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Complex regional pain syndrome

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Complex regional pain syndrome
Other namesAlgodystrophy; Amplified musculoskeletal pain syndrome; hyponym: reflex sympathetic dystrophy (RSD); hyponym: causalgia; hyponym: reflex neurovascular dystrophy (RND)
Leg of an individual (left) with complex regional pain syndrome following tibial bone fracture
SpecialtyNeurology, psychiatry, anesthesiology
SymptomsPain, allodynia, hypo- or hyperesthesia, skin temperature abnormalities, atrophy, stiffness
TreatmentPhysical therapy (more effective with early diagnosis); medications (e.g., anticonvulsants, opioids, muscle relaxers, etc.); sympathetic nerve blockade; ketamine infusions; lidocaine infusions; implantable pharmaceuticals; amputation
MedicationAnticonvulsants (e.g., gabapentin); muscle relaxers (e.g., baclofen), ketamine or lidocaine infusions[citation needed]

Complex regional pain syndrome (CRPS Type 1 and Type 2) is a severe form of chronic pain, in which pain from a physical trauma outlasts the expected recovery time. The symptoms of types 1 and 2 are the same except type 2 is associated with nerve injury.

Usually starting in a limb, CRPS manifests as pain, swelling, limited range of motion, and/or changes to the skin and bones. It may initially affect one limb and then spread throughout the body; 35% of affected individuals report symptoms throughout the body.[1] Two types are thought to exist: CRPS type 1 (previously referred to as reflex sympathetic dystrophy) and CRPS type 2 (previously referred to as causalgia). It is possible to have both types.[2]

Amplified musculoskeletal pain syndrome, a condition that is similar to CRPS, primarily affects pediatric patients, falls under rheumatology and pediatrics, and is generally considered a subset of CRPS type I.[3]


The classification system in use by the International Association for the Study of Pain (IASP) divides CRPS into two types based on the presence or absence of measurable nerve pathophysiology.[4][5]

International Association for the Study of Pain Classification
Type Clinical findings Synonyms
Type I CRPS without evidence of neuropathology in the affected limb. This accounts for about 90% of CRPS. reflex sympathetic dystrophy, RSD, Sudeck's atrophy
Type II CRPS with evidence of neuropathology in the affected limb. causalgia

Signs and symptoms[edit]

Severe CRPS of right arm
CRPS visible on hands and wrists

Clinical features of CRPS have been found to be inflammation resulting from the release of certain pro-inflammatory chemical signals from surrounding nerve cells; hypersensitization of pain receptors; dysfunction of local vasoconstriction and vasodilation; and maladaptive neuroplasticity.[6]

The signs and symptoms of CRPS usually manifest near the injury site. The most common symptoms are extreme pain, including burning, stabbing, grinding, and throbbing. The pain is out of proportion to the severity of the initial injury.[7] Moving or touching the limb is disproportionately painful (allodynia). Other findings are aspects of disuse including swelling, stiffness (limited range of motion), and disuse related changes to the skin (temperature, color, sweating, texture) and bones (disuse osteoporosis).[8][9]

A prior concept of CRPS having three stages is no longer in wide use.[10] The trend is now to consider distinct sub-types of CRPS.[10]


Complex regional pain syndrome is uncommon, and its cause is not clearly understood. CRPS typically develops after an injury, surgery, heart attack, or stroke.[7][11] Investigators estimate that 2–5% of those with peripheral nerve injury,[12] and 13–70% of those with hemiplegia (paralysis of one side of the body)[13] will develop CRPS. In addition, some studies have indicated that cigarette smoking was strikingly present in patients and is statistically linked to RSD. This may be involved in its pathology by enhancing sympathetic activity, vasoconstriction, or by some other unknown neurotransmitter-related mechanism. This hypothesis was based on a retrospective analysis of 53 patients with RSD, which showed that 68% of patients were smokers, compared to only 37% of the control population. The results are preliminary and are limited by their retrospective nature.[14] 7% of people who have CRPS in one limb later develop it in another limb.[15]


Inflammation and alteration of pain perception in the central nervous system are proposed to play important roles. The persistent pain and the perception of nonpainful stimuli as painful are thought to be caused by inflammatory molecules (IL-1, IL-2, TNF-alpha) and neuropeptides (substance P) released from peripheral nerves. This release may be caused by inappropriate cross-talk between sensory and motor fibers at the affected site.[16] CRPS is not a psychological illness, yet pain can cause psychological problems, such as anxiety and depression. Often, impaired social and occupational function occur.[17]

Complex regional pain syndrome is a multifactorial disorder with clinical features of neurogenic inflammation (inflammation mediated by nerve cells), nociceptive sensitisation (which causes extreme sensitivity or allodynia), vasomotor dysfunction (blood flow problems which cause swelling and discolouration) and maladaptive neuroplasticity (where the brain changes and adapts with constant pain signals); CRPS is the result of an "aberrant [inappropriate] response to tissue injury".[6] The "underlying neuronal matrix" of CRPS is seen to involve cognitive and motor as well as nociceptive processing; pinprick stimulation of a CRPS affected limb was painful (mechanical hyperalgesia) and showed a "significantly increased activation" of not just the S1 cortex (contralateral), S2 (bilateral) areas, and insula (bilateral) but also the associative-somatosensory cortices (contralateral), frontal cortices, and parts of the anterior cingulate cortex.[18] In contrast to previous thoughts reflected in the name RSD, it appears that there is reduced sympathetic nervous system outflow, at least in the affected region (although there may be sympatho-afferent coupling).[19] Wind-up (the increased sensation of pain with time)[20] and central nervous system (CNS) sensitization are key neurologic processes that appear to be involved in the induction and maintenance of CRPS.[21]

Compelling evidence shows that the N-methyl-D-aspartate (NMDA) receptor has significant involvement in the CNS sensitization process.[22] It is also hypothesized that elevated CNS glutamate levels promote wind-up and CNS sensitization.[21] In addition, there exists experimental evidence demonstrating the presence of NMDA receptors in peripheral nerves.[23] Because immunological functions can modulate CNS physiology, a variety of immune processes have also been hypothesized to contribute to the initial development and maintenance of peripheral and central sensitization.[24][25] Furthermore, trauma-related cytokine release, exaggerated neurogenic inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical reorganisation,[26] and oxidative damage (e.g., by free radicals) are all factors which have been implicated in the pathophysiology of CRPS.[27] In addition, autoantibodies are present in a wide number of CRPS patients and IgG has been recognized as one of the causes of hypersensitivity that stimulates A and C nociceptors, attributing to the inflammation.[28]

The mechanisms leading to reduced bone mineral density (up to overt osteoporosis) are still unknown. Potential explanations include a dysbalance of the activities of sympathetic and parasympathetic autonomic nervous system[29][30][31] and mild secondary hyperparathyroidism.[32] However, the trigger of secondary hyperparathyroidism has not yet been identified.[citation needed]

In summary, the pathophysiology of complex regional pain syndrome has not yet been defined; CRPS, with its variable manifestations, could be the result of multiple pathophysiological processes.[19]


Diagnosis is primarily based on clinical findings. The original diagnostic criteria for CRPS adopted by the International Association for the Study of Pain (IASP) in 1994 have now been superseded in both clinical practice and research by the "Budapest Criteria" which were created in 2003 and have been found to be more sensitive and specific.[33] They have since been adopted by the IASP. The criteria require there to be pain as well as a history and clinical evidence of sensory, vasomotor, sudomotor, and motor or trophic changes. It is also stated that it is a diagnosis of exclusion.[34]

To make a clinical diagnosis all four of the following criteria must be met:[35]

  1. Continuing pain, which is disproportionate to any inciting event
  2. Must report at least one symptom in three of the four following categories.
    • Sensory: Reports of hyperesthesia
    • Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
    • Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry
    • Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
  3. Must display at least one sign at time of evaluation in two or more of the following categories
    • Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
    • Vasomotor: Evidence of temperature asymmetry (>1 °C) and/or skin color changes and/or asymmetry
    • Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry
    • Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
  4. There is no other diagnosis that better explains the signs and symptoms

Diagnostic adjuncts[edit]

No specific test is available for CRPS, which is diagnosed primarily through observation of the symptoms. However, thermography, sweat testing, X-rays, electrodiagnostics, and sympathetic blocks can be used to build up a picture of the disorder. Diagnosis is complicated by the fact that some patients improve without treatment. A delay in diagnosis and/or treatment for this syndrome can result in severe physical and psychological problems. Early recognition and prompt treatment provide the greatest opportunity for recovery.[citation needed]


Presently, established empirical evidence suggests against thermography's efficacy as a reliable tool for diagnosing CRPS. Although CRPS may, in some cases, lead to measurably altered blood flow throughout an affected region, many other factors can also contribute to an altered thermographic reading, including the patient's smoking habits, use of certain skin lotions, recent physical activity, and prior history of trauma to the region. Also, not all patients diagnosed with CRPS demonstrate such "vasomotor instability"—particularly those in the later stages of the disease.[36] Thus, thermography alone cannot be used as conclusive evidence for—or against—a diagnosis of CRPS and must be interpreted in light of the patient's larger medical history and prior diagnostic studies.[37]

In order to minimise the confounding influence of external factors, patients undergoing infrared thermographic testing must conform to special restrictions regarding the use of certain vasoconstrictors (namely, nicotine and caffeine), skin lotions, physical therapy, and other diagnostic procedures in the days prior to testing. Patients may also be required to discontinue certain pain medications and sympathetic blockers. After a patient arrives at a thermographic laboratory, he or she is allowed to reach thermal equilibrium in a 16–20 °C, draft-free, steady-state room wearing a loose fitting cotton hospital gown for approximately twenty minutes. A technician then takes infrared images of both the patient's affected and unaffected limbs, as well as reference images of other parts of the patient's body, including his or her face, upper back, and lower back. After capturing a set of baseline images, some labs further require the patient to undergo cold-water autonomic-functional-stress-testing to evaluate the function of their autonomic nervous system's peripheral vasoconstrictor reflex. This is performed by placing a patient's unaffected limb in a cold water bath (approximately 20 °C) for five minutes while collecting images. In a normal, intact, functioning autonomic nervous system, a patient's affected extremity will become colder. Conversely, warming of an affected extremity may indicate a disruption of the body's normal thermoregulatory vasoconstrictor function, which may sometimes indicate underlying CRPS.[38]


Scintigraphy, plain radiographs, and magnetic resonance imaging may all be useful diagnostically. Patchy osteoporosis (post-traumatic osteoporosis), which may be due to disuse of the affected extremity, can be detected through X-ray imagery as early as two weeks after the onset of CRPS. A bone scan of the affected limb may detect these changes even sooner and can almost confirm the disease. Bone densitometry can also be used to detect changes in bone mineral density. It can also be used to monitor the results of treatment since bone densitometry parameters improve with treatment.[citation needed]


Ultrasound-based osteodensitometry (ultrasonometry) may be potential future radiation-free technique to identify reduced bone mineral density in CRPS.[32] Additionally, this method promises to quantify the bone architecture in the periphery of affected limbs.[32] This method is still under experimental development.[citation needed]

Electrodiagnostic testing[edit]

Electromyography (EMG) and nerve conduction studies (NCS) are important ancillary tests in CRPS because they are among the most reliable methods of detecting nerve injury. They can be used as one of the primary methods to distinguish between CRPS types I and II, which differ based on evidence of actual nerve damage. EMG and NCS are also among the best tests for ruling in or out alternative diagnoses. CRPS is a "diagnosis of exclusion", which requires that no other diagnosis can explain the patient's symptoms. This is very important to emphasise because patients otherwise can be given a wrong diagnosis of CRPS when they actually have a treatable condition that better accounts for their symptoms. An example is severe carpal tunnel syndrome (CTS), which can often present in a very similar way to CRPS. Unlike CRPS, CTS can often be corrected with surgery to alleviate the pain and avoid permanent nerve damage and malformation.[39]

Both EMG and NCS involve some measure of discomfort. EMG involves the use of a tiny needle inserted into specific muscles to test the associated muscle and nerve function. Both EMG and NCS involve very mild shocks that in normal patients are comparable to a rubber band snapping on the skin. Although these tests can be very useful in CRPS, thorough informed consent must be obtained prior to the procedure, particularly in patients experiencing severe allodynia. In spite of the utility of the test, these patients may wish to decline the procedure to avoid discomfort.[citation needed]


  • Type I, formerly known as reflex sympathetic dystrophy (RSD), Sudeck's atrophy, or algoneurodystrophy, does not exhibit demonstrable nerve lesions. As the vast majority of patients diagnosed with CRPS have this type, it is most commonly referred to in medical literature as type I.[citation needed]
  • Type II, formerly known as causalgia, has evidence of obvious nerve damage. Despite evidence of nerve injury, the cause or the mechanisms of CRPS type II are as unknown, as the mechanisms of type I.[citation needed]

Patients are frequently classified into two groups based upon temperature: "warm" or "hot" CRPS in one group and "cold" CRPS in the other group. The majority of patients (about 70%) have the "hot" type, which is said to be an acute form of CRPS.[40] Cold CRPS is said to be indicative of a more chronic CRPS and is associated with poorer McGill Pain Questionnaire scores, increased central nervous system reorganisation, and a higher prevalence of dystonia.[40] Prognosis is not favourable for cold CRPS patients; longitudinal studies suggest these patients have "poorer clinical pain outcomes and show persistent signs of central sensitisation correlating with disease progression".[41]


Vitamin C supplementation may be useful in prevention of the syndrome following fracture of the forearm, foot, or ankle.[42]


Treatment of CRPS often involves a number of modalities.[43]


Physical and occupational therapy have low-quality evidence to support their use.[44] Physical therapy interventions may include transcutaneous electrical nerve stimulation, progressive weight bearing, graded tactile desensitization, massage, and contrast bath therapy. In a retrospective cohort (unblinded, non-randomised and with intention-to-treat) of fifty patients diagnosed with CRPS, the subjective pain and body perception scores of patients decreased after engagement with a two-week multidisciplinary rehabilitation programme. The authors call for randomised controlled trials to probe the true value of multidisciplinary programs for CRPS patients.[45]

Mirror box therapy[edit]

Mirror box therapy uses a mirror box, or a stand-alone mirror, to create a reflection of the normal limb such that the patient thinks they are looking at the affected limb. Movement of this reflected normal limb is then performed so that it looks to the patient as though they are performing movement with the affected limb. Mirror box therapy appears to be beneficial at least in early CRPS.[46] However, beneficial effects of mirror therapy in the long term is still unproven.[47]

Graded motor imagery[edit]

Graded motor imagery appears to be useful for people with CRPS-1.[48] Graded motor imagery is a sequential process that consists of (a) laterality reconstruction, (b) motor imagery, and (c) mirror therapy.[43][49]

Transcutaneous Electrical Nerve Stimulation (TENS)

Transcutaneous Electrical Nerve Stimulation (TENS) is a therapy that uses low-voltage electrical signals to provide pain relief through electrodes that are placed on the surface of the skin. Evidence supports its use in treating pain and edema associated with CRPS, but it does not seem to increase functional ability in CRPS patients.[50]


Tentative evidence supports the use of bisphosphonates, calcitonin, and ketamine.[44][51] Nerve blocks with guanethidine appear to be harmful.[44] Evidence for sympathetic nerve blocks generally is insufficient to support their use.[52] Intramuscular botulinum injections may benefit people with symptoms localized to one extremity.[53]


Ketamine, a dissociative anesthetic, appears promising as a treatment for CRPS.[54] It may be used in low doses if other treatments have not worked.[55][56] No benefit on either function or depression, however, has been seen.[56]

Bisphosphonate treatment[edit]

As of 2013, high-quality evidence supports the use of bisphosphonates (either orally or via IV infusion) in the treatment of CRPS.[51] Bisphosphonates inhibit osteoclasts: cells involved in the resorption of bone. Bone remodeling (via osteoclast activity in resorption of bone) is thought to sometimes be hyperactive in CRPS. It is hypothesized that bone resorption causes acidification of the intercellular milieu which, in turn, activates nerves involved in nociception that densely innervate bone and causes pain.[51] Therefore, inhibiting bone resorption and remodeling is thought to help with regard to CRPS pain.[51] CRPS involving high levels of bone resorption, as seen on bone scan, is more likely to respond to bisphosphonate therapy.[51]


Opioids such as oxycodone, morphine, hydrocodone, and fentanyl have a controversial place in treatment of CRPS. These drugs must be prescribed and monitored under close supervision of a physician as they can quickly lead to physical dependence and addiction.[57] To date so far, no long-term studies of oral opioid use in treating neuropathic pain, including CRPS, have been performed. The consensus among experts is that opioids should not be a first-line therapy and should be considered only after all other modalities (e.g., non-opioid medications, physical therapy, and procedures) have been trialed.[58]


Spinal cord stimulators[edit]

Spinal cord stimulation appears to be an effective therapy in the management of patients with CRPS type I (level A evidence) and type II (level D evidence).[59] Although they improve patient pain and quality of life, evidence is unclear regarding effects on mental health and general functioning.[60]

Dorsal root ganglion stimulation is a type of neurostimulation that is effective in the management of focal neuropathic pain. The FDA approved its use in February 2016. The ACCURATE Study demonstrated superiority of dorsal root ganglion stimulation over spinal (dorsal column) stimulation in the management of CRPS and causalgia.[61]


Surgical, chemical, or radiofrequency sympathectomy—interruption of the affected portion of the sympathetic nervous system—can be used as a last resort in patients with impending tissue loss, edema, recurrent infection, or ischemic necrosis.[62] However, little evidence supports these permanent interventions to alter the pain symptoms of the affected patients, and in addition to the normal risks of surgery, such as bleeding and infection, sympathectomy has several specific risks, such as adverse changes in how nerves function.[citation needed]


No randomized study in medical literature has studied the response with amputation of patients who have failed the above-mentioned therapies and who continue to be in pain. Nonetheless, on average, about half of the patients will have resolution of their pain, while half will develop phantom limb pain and/or pain at the amputation site. As in any other chronic pain syndrome, the brain likely becomes chronically stimulated with pain, and late amputation may not work as well as it might be expected. In a survey of 15 patients with CRPS type 1, 11 responded that their lives were better after amputation.[63]


Cannabidiol (CBD), despite evidence of very low quality, is proposed to relieve pain.[64]


The prognosis in CRPS is improved with early and aggressive treatment; with the risk of chronic, debilitating pain being reduced with the early treatment.[65] If treatment is delayed, however, the disorder can quickly spread to the entire limb, and changes in bone, nerve, and muscle may become irreversible. The prognosis is worse with the chronic "cold" form of CRPS and with CRPS affecting the upper extremities.[65] Disuse of the limb after an injury or psychological distress related to an injury are also associated with a poorer prognosis in CRPS.[65] Some cases of CRPS may resolve spontaneously (with 74% of patients in a population-based study in Minnesota undergoing complete resolution of symptoms, often spontaneously), but others may develop chronic pain for many years.[65] Once one is diagnosed with CRPS, should it go into remission, the likelihood of it resurfacing after going into remission is significant. Taking precautions and seeking immediate treatment upon any injury is important.[66]


CRPS can occur at any age, with the average age at diagnosis being 42.[12] It affects both men and women; however, CRPS is three times more frequent in females than males.[12]

CRPS affects both adults and children, and the number of reported CRPS cases among adolescents and young adults has been increasing,[67] with a recent observational study finding an incidence of 1.16/100,000 among children in Scotland.[68]


The condition currently known as CRPS was originally described by Ambroise Paré. He successfully treated a severe and persistent pain syndrome that occurred to the French King Charles IX of Valois after a limb phlebotomy [1]. During the American Civil War, Silas Weir Mitchell is sometimes also credited with inventing the name "causalgia".[69] However, this term was actually coined by Mitchell's friend Robley Dunglison from the Greek words for heat and for pain.[70] Contrary to what is commonly accepted, it emerges that these causalgias were certainly major by the importance of the vasomotor and sudomotor symptoms but stemmed from minor neurological lesions. In the 1940s, the term reflex sympathetic dystrophy came into use to describe this condition, based on the theory that sympathetic hyperactivity was involved in the pathophysiology.[71] In 1959, Noordenbos observed in causalgia patients that "the damage of the nerve is always partial."[72] Misuse of the terms, as well as doubts about the underlying pathophysiology, led to calls for better nomenclature. In 1993, a special consensus workshop held in Orlando, Florida, provided the umbrella term "complex regional pain syndrome", with causalgia and RSD as subtypes.[73]


The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health, supports and conducts research on the brain and central nervous system, including research relevant to RSDS, through grants to major medical institutions across the country. NINDS-supported scientists are working to develop effective treatments for neurological conditions and ultimately, to find ways of preventing them. Investigators are studying new approaches to treat CRPS and intervene more aggressively after traumatic injury to lower the patient's chances of developing the disorder. In addition, NINDS-supported scientists are studying how signals of the sympathetic nervous system cause pain in CRPS patients. Using a technique called microneurography, these investigators are able to record and measure neural activity in single nerve fibers of affected patients. By testing various hypotheses, these researchers hope to discover the unique mechanism that causes the spontaneous pain of CRPS, and that discovery may lead to new ways of blocking pain. Other studies to overcome chronic pain syndromes are discussed in the pamphlet "Chronic Pain: Hope Through Research", published by the NINDS.[citation needed]

Research into treating the condition with mirror visual feedback is being undertaken at the Royal National Hospital for Rheumatic Disease in Bath. Patients are taught how to desensitize in the most effective way, then progress to using mirrors to rewrite the faulty signals in the brain that appear responsible for this condition.[74] However, while CRPS can go into remission, the chance of it reoccurring is significant.[citation needed]

The Netherlands has the most comprehensive program of research into CRPS, as part of a multimillion-Euro initiative called TREND.[75] German and Australian research teams are also pursuing better understanding and treatments for CRPS.[citation needed][76]

In other animal species[edit]

CRPS has also been described in non-human animals, such as cattle.[77]

Notable cases[edit]


  1. ^ Schwartzman, R.J.; Erwin, K.L.; Alexander, G.M. (May 2009). "The natural history of complex regional pain syndrome". The Clinical Journal of Pain. 25 (4): 273–280. doi:10.1097/AJP.0b013e31818ecea5. PMID 19590474. S2CID 10909080.
  2. ^ Harden, R.N.; Bruehl, S.; Stanton-Hicks, M.; Wilson, P.R. (May 2007). "Proposed new diagnostic criteria for complex regional pain syndrome". Pain Medicine. 8 (4): 326–331. doi:10.1111/j.1526-4637.2006.00169.x. PMID 17610454.
  3. ^ "Amplified Musculoskeletal Pain Syndrome (AMPS) in Children". Cleveland Clinic. Retrieved 2024-02-10.
  4. ^ Young-Do, K (1970). "Diagnosis of complex regional pain syndrome". Annals of Clinical Neurophysiology. 24 (2): 35–45. doi:10.14253/acn.2022.24.2.35. S2CID 253273786.
  5. ^ Goebel, A; Birklein, F; Brunner, F; Clark, JD; Gierthmühlen, J; Harden, N; Huygen, F; Knudsen, L; McCabe, C; Lewis, J; Maihöfner, C; Magerl, W; Moseley, GL; Terkelsen, A; Thomassen, I; Bruehl, S (2021). "The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria". Pain. 162 (9): 2346–2348. doi:10.1097/j.pain.0000000000002245. PMC 8374712. PMID 33729210. S2CID 232263568.
  6. ^ a b Marinus J, Moseley GL, Birklein F, Baron R, Maihöfner C, Kingery WS, van Hilten JJ (July 2011). "Clinical features and pathophysiology of complex regional pain syndrome". The Lancet. Neurology. 10 (7): 637–648. doi:10.1016/S1474-4422(11)70106-5. PMC 5511749. PMID 21683929.
  7. ^ a b "Complex regional pain syndrome - Symptoms and causes". Mayo Clinic.
  8. ^ Taylor SS, Noor N, Urits I, Paladini A, Sadhu MS, Gibb C, et al. (December 2021). "Complex Regional Pain Syndrome: A Comprehensive Review". Pain and Therapy. 10 (2) (published 24 June 2021): 875–892. doi:10.1007/s40122-021-00279-4. PMC 8586273. PMID 34165690.
  9. ^ Rolvien, T; Amling, M (2022). "Disuse Osteoporosis: Clinical and Mechanistic Insights". Calcif Tissue Int. 110 (5): 592–604. doi:10.1007/s00223-021-00836-1. PMC 9013332. PMID 33738515. S2CID 232304611.
  10. ^ a b Bruehl S, Harden RN, Galer BS, Saltz S, Backonja M, Stanton-Hicks M (January 2002). "Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome?". Pain. 95 (1–2): 119–124. doi:10.1016/s0304-3959(01)00387-6. PMID 11790474. S2CID 20773804.
  11. ^ "Complex regional pain syndrome". nhs.uk. 2017-10-19.
  12. ^ a b c Veldman PH, Reynen HM, Arntz IE, Goris RJ (October 1993). "Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients". Lancet. 342 (8878): 1012–1016. doi:10.1016/0140-6736(93)92877-V. PMID 8105263. S2CID 39843988.
  13. ^ Yu D (August 2004). "Shoulder pain in hemiplegia". Physical Medicine and Rehabilitation Clinics of North America. 15 (3): vi–vii, 683–97. doi:10.1016/S1047-9651(03)00130-X. PMID 15219895.
  14. ^ Pawelka S, Fialka V, Ernst E (January 1993). "Reflex sympathetic dystrophy and cigarette smoking". The Journal of Hand Surgery. 18 (1): 168–169. doi:10.1016/0363-5023(93)90273-6. PMID 8423309.
  15. ^ Goebel A, Turner-Stokes LF (May 2012). Complex regional pain syndrome in adults: UK guidelines for diagnosis, referral and management in primary and secondary care. Royal College of Physicians London.
  16. ^ Bussa M, Guttilla D, Lucia M, Mascaro A, Rinaldi S (July 2015). "Complex regional pain syndrome type I: a comprehensive review". Acta Anaesthesiologica Scandinavica. 59 (6): 685–697. doi:10.1111/aas.12489. PMID 25903457. S2CID 20134091.
  17. ^ Lohnberg JA, Altmaier EM (June 2013). "A review of psychosocial factors in complex regional pain syndrome". Journal of Clinical Psychology in Medical Settings. 20 (2): 247–254. doi:10.1007/s10880-012-9322-3. PMID 22961122. S2CID 14756892.
  18. ^ Maihöfner C, Forster C, Birklein F, Neundörfer B, Handwerker HO (March 2005). "Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study". Pain. 114 (1–2): 93–103. doi:10.1016/j.pain.2004.12.001. PMID 15733635. S2CID 19187294.
  19. ^ a b Howard W (2012). "Complex regional pain syndrome (CRPS), a brief review" (PDF). Australasian anaesthesia 2011: invited papers and selected continuing education lectures. Melbourne, Vic.: Australian and New Zealand College of Anaesthetists. pp. 1–6. ISBN 978-0-9775174-7-3. Archived from the original (PDF) on 3 February 2015.
  20. ^ "Pain". Courses.washington.edu. University of Washington. Archived from the original on 14 February 2005. Retrieved 2013-12-23.
  21. ^ a b Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE (September 2004). "Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome". Pain Medicine. 5 (3): 263–275. doi:10.1111/j.1526-4637.2004.04043.x. PMID 15367304.
  22. ^ Kiefer RT, Rohr P, Ploppa A, Nohé B, Dieterich HJ, Grothusen J, et al. (2008). "A pilot open-label study of the efficacy of subanesthetic isomeric S(+)-ketamine in refractory CRPS patients". Pain Medicine. 9 (1): 44–54. doi:10.1111/j.1526-4637.2006.00223.x. PMID 18254766.
  23. ^ Pöyhiä R, Vainio A (January 2006). "Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia". The Clinical Journal of Pain. 22 (1): 32–36. doi:10.1097/01.ajp.0000149800.39240.95. PMID 16340591. S2CID 14035667.
  24. ^ Watkins LR, Maier SF (February 2005). "Immune regulation of central nervous system functions: from sickness responses to pathological pain". Journal of Internal Medicine. 257 (2): 139–155. doi:10.1111/j.1365-2796.2004.01443.x. PMID 15656873. S2CID 24853745.
  25. ^ Koffler SP, Hampstead BM, Irani F, Tinker J, Kiefer RT, Rohr P, Schwartzman RJ (August 2007). "The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome". Archives of Clinical Neuropsychology. 22 (6): 719–729. doi:10.1016/j.acn.2007.05.005. PMID 17611073.
  26. ^ Birklein F (February 2005). "Complex regional pain syndrome". Journal of Neurology. 252 (2): 131–138. CiteSeerX doi:10.1007/s00415-005-0737-8. PMID 15729516. S2CID 2965351.
  27. ^ Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW (July 2007). "Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study". The Journal of Bone and Joint Surgery. American Volume. 89 (7): 1424–1431. doi:10.2106/JBJS.F.01147. PMID 17606778. S2CID 7200059.
  28. ^ Cuhadar U, Gentry C, Vastani N, Sensi S, Bevan S, Goebel A, Andersson DA (December 2019). "Autoantibodies produce pain in complex regional pain syndrome by sensitizing nociceptors". Pain. 160 (12): 2855–2865. doi:10.1097/j.pain.0000000000001662. PMID 31343542.
  29. ^ Bajayo A, Bar A, Denes A, Bachar M, Kram V, Attar-Namdar M, et al. (September 2012). "Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual". Proceedings of the National Academy of Sciences of the United States of America. 109 (38): 15455–15460. Bibcode:2012PNAS..10915455B. doi:10.1073/pnas.1206061109. PMC 3458367. PMID 22949675.
  30. ^ Kondo H, Takeuchi S, Togari A (March 2013). "β-Adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species". American Journal of Physiology. Endocrinology and Metabolism. 304 (5): E507–E515. doi:10.1152/ajpendo.00191.2012. PMID 23169789.
  31. ^ Nencini S, Ivanusic JJ (2016). "The Physiology of Bone Pain. How Much Do We Really Know?". Frontiers in Physiology. 7: 157. doi:10.3389/fphys.2016.00157. PMC 4844598. PMID 27199772.
  32. ^ a b c Bazika-Gerasch B, Maier C, Kumowski N, Fiege C, Kaisler M, Vollert J, Dietrich JW (June 2019). "Compared to limb pain of other origin, ultrasonographic osteodensitometry reveals loss of bone density in complex regional pain syndrome". Pain. 160 (6): 1261–1269. doi:10.1097/j.pain.0000000000001520. PMID 30747906. S2CID 73428940.
  33. ^ Harden NR, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, et al. (August 2010). "Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome". Pain. 150 (2): 268–274. doi:10.1016/j.pain.2010.04.030. PMC 2914601. PMID 20493633.
  34. ^ Frontera WR, Silver JK, Rizzo TD (2014-09-05). Essentials of Physical Medicine and Rehabilitation E-Book. Elsevier Health Sciences. ISBN 978-0-323-22272-3.
  35. ^ Harden NR, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, et al. (August 2010). "Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome". Pain. 150 (2): 268–274. doi:10.1016/j.pain.2010.04.030. PMC 2914601. PMID 20493633. S2CID 30417585.
  36. ^ Birklein F, Künzel W, Sieweke N (August 2001). "Despite clinical similarities there are significant differences between acute limb trauma and complex regional pain syndrome I (CRPS I)". Pain. 93 (2): 165–171. doi:10.1016/s0304-3959(01)00309-8. PMID 11427328. S2CID 20172363.
  37. ^ Wasner G, Schattschneider J, Baron R (July 2002). "Skin temperature side differences--a diagnostic tool for CRPS?". Pain. 98 (1–2): 19–26. doi:10.1016/s0304-3959(01)00470-5. PMID 12098613. S2CID 24474769.
  38. ^ Gulevich SJ, Conwell TD, Lane J, Lockwood B, Schwettmann RS, Rosenberg N, Goldman LB (March 1997). "Stress infrared telethermography is useful in the diagnosis of complex regional pain syndrome, type I (formerly reflex sympathetic dystrophy)". The Clinical Journal of Pain. 13 (1): 50–59. doi:10.1097/00002508-199703000-00008. PMID 9084952. S2CID 21310682.
  39. ^ "Reflex Sympathetic Dystrophy Clinical Practice Guidelines". Rsdfoundation.org. 2003-01-01. Archived from the original on 2013-11-02. Retrieved 2013-12-23.
  40. ^ a b Eberle T, Doganci B, Krämer HH (February 2009). "Warm and cold complex regional pain syndromes: differences beyond skin temperature?". Neurology. 72 (6): 505–12. doi:10.1212/01.wnl.0000341930.35494.66. PMID 19204260. S2CID 6670243.
  41. ^ Vaneker M, Wilder-Smith OH, Schrombges P, de Man-Hermsen I, Oerlemans HM (May 2005). "Patients initially diagnosed as "warm" or "cold" CRPS 1 show differences in central sensory processing some eight years after diagnosis: a quantitative sensory testing study". Pain. 115 (1–2): 204–11. doi:10.1016/j.pain.2005.02.031. PMID 15836983. S2CID 11529390.
  42. ^ Meena S, Sharma P, Gangary SK, Chowdhury B (May 2015). "Role of vitamin C in prevention of complex regional pain syndrome after distal radius fractures: a meta-analysis". European Journal of Orthopaedic Surgery & Traumatology. 25 (4): 637–641. doi:10.1007/s00590-014-1573-2. PMID 25488053. S2CID 22016034.
  43. ^ a b Shah A, Kirchner JS (June 2011). "Complex regional pain syndrome". Foot and Ankle Clinics. 16 (2): 351–66. CiteSeerX doi:10.1016/j.fcl.2011.03.001. PMID 21600455.
  44. ^ a b c Ferraro, Michael C.; Cashin, Aidan G.; Wand, Benedict M.; Smart, Keith M.; Berryman, Carolyn; Marston, Louise; Moseley, G. Lorimer; McAuley, James H.; O'Connell, Neil E. (2023-06-12). "Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews". The Cochrane Database of Systematic Reviews. 2023 (6): CD009416. doi:10.1002/14651858.CD009416.pub3. ISSN 1469-493X. PMC 10259367. PMID 37306570.
  45. ^ Lewis JS, Kellett S, McCullough R, Tapper A, Tyler C, Viner M, Palmer S (November 2019). "Body Perception Disturbance and Pain Reduction in Longstanding Complex Regional Pain Syndrome Following a Multidisciplinary Rehabilitation Program". Pain Medicine. 20 (11): 2213–2219. doi:10.1093/pm/pnz176. PMID 31373373.
  46. ^ O'Connell NE, Wand BM, McAuley J, Marston L, Moseley GL (April 2013). "Interventions for treating pain and disability in adults with complex regional pain syndrome". The Cochrane Database of Systematic Reviews. 2013 (4): CD009416. doi:10.1002/14651858.CD009416.pub2. PMC 6469537. PMID 23633371.
  47. ^ Moseley LG, Zalucki NM, Wiech K (July 2008). "Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain". Pain. 137 (3): 600–608. doi:10.1016/j.pain.2007.10.021. PMID 18054437. S2CID 2757963.
  48. ^ Daly AE, Bialocerkowski AE (April 2009). "Does evidence support physiotherapy management of adult Complex Regional Pain Syndrome Type One? A systematic review". European Journal of Pain. 13 (4): 339–53. doi:10.1016/j.ejpain.2008.05.003. PMID 18619873. S2CID 207607466.
  49. ^ "Graded Motor Imagery". Graded Motor Imagery. Archived from the original on 2014-01-02. Retrieved 2013-12-23.
  50. ^ Duong S, Bravo D, Todd KJ, Finlayson RJ, Tran Q (June 2018). "Treatment of complex regional pain syndrome: an updated systematic review and narrative synthesis". Canadian Journal of Anaesthesia. 65 (6): 658–684. doi:10.1007/s12630-018-1091-5. PMID 29492826.
  51. ^ a b c d e Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M, et al. (February 2013). "Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition". Pain Medicine. 14 (2): 180–229. doi:10.1111/pme.12033. PMID 23331950.
  52. ^ O'Connell NE, Wand BM, Gibson W, Carr DB, Birklein F, Stanton TR (July 2016). "Local anaesthetic sympathetic blockade for complex regional pain syndrome". The Cochrane Database of Systematic Reviews (Submitted manuscript). 7 (7): CD004598. doi:10.1002/14651858.CD004598.pub4. PMC 7202132. PMID 27467116.
  53. ^ Kharkar S, Ambady P, Venkatesh Y, Schwartzman RJ (2011). "Intramuscular botulinum toxin in complex regional pain syndrome: case series and literature review". Pain Physician. 14 (5): 419–424. PMID 21927045. Archived from the original on 2015-02-03.
  54. ^ Azari P, Lindsay DR, Briones D, Clarke C, Buchheit T, Pyati S (March 2012). "Efficacy and safety of ketamine in patients with complex regional pain syndrome: a systematic review". CNS Drugs. 26 (3): 215–228. doi:10.2165/11595200-000000000-00000. PMID 22136149. S2CID 26780542.
  55. ^ Schwartzman RJ, Alexander GM, Grothusen JR (May 2011). "The use of ketamine in complex regional pain syndrome: possible mechanisms". Expert Review of Neurotherapeutics. 11 (5): 719–734. doi:10.1586/ern.11.31. PMID 21539489. S2CID 18063794.
  56. ^ a b Niesters M, Martini C, Dahan A (February 2014). "Ketamine for chronic pain: risks and benefits". British Journal of Clinical Pharmacology. 77 (2): 357–367. doi:10.1111/bcp.12094. PMC 4014022. PMID 23432384.
  57. ^ "Complex Regional Pain Syndrome Fact Sheet". National Institute of Neurological Disorders and Stroke.
  58. ^ Stengel M, Binder A, Baron R (2007). "Update on the diagnosis and management of complex regional pain syndrome". Adv Pain Manage. 3 (1): 96–104.
  59. ^ Taylor RS, Van Buyten JP, Buchser E (February 2006). "Spinal cord stimulation for complex regional pain syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors". European Journal of Pain. 10 (2): 91–101. doi:10.1016/j.ejpain.2005.02.004. PMID 16310712. S2CID 27988384.
  60. ^ Visnjevac O, Costandi S, Patel BA, Azer G, Agarwal P, Bolash R, Mekhail NA (April 2017). "A Comprehensive Outcome-Specific Review of the Use of Spinal Cord Stimulation for Complex Regional Pain Syndrome". Pain Practice. 17 (4): 533–545. doi:10.1111/papr.12513. PMID 27739179. S2CID 20443171.
  61. ^ Brucăr M (1969). "The cleavable hydatiform polycystic pseudotumoural disease". Romanian Medical Review. 13 (3): 52–61. PMID 5359787.
  62. ^ Stanton-Hicks M, Baron R, Boas R, Gordh T, Harden N, Hendler N, et al. (June 1998). "Complex Regional Pain Syndromes: guidelines for therapy". The Clinical Journal of Pain. 14 (2): 155–166. doi:10.1097/00002508-199806000-00012. PMID 9647459.
  63. ^ Bodde MI, Dijkstra PU, den Dunnen WF, Geertzen JH (October 2011). "Therapy-resistant complex regional pain syndrome type I: to amputate or not?". The Journal of Bone and Joint Surgery. American Volume. 93 (19): 1799–1805. doi:10.2106/JBJS.J.01329. hdl:11370/64f97da0-c435-4382-bd23-e0d91dad0c7e. PMID 22005865. S2CID 12589466.
  64. ^ "WorkSafeBC". www.worksafebc.com. Retrieved 2023-07-20.
  65. ^ a b c d Lloyd EC, Dempsey B, Romero L (July 2021). "Complex Regional Pain Syndrome". American Family Physician. 104 (1): 49–55. PMID 34264598.
  66. ^ "Complex Regional Pain Syndrome (CRPS): Management and Treatment". Cleveland Clinic. Archived from the original on 7 August 2020. Retrieved 10 August 2020.
  67. ^ "RSDSA :: Reflex Sympathetic Dystrophy Syndrome Association". Rsds.org. 2010-01-21. Archived from the original on 2010-03-24. Retrieved 2010-04-10.
  68. ^ Abu-Arafeh H, Abu-Arafeh I (August 2016). "Complex regional pain syndrome in children: incidence and clinical characteristics". Archives of Disease in Childhood. 101 (8): 719–723. doi:10.1136/archdischild-2015-310233. PMID 27005945. S2CID 35072465.
  69. ^ Mitchell SE (1872). Injuries of Nerves and their Consequences. Philadelphia: JB Lippincott. 377 pages.
  70. ^ Richards RL (January 1967). "The term 'causalgia'". Medical History. 11 (1): 97–99. doi:10.1017/s0025727300011789. PMC 1033672. PMID 5341040.
  71. ^ Evans JA (March 1947). "Reflex sympathetic dystrophy; report on 57 cases". Annals of Internal Medicine. 26 (3): 417–426. doi:10.7326/0003-4819-26-3-417. PMID 20288177.
  72. ^ Noordenbos W (1959). PAIN Problems pertaining to the transmission of nerve impulses which give rise to pain. Amsterdam: Elsevier.[page needed]
  73. ^ Stanton-Hicks M, Jänig W, Hassenbusch S, Haddox JD, Boas R, Wilson P (October 1995). "Reflex sympathetic dystrophy: changing concepts and taxonomy". Pain. 63 (1): 127–133. doi:10.1016/0304-3959(95)00110-E. PMID 8577483. S2CID 1085473.
  74. ^ McCabe CS, Haigh RC, Ring EF, Halligan PW, Wall PD, Blake DR (January 2003). "A controlled pilot study of the utility of mirror visual feedback in the treatment of complex regional pain syndrome (type 1)". Rheumatology. 42 (1). Oxford University Press (OUP): 97–101. doi:10.1093/rheumatology/keg041. PMID 12509620.
  75. ^ "TREND homepage". Archived from the original on December 24, 2009..
  76. ^ Raja SN, Grabow TS (2003). "Complex regional pain syndrome". Anesthesiology. 98 (3): 1254–1260. doi:10.1097/00000542-200303000-00048. PMID 11981168.
  77. ^ Bergadano A, Moens Y, Schatzmann U (May 2006). "Continuous extradural analgesia in a cow with complex regional pain syndrome". Veterinary Anaesthesia and Analgesia. 33 (3): 189–192. doi:10.1111/j.1467-2995.2005.00245.x. PMID 16634945.
  78. ^ Paula Abdul "Paula Abdul: Putting the Spotlight on Rare Disease". Archived from the original on 2015-06-02. Retrieved 2015-06-02.
  79. ^ Crowe J (22 May 2011). "Jill Kinmont Boothe is still going strong". LA Times.
  80. ^ "Paralympic ban devastating - Brown". BBC Sport. 20 April 2014.
  81. ^ "Gemma Collis-McCann". British Paralympic Association.
  82. ^ "Radene Marie Cook". U.S. Pain Foundation. 2017-12-02.
  83. ^ "Actor Shin Dong Wook suffering from rare disease".
  84. ^ Tennant F (July–August 2007). "Howard Hughes & Pseudoaddiction" (PDF). Practical Pain Management. 6 (7): 12–29. Archived from the original (PDF) on September 25, 2007. Retrieved January 7, 2011.
  85. ^ Etienne, Vanessa; Roedel, Abby (7 June 2023). "A Shocking Accusation of Munchausen by Proxy Leads to a Mom's Death by Suicide: 'I Want Justice' (Exclusive)". People. Retrieved 28 September 2023.
  86. ^ "Rachel Morris". British Paralympic Association. Archived from the original on 2012-09-01.
  87. ^ Burtt K (13 March 2015). Geehr EC (ed.). "Cynthia Toussaint". Lifescript. Archived from the original on 2015-06-27.
  88. ^ "Rolstoelatlete Marieke Vervoort is overleden". De Standaard. 22 October 2019.

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