPS) is a chronic neurological disease with a prevalence of 5.4 – 26.2% per 100,000 people. It can be categorized into two subtypes, depending on the absence (CRPS I, previously known as reflex sympathetic dystrophy) or presence (CRPS II, previously known as causalgia) of nerve lesions. It differs from other pain syndromes due to the presence of autoimmune function disorder, regional inflammatory lesions, as well as the loss of dermatomal distribution. It is often characterized by allodynia, hyperalgesia, change in skin temperature, and swelling. Epidemiological analyses indicate that the female gender, injury to the upper extremity, as well as injury resulting from high-intensity force, represent risk factors for the development of this disorder [1].

This disease is characterized by varying clinical presentation and development, as well as by difficult diagnostics and treatment. The pathohistological mechanism of this disease is also not clearly defined [1]. Many patients experience a significant decrease in the quality of life and a poor prognosis, despite treatment. Timely diagnosis and early start of treatment are of key importance for limiting the progression of the disease and improving the quality of life.

The aim of this paper is to present the latest discoveries from existing literature related to the epidemiology, pathophysiology, and contemporary treatment of CRPS.

BACKGROUND

During the Civil War in the United States of America, in the year 1864, an American doctor, Silas Weir Mitchell was the first to describe one of the earliest cases of CRPS. At the time, he described a particular type of pain, which developed as a complication of injuries caused by firearms. His patients complained of burning pain accompanied by glowing red skin [2]. Mitchell named this condition causalgia. In 1900, Sudeck described radiographically visible patchy osteopenia, while in the 1950s, Evans introduced the term reflex sympathetic dystrophy (RSD), believing that sympathetic hyperactivity was responsible for the development of this disorder. In 1994, the International Association for the Study of Pain introduced the term complex regional pain syndrome (CRPS). CRPS I, previously known as reflex sympathetic dystrophy, results from trauma without nerve damage and it is responsible for a majority of cases of this syndrome. CRPS II, previously known as causalgia, involves recognizable nerve lesions, resulting from trauma or surgical procedure [1].

PATHOPHYSIOLOGY

The first theory on the pathophysiology of CRPS relates to disturbance in sympathetic activity. This is why CRPS was previously referred to as reflex sympathetic dystrophy. With time, other potential mechanisms influencing the development of this syndrome were also identified, which is why it was renamed, and is now referred to as complex regional pain syndrome [3]. The pathophysiology of CRPS is very complicated and very hard to explain. It is highly probable that inflammation plays a part in its development, especially in its early stages. This can be recognized by the signs of acute inflammatory process, such as redness, swelling, elevated temperature, and pain. Additionally, the elevation of pro-inflammatory cytokines (TNF α and MIP-1β) is also present, as well as the decrease of anti-inflammatory proteins (IL-1Ra) [4]. Studies also indicate an autoimmune process, which is involved in the development and progression of CRPS [5]. Peripheral sensitization, as the result of initial inflammatory and immunological responses, leads to central sensitization and is probably involved in the pathophysiology of the disease [4].

There is certain evidence indicating that psychological stress may make the patient more susceptible to the development of the disease. Patients with posttraumatic stress disorder (PTSD) are at higher risk of developing CRPS [6]. In many such patients, PTSD was present before the development of CRPS, which indicates a predisposition stemming from this disorder [7]. What is more definite is that psychological stress affects the progression of the disease. Patients who have a higher level of anxiety, a more marked sense of disability, and a greater fear of pain, have a less favorable outcome. This is probably the result of an increased release of catecholamines due to an elevated level of anxiety, which leads to the increase in nociceptive sensitization. Currently, the impact of genetics on the development of CRPS is being researched [1].

Instead of individually investigating all the above-mentioned pathophysiological factors in the development of CRPS, independently of one another, it makes more sense to observe them in complex, albeit as yet unelucidated interactions, which lead to the general manifestations of CRPS.

EPIDEMIOLOGY

Due to the fact that the diagnosis of CRPS is a clinical one, the incidence of the development of this complication varies in different studies. Epidemiological data from two large studies show an incidence of between 5.5/100,000 per year [8] and 26.2/100,000 per year [9]. Based on the largest population study dealing with CRPS, it has been established that the female sex, being Caucasian, a higher socioeconomic status, an anamnesis of depression and headache, as well as a history of substance abuse, were linked to the development of CRPS [10].

DIAGNOSTIC CRITERIA

There is no definitive test for confirming the diagnosis of CRPS. The currently accepted diagnostic criteria for the CRPS diagnosis are the Budapest Criteria, defined in 2003.

The Budapest Criteria include: 1) continuing pain, which is disproportionate to any inciting event; 2) at least one symptom in three of the four categories (sensory, vasomotor, sudomotor/edema, and/or motor/ trophic); 3) at time of evaluation, there must be at least one sign in two or more of the previously stated categories; 4) there is no other diagnosis that better explains the signs and symptoms [10].

Sensory symptoms involve reports or presence of hyperesthesia and/or allodynia. Vasomotor symptoms refer to reports or presence of temperature asymmetry and/or skin color changes and/or skin color asymmetry. Sudomotor/edema symptoms involve reports or presence of edema and/or sweating changes and/ or sweating asymmetry. Motor/trophic symptoms involve reports or presence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin) [10].

The Budapest Criteria additionally categorize CRPS as Type I and Type II. A patient fulfills the clinical criteria for CRPS after relevant nerve injury (CRPS II) or without relevant nerve injury (CRPS I). Nerve injury may be diagnosed either with electromyography or with a neurological examination.

In order to additionally quantify the severity of the disease, in 2010, Harden et al. developed a score assessing the severity of the disease – CRPS severity score (CSS). Based on this score, 17 different symptoms are assessed, whereby each symptom is given one point [1].

In addition to clinical diagnostic criteria, some authors have defined ‘warm’ and ‘cold’ subtypes, which differentiate initial symptoms of increased skin temperature and edema, in one category of patients, and a colder extremity, in the other. The understanding of potentially different subtypes supports earlier reports given by patients who did not go through the three typical sequential clinical stages – from the initial stage (Stage 1), the edema stage (Stage 2), to the final trophic stage (Stage 3). Instead, patients may experience symptoms pertaining to any of the stages [1].

Although clinical diagnosis based on anamnesis and clinical examination is the most widely accepted one, certain diagnostic tests have also been investigated for the purpose of diagnosis confirmation. Thermography is the most frequently used and basic adjunct diagnostic method applied in patients with CRPS. Temperature changes of ≥1 °C are considered significant. Yet, greater temperature differences do not correlate with the perception of pain [4]. However, this method does not have good specificity and sensitivity and cannot be advised for these patients. Bone scintigraphy is currently the diagnostic method with the greatest sensitivity and specificity for patients with CRPS. A systematic literature review shows that bone scintigraphy cannot be used for excluding the diagnosis, but it can be used for confirming it [11]. Radiography has low sensitivity, however, if it is positive, it can be used to support the diagnosis [11].

TREATMENT

The treatment of CRPS involves a multimodal approach based on nonpharmacological and pharmacological measures. The success of treatment largely depends on the timely start of treatment. At the very beginning of treatment, it is important to alleviate the pain in the patent, as much as possible, and to initiate active movements within the scope of the patient’s abilities. Passive movements, against the will or outside the control of the patient, are contraindicated. Analgesic therapy is the most important component in this stage of the treatment. With pain reduction, gradual activation becomes more and more important.

Pharmacotherapy

Anti-inflammatory drugs

Drugs that are traditionally used to treat CRPS are nonsteroid anti-inflammatory drugs (NSAID) and corticosteroids. Anti-inflammatory therapy is rightly used in CRPS treatment, especially in the early months of this syndrome, due to the fact that inflammation plays a part in CRPS, especially in its initial stages.

Nonsteroid anti-inflammatory drugs can be used as initial therapy in the treatment of CRPS. However, studies investigating the use of nonsteroid anti-inflammatory drugs in CRPS were small, and the results were inconsistent [12],[13]. Nonsteroid anti-inflammatory drugs act through the inhibition of cyclooxygenase 1 and 2 by reducing prostaglandins that cause the inflammation.

Conversely, corticosteroids can reduce inflammation through different mechanisms. Published studies support the short-term use of corticosteroids in the treatment of patients in the early stages of CRPS, if there is a marked inflammatory component [14],[15]. In its guidelines for treating CRPS, from 2018, the German Neurological Society advises treatment with prednisolone equivalent at a dose of > 30 – 40 mg/day, in acute CRPS, over a period of more than four weeks (up to six months). The guidelines state that the authors themselves have had better experience with initially significantly higher doses (prednisolone equivalent >/= 100 mg, orally), which should then gradually be reduced over a period of 2.5 weeks. It is also noted that it is often necessary to adjust the dose individually, as well as to repeat treatment in case of the exacerbation of symptoms [18]. Corticosteroids, however, are not recommended in chronic CRPS, wherein symptoms last longer than three months. Also, a careful selection of patients and the duration of corticosteroid application are of great importance, due to well documented adverse effects.

Drugs for neuropathic pain

Drugs for neuropathic pain have not been thoroughly investigated in the treatment of CRPS. The use of drugs for neuropathic pain is based on the established use of this group of drugs in the treatment of other neuropathic conditions. In a limited number of studies, gabapentin has proven to be efficient in reducing pain in patients with CRPS [18]. Brown et al. compared the efficiency of amitriptyline against gabapentin in a randomized controlled study, and they demonstrated significant reduction of pain, which did not vary amongst the groups [19].

Bisphosphonates

Bisphosphonates are frequently used in CRPS treatment. Although the precise mechanism of their action is not clear, current research indicates that bisphosphonates may act by modulating inflammatory mediators, as well as the proliferation and migration of bone marrow cells [20]. Cochrane’s literature review, from 2013, indicates a low level of evidence on the efficiency of bisphosphonates in reducing pain in patients with CRPS [21]. A recent meta-analysis, however, demonstrates the efficiency of this group of drugs in the treatment of pain in patients with CRPS I [22]. According to the recommendations of the German Neurological Society, alendronate is either administered orally in high doses of 40 mg/24 h or intravenously (7.5 mg), for three consecutive days [18].

Antioxidants

Treatment of CRPS with antioxidants is based on the premise that local inflammation in CRPS produces oxygen free radicals [20]. Vitamin C is the only antioxidant for which proof exists that it can act preventively on the development of CRPS, if it is administered preventively in surgical treatment of the extremities. The most recent meta-analysis shows a significant reduction of risk when 500 mg of vitamin C are taken daily over a period of 50 days [23].

Ketamine

Ketamine is an antagonist of the NMDA receptor in the peripheral and central nervous system [4],[20],[24]. In their literature overview, Zhao et al. concluded that existing studies support the clinical efficiency of ketamine infusions, but also that additional randomized controlled studies are necessary in order to additionally confirm their efficiency [24].

Other

Lately, thanks to the advanced understanding of molecular and cellular mechanisms that are at the heart of the development of CRPS, different new pharmacotherapeutic approaches have been investigated, for the purpose of improving the success of treatment. Amongst the newest drugs is naltrexone, an opioid antagonist, which, in small doses, inhibits the activation of microglia, thus reducing the inflammatory response. As new alternatives in CRPS treatment, ketamine, botulinum toxin A, and cannabinoids can also be considered. However, new studies, which would prove the efficiency and safety of this group of drugs, are necessary [20].

Procedures

Sympathetic nerve blocks

Despite the small body of evidence justifying the use of sympathetic nerve blocks, they are often used by doctors who are involved in interventional pain management. Sympathetic nerve blocks are administered due to the premise that the pathophysiology of CRPS is partially linked to a disturbance in the autonomous function of the affected limb and the excess response to catecholamines [1].

Stimulation of the spinal cord and the ganglia of the dorsal horns

Spinal cord stimulation is a neuromodulation technique which reduces pain through electrical stimulation of the spinal cord dorsal horns. Implanted electrodes emit impulses, which modulate the sensation of pain through a complex mechanism. The results of studies investigating the validity of the application of this method in CRPS patients are inconsistent [25]. Further studies are necessary in order to assess the efficiency and safety of this method.

Stimulation of the ganglia of the dorsal horns is a new developing technique, whereby electrical stimulation is applied to the dorsal horns. This form of stimulation is more specific, as compared to spinal cord stimulation, as it can specifically target painful regions of the extremities. Further research to this effect is necessary [1].

One of the recently developed methods of treatment, which may have the desired effect, is transcranial magnetic stimulation (TMS). This is a safe and noninvasive technique, which produces a short-lasting magnetic impulse in the brain and may induce cortical excitability. Further research is necessary for the purpose of reaching a definitive conclusion [20].

Nonpharmacological treatment

Nonpharmacological treatment entails a multidisciplinary approach, which includes physical, occupational, and psychological therapy. Due to the pain that accompanies this condition, patients avoid using the affected limb. In patients with CRPS, the goal of physical and occupational therapy is to improve the functionality and mobility of the extremities, as well as to reduce pain. Such therapy also prevents later complications, such as contractures, which form due to the avoidance of painful movements. It is advised that these forms of treatment should be applied early on in the rehabilitation process, as they are considered first-line therapies [1].

Pain management is very important during rehabilitation. As soon as pain allows the activation of the extremities, the affected joints can be mobilized. Later, resistance exercises are introduced, and if the lower extremities are affected, walking exercises are also included. Patients should be encouraged to actively use the affected limb in each stage of the disease.

Cochrane’s review, from 2012 and 2016, which analyzed different physiotherapeutic interventions, singled out two forms of therapy with the highest rehabilitation potential, which can reduce pain and improve functionality and the quality of life in patients with CRPS I. These are mirror therapy and graded motor imagery [26],[27]. These two methods of therapy have become important components in the treatment of CRPS patients.

Mirror therapy, as an isolated therapeutic procedure, is especially efficient in acute forms of CRPS, especially after stroke [28]. In chronic CRPS, graded motor imagery is efficient. It consists of recognizing the left and right side in the mirror, imagining movement, and mirror therapy [29]. Two studies have shown improvement in pain and a decrease in functional disability in patients with CRPS, within six months, when this method was applied [26],[29].

Following instructions from the therapist, patients carry out these two forms of therapy independently, for ten minutes every waking hour, over a period of six weeks [18].

Psychotherapeutic interventions

Psychotherapeutic interventions are an important component of treatment in patients suffering from CRPS, especially when there is an accompanying mental illness or when the symptomatology, despite appropriate therapy, does not change over a longer period of time [30].

There are two studies, with a small number of patients, confirming the efficiency of psychotherapeutic interventions in CRPS, as compared to isolated physical therapy [31],[32]. However, the results of a great number of studies on patients with chronic pain syndrome may be applied with a high degree of probability to patients suffering from CRPS [33].

CONCLUSION

CRPS is a complex multifactorial disease. Although our understanding of this disease has advanced greatly since it was described and defined for the first time, it has as yet not been fully clarified. Larger high-quality studies are necessary to facilitate a better understanding of the underlying mechanisms of this syndrome, which would enable the development of precisely targeted treatments. This is why constant research efforts, directed towards devising combinations of therapeutic methods for future treatment of CRPS, are necessary.

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 3

September 2022

Pages 374-383
  • Keywords:
    complex regional pain syndrome, pain, chronic pain
  • Received:
    11 August 2022
  • Revised:
    17 August 2022
  • Accepted:
    23 August 2022
  • Online first:
    25 September 2022
  • DOI:
  • Cite this article:
    Dubljanin-Raspopović E, Tulić G, Nedeljković U, Ilić N, Aleksić M, Kadija M, et al. Complex regional pain syndrome: Literature review as a guide for the practicing clinician. Serbian Journal of the Medical Chamber. 2022;3(3):374-83. doi: 10.5937/smclk3-39589
Corresponding author

Emilija Dubljanin Raspopović
Center for Physical Medicine and Rehabilitation,
University Clinical Center of Serbia
26 Višegradska Street, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


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REFERENCES

1. Shim H, Rose J, Halle S, Shekane P. Complex regional pain syndrome: a narrative review for the practising clinician. Br J Anaesth. 2019 Aug;123(2):e424-e433. doi: 10.1016/j.bja.2019.03.030. [CROSSREF]

2. Mitchell SW, Morehouse GR, Keen WW. Gunshot wounds and other injuries of nerves. New York: Lippincott, 1864.

3. Kessler A, Yoo M, Calisoff R. Complex regional pain syndrome: An updated comprehensive review. NeuroRehabilitation. 2020;47(3):253-64. doi: 10.3233/NRE-208001. [CROSSREF]

4. Lenz M, Üçeyler N, Frettlöh J, Höffken O, Krumova EK, Lissek S, et al. Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months. Pain. 2013 Oct;154(10):2142-9. doi: 10.1016/j. pain.2013.06.039. [CROSSREF]

5. Goebel A, Blaes F. Complex regional pain syndrome, prototype of a novel kind of autoimmune disease. Autoimmun Rev. 2013 Apr;12(6):682-6. doi: 10.1016/j.autrev.2012.10.015.  [CROSSREF]

6. Speck V, Schlereth T, Birklein F, Maihöfner C. Increased prevalence of posttraumatic stress disorder in CRPS. Eur J Pain. 2017 Mar;21(3):466-73. doi: 10.1002/ejp.940. [CROSSREF]

7. Urits I, Shen AH, Jones MR, Viswanath O, Kaye AD. Complex Regional Pain Syndrome, Current Concepts and Treatment Options. Curr Pain Headache Rep. 2018 Feb 5;22(2):10. doi: 10.1007/s11916-018-0667-7. [CROSSREF]

8. 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 May;103(1-2):199-207. doi: 10.1016/s0304- 3959(03)00065-4. [CROSSREF]

9. 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 May;129(1-2):12-20. doi: 10.1016/j.pain.2006.09.008.  [CROSSREF]

10. Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, et al. Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain. 2010 Aug;150(2):268-74. doi: 10.1016/j. pain.2010.04.030. [CROSSREF]

11. Wertli MM, Brunner F, Steurer J, Held U. Usefulness of bone scintigraphy for the diagnosis of Complex Regional Pain Syndrome 1: A systematic review and Bayesian meta-analysis. PLoS One. 2017 Mar 16;12(3):e0173688. doi: 10.1371/journal.pone.0173688.  [CROSSREF]

12. Breuer AJ, Mainka T, Hansel N, Maier C, Krumova EK. Short-term treatment with parecoxib for complex regional pain syndrome: a randomized, placebo-controlled double-blind trial. Pain Physician. 2014 Mar-Apr;17(2):127-37. [CROSSREF]

13. Eckmann MS, Ramamurthy S, Griffin JG. Intravenous regional ketorolac and lidocaine in the treatment of complex regional pain syndrome of the lower extremity: a randomized, double-blinded, crossover study. Clin J Pain. 2011 Mar-Apr;27(3):203-6. doi: 10.1097/AJP.0b013e3181fd5150. [CROSSREF]

14. Kalita J, Vajpayee A, Misra UK. Comparison of prednisolone with piroxicam in complex regional pain syndrome following stroke: a randomized controlled trial. QJM. 2006 Feb;99(2):89-95. doi: 10.1093/qjmed/hcl004. [CROSSREF]

15. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand. 1982;148(8):653-5.

16. Deutsche Gesellschaft fur Neurologie. Diagnostik and Therapie komplexer regionaler Schmerzystem. Dostupno na: https://dgn.org/leitlinien/ll-030-116-diagnostik-und-therapie-komplexer-regionaler-schmerzsyndrome-crps-2018/ [HTTP]

17. Serpell MG; Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002 Oct;99(3):557-66. doi: 10.1016/S0304-3959(02)00255-5. [CROSSREF]

18. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004 Sep 29;4:13. doi: 10.1186/1471-2377- 4-13. [CROSSREF]

19. Brown S, Johnston B, Amaria K, Watkins J, Campbell F, Pehora C, et al. A randomized controlled trial of amitriptyline versus gabapentin for complex regional pain syndrome type I and neuropathic pain in children. Scand J Pain. 2016 Oct;13:156-163. doi: 10.1016/j.sjpain.2016.05.039. [CROSSREF]

20. Taylor SS, Noor N, Urits I, Paladini A, Sadhu MS, Gibb C, et al. Complex Regional Pain Syndrome: A Comprehensive Review. Pain Ther. 2021 Dec;10(2):875- 892. doi: 10.1007/s40122-021-00279-4. [CROSSREF]

21. O’Connell NE, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev. 2013 Apr 30;2013(4):CD009416. doi: 10.1002/14651858.CD009416.pub2. [CROSSREF]

22. Chevreau M, Romand X, Gaudin P, Juvin R, Baillet A. Bisphosphonates for treatment of Complex Regional Pain Syndrome type 1: A systematic literature review and meta-analysis of randomized controlled trials versus placebo. Joint Bone Spine. 2017 Jul;84(4):393-9. doi: 10.1016/j.jbspin.2017.03.009. [CROSSREF]

23. Aïm F, Klouche S, Frison A, Bauer T, Hardy P. Efficacy of vitamin C in preventing complex regional pain syndrome after wrist fracture: A systematic review and meta-analysis. Orthop Traumatol Surg Res. 2017 May;103(3):465- 70. doi: 10.1016/j.otsr.2016.12.021.  [CROSSREF]

24. Zhao J, Wang Y, Wang D. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. Curr Pain Headache Rep. 2018 Feb 5;22(2):12. doi: 10.1007/s11916-018- 0664-x.  [CROSSREF]

25. Visnjevac O, Costandi S, Patel BA, Azer G, Agarwal P, Bolash R, et al. A Comprehensive Outcome-Specific Review of the Use of Spinal Cord Stimulation for Complex Regional Pain Syndrome. Pain Pract. 2017 Apr;17(4):533-45. doi: 10.1111/papr.12513. [CROSSREF]

26. Smart KM, Wand BM, O’Connell NE. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst Rev. 2016 Feb 24;2(2):CD010853. doi: 10.1002/14651858. CD010853.pub2. [CROSSREF]

27. Smart KM, Ferraro MC, Wand BM, O’Connell NE. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst Rev. 2022 May 17;5(5):CD010853. doi: 10.1002/14651858.CD010853.pub3.  [CROSSREF]

28. Cacchio A, De Blasis E, Necozione S, di Orio F, Santilli V. Mirror therapy for chronic complex regional pain syndrome type 1 and stroke. N Engl J Med. 2009 Aug 6;361(6):634-6. doi: 10.1056/NEJMc0902799. [CROSSREF]

29. Moseley GL. Graded motor imagery is effective for long-standing complex regional pain syndrome: a randomised controlled trial. Pain. 2004 Mar;108(1- 2):192-8. doi: 10.1016/j.pain.2004.01.006.  [CROSSREF]

30. Bean DJ, Johnson MH, Heiss-Dunlop W, Kydd RR. Extent of recovery in the first 12  months of complex regional pain syndrome type-1: A prospective study. Eur J Pain. 2016 Jul;20(6):884-94. doi: 10.1002/ejp.813.  [CROSSREF]

31. Lee BH, Scharff L, Sethna NF, McCarthy CF, Scott-Sutherland J, Shea AM, et al. Physical therapy and cognitive-behavioral treatment for complex regional pain syndromes. J Pediatr. 2002 Jul;141(1):135-40. doi: 10.1067/ mpd.2002.124380. [CROSSREF]

32. Bruehl S, Chung OY. Psychological and behavioral aspects of complex regional pain syndrome management. Clin J Pain. 2006 Jun;22(5):430-7. doi: 10.1097/01.ajp.0000194282.82002.79. [CROSSREF]

33. Turner JA, Mancl L, Aaron LA. Short- and long-term efficacy of brief cognitive-behavioral therapy for patients with chronic temporomandibular disorder pain: a randomized, controlled trial. Pain. 2006 Apr;121(3):181-194. doi: 10.1016/j.pain.2005.11.017. [CROSSREF]

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7. Urits I, Shen AH, Jones MR, Viswanath O, Kaye AD. Complex Regional Pain Syndrome, Current Concepts and Treatment Options. Curr Pain Headache Rep. 2018 Feb 5;22(2):10. doi: 10.1007/s11916-018-0667-7. [CROSSREF]

8. 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 May;103(1-2):199-207. doi: 10.1016/s0304- 3959(03)00065-4. [CROSSREF]

9. 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 May;129(1-2):12-20. doi: 10.1016/j.pain.2006.09.008.  [CROSSREF]

10. Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, et al. Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain. 2010 Aug;150(2):268-74. doi: 10.1016/j. pain.2010.04.030. [CROSSREF]

11. Wertli MM, Brunner F, Steurer J, Held U. Usefulness of bone scintigraphy for the diagnosis of Complex Regional Pain Syndrome 1: A systematic review and Bayesian meta-analysis. PLoS One. 2017 Mar 16;12(3):e0173688. doi: 10.1371/journal.pone.0173688.  [CROSSREF]

12. Breuer AJ, Mainka T, Hansel N, Maier C, Krumova EK. Short-term treatment with parecoxib for complex regional pain syndrome: a randomized, placebo-controlled double-blind trial. Pain Physician. 2014 Mar-Apr;17(2):127-37. [CROSSREF]

13. Eckmann MS, Ramamurthy S, Griffin JG. Intravenous regional ketorolac and lidocaine in the treatment of complex regional pain syndrome of the lower extremity: a randomized, double-blinded, crossover study. Clin J Pain. 2011 Mar-Apr;27(3):203-6. doi: 10.1097/AJP.0b013e3181fd5150. [CROSSREF]

14. Kalita J, Vajpayee A, Misra UK. Comparison of prednisolone with piroxicam in complex regional pain syndrome following stroke: a randomized controlled trial. QJM. 2006 Feb;99(2):89-95. doi: 10.1093/qjmed/hcl004. [CROSSREF]

15. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand. 1982;148(8):653-5.

16. Deutsche Gesellschaft fur Neurologie. Diagnostik and Therapie komplexer regionaler Schmerzystem. Dostupno na: https://dgn.org/leitlinien/ll-030-116-diagnostik-und-therapie-komplexer-regionaler-schmerzsyndrome-crps-2018/ [HTTP]

17. Serpell MG; Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002 Oct;99(3):557-66. doi: 10.1016/S0304-3959(02)00255-5. [CROSSREF]

18. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004 Sep 29;4:13. doi: 10.1186/1471-2377- 4-13. [CROSSREF]

19. Brown S, Johnston B, Amaria K, Watkins J, Campbell F, Pehora C, et al. A randomized controlled trial of amitriptyline versus gabapentin for complex regional pain syndrome type I and neuropathic pain in children. Scand J Pain. 2016 Oct;13:156-163. doi: 10.1016/j.sjpain.2016.05.039. [CROSSREF]

20. Taylor SS, Noor N, Urits I, Paladini A, Sadhu MS, Gibb C, et al. Complex Regional Pain Syndrome: A Comprehensive Review. Pain Ther. 2021 Dec;10(2):875- 892. doi: 10.1007/s40122-021-00279-4. [CROSSREF]

21. O’Connell NE, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev. 2013 Apr 30;2013(4):CD009416. doi: 10.1002/14651858.CD009416.pub2. [CROSSREF]

22. Chevreau M, Romand X, Gaudin P, Juvin R, Baillet A. Bisphosphonates for treatment of Complex Regional Pain Syndrome type 1: A systematic literature review and meta-analysis of randomized controlled trials versus placebo. Joint Bone Spine. 2017 Jul;84(4):393-9. doi: 10.1016/j.jbspin.2017.03.009. [CROSSREF]

23. Aïm F, Klouche S, Frison A, Bauer T, Hardy P. Efficacy of vitamin C in preventing complex regional pain syndrome after wrist fracture: A systematic review and meta-analysis. Orthop Traumatol Surg Res. 2017 May;103(3):465- 70. doi: 10.1016/j.otsr.2016.12.021.  [CROSSREF]

24. Zhao J, Wang Y, Wang D. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. Curr Pain Headache Rep. 2018 Feb 5;22(2):12. doi: 10.1007/s11916-018- 0664-x.  [CROSSREF]

25. Visnjevac O, Costandi S, Patel BA, Azer G, Agarwal P, Bolash R, et al. A Comprehensive Outcome-Specific Review of the Use of Spinal Cord Stimulation for Complex Regional Pain Syndrome. Pain Pract. 2017 Apr;17(4):533-45. doi: 10.1111/papr.12513. [CROSSREF]

26. Smart KM, Wand BM, O’Connell NE. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst Rev. 2016 Feb 24;2(2):CD010853. doi: 10.1002/14651858. CD010853.pub2. [CROSSREF]

27. Smart KM, Ferraro MC, Wand BM, O’Connell NE. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst Rev. 2022 May 17;5(5):CD010853. doi: 10.1002/14651858.CD010853.pub3.  [CROSSREF]

28. Cacchio A, De Blasis E, Necozione S, di Orio F, Santilli V. Mirror therapy for chronic complex regional pain syndrome type 1 and stroke. N Engl J Med. 2009 Aug 6;361(6):634-6. doi: 10.1056/NEJMc0902799. [CROSSREF]

29. Moseley GL. Graded motor imagery is effective for long-standing complex regional pain syndrome: a randomised controlled trial. Pain. 2004 Mar;108(1- 2):192-8. doi: 10.1016/j.pain.2004.01.006.  [CROSSREF]

30. Bean DJ, Johnson MH, Heiss-Dunlop W, Kydd RR. Extent of recovery in the first 12  months of complex regional pain syndrome type-1: A prospective study. Eur J Pain. 2016 Jul;20(6):884-94. doi: 10.1002/ejp.813.  [CROSSREF]

31. Lee BH, Scharff L, Sethna NF, McCarthy CF, Scott-Sutherland J, Shea AM, et al. Physical therapy and cognitive-behavioral treatment for complex regional pain syndromes. J Pediatr. 2002 Jul;141(1):135-40. doi: 10.1067/ mpd.2002.124380. [CROSSREF]

32. Bruehl S, Chung OY. Psychological and behavioral aspects of complex regional pain syndrome management. Clin J Pain. 2006 Jun;22(5):430-7. doi: 10.1097/01.ajp.0000194282.82002.79. [CROSSREF]

33. Turner JA, Mancl L, Aaron LA. Short- and long-term efficacy of brief cognitive-behavioral therapy for patients with chronic temporomandibular disorder pain: a randomized, controlled trial. Pain. 2006 Apr;121(3):181-194. doi: 10.1016/j.pain.2005.11.017. [CROSSREF]


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