Studies 2004


There is an ever increasing body of CRPS research which covers many aspects of this disease. The following is a list of CRPS studies in 2004. Since new studies are always being done, this file will be edited frequently.


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Studies A-M

Studies N-Z




For a copy of this or any CRPS article, visit McMaster Health Sciences Library. Search Pub Med using the PMID number listed.


Backonja MM, Serra
Pharmacologic management part 2: lesser-studied neuropathic pain diseases.

J.Pain Med. 2004 Mar;5 Suppl 1:S48-59.

University of Wisconsin Hospital and Clinics, Madison, Wisconsin; Neuropathic Pain Unit, Hospital General de Catalunya, Barcelona, Spain.

This second part of a review of the pharmacologic management of neuropathic pain diseases describes the current treatment options for three lesser-studied neuropathic syndromes: Central post-stroke pain, spinal cord injury, and complex regional pain syndrome II. Diagnosis can be difficult in patients with these syndromes, because the pain experienced is much greater and of a different type than would normally be expected following a stroke or injury to the spinal cord or a peripheral nerve. Even when an accurate and timely diagnosis is made, treatment options are limited and frequently suboptimal. However, the results of published trials do support the use of anticonvulsants and/or tricyclic antidepressants as first-line pharmacotherapy in these three neuropathic pain syndromes. To maximize treatment outcomes, future research must: Continue to more fully elucidate the relationship between the signs and symptoms of pain and the underlying pathophysiology; Delineate the natural history of central post-stroke pain, spinal cord injury, and complex regional pain syndrome; Identify patient-related factors that may indicate an increased risk of developing neuropathic pain following stroke or nerve injury; Investigate emerging treatments that target underlying pain mechanisms.

PMID: 14996229

***Carter ML.

Spinal cord stimulation in chronic pain: a review of the evidence.
Anesth Intensive Care. 2004 Feb;32(1):11-21.

Department of Anaesthesia, Bundaberg Base Hospital, PO Box 34, Bundaberg, Qld 4670.

This review looks at the evidence for the effectiveness of spinal cord stimulation in various chronic pain states. Spinal cord stimulation can only be effective when appropriate dorsal column fibres in the spinal cord are preserved and able to be stimulated. Spinal cord stimulation has been shown to have little to offer for patients with some diagnoses. Although 50 to 60% of patients with failed back surgery syndrome obtain significant pain relief with this technique, the strength of the evidence available is insufficient to clearly advocate its use in all patients with this condition. Though limited in quantity and quality, better evidence exists for its use in neuropathic pain, complex regional pain syndrome, angina pectoris and critical limb ischaemia. There is a lack of high quality evidence relating to spinal cord stimulation due to difficulties in conducting randomized controlled trials in this area. Serious methodological problems are encountered in blinding, recruitment and assessment in nearly all published trials of spinal cord stimulation. Suggestions regarding appropriate methodologies for trials which would produce better quality evidence are summarized.

PMID: 15058115

Cordivari C, Misra VP, Catania S, Lees AJ.

New therapeutic indications for botulinum toxins.
Mov Disord. 2004 Mar;19 Suppl 8:S157-61.

Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.

The efficacy of botulinum toxin (BTX) without systemic effects has led to the rapid development of applications in neuromuscular disorders, hyperactivity of sudomotor cholinergic-mediated glandular function, and pain syndromes. The successful use of BTX in conditions with muscle overactivity, such as dystonia and spasticity, has been established and new areas in the field of movement disorders such as tics, tremor, myoclonic jerks, and stuttering has been explored with satisfactory results. Strategies to temporarily inactivate muscle function after orthopaedic or neurosurgery have also been developed. BTX treatment of hyperhidrosis was followed by its application in other hypersecretory conditions (hyperlacrimation and nasal hypersecretion) and in excessive drooling. Studies are in progress, aimed at optimising the technique and protocol of administration. Other applications for BTX have been proposed in gastroenterological and urogenital practice; it appears to be effective in replacing standard surgical procedures. Trials of BTX in painful conditions are ongoing mainly on refractory tension headache, migraine, and backache as well as dystonia-complex regional pain syndrome and myofascial pain with promising results. Recently, the fastest growing use for BTX toxin has been in the cosmetic applications. Clearly, the indications for the use of BTX are expanding, but further clinical trials will be needed in many different areas. Copyright 2004 Movement Disorder Society

PMID: 15027069

Drummond PD, Finch PM.

Persistence of pain induced by startle and forehead cooling after sympathetic blockade in patients with complex regional pain syndrome.
J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):98-102

School of Psychology, Murdoch University, Perth, Western Australia, Australia.

BACKGROUND: Stimuli arousing sympathetic activity can increase ratings of clinical pain in patients with complex regional pain syndrome (CRPS). OBJECTIVE: To determine whether the increase in pain is mediated by peripheral sympathetic activity. METHODS: The effect of sympathetic ganglion blockade on pain evoked by a startle stimulus and cooling the forehead was investigated in 36 CRPS patients. RESULTS: Loss of vasoconstrictor reflexes and warming of the limb indicated that sympathetic blockade was effective in 26 cases. Before sympathetic blockade, pain increased in 12 of these 26 patients when they were startled. Pain increased in seven of the 12 patients and in another five cases when their forehead was cooled. As expected, pain that increased during sympathetic arousal generally subsided in patients with signs of sympathetic blockade. However, pain still increased in three of 12 of patients after the startle stimulus and in six of 12 of patients during forehead cooling, despite indisputable sympathetic blockade. CONCLUSIONS: These findings suggest that stimuli arousing sympathetic activity act by a central process to exacerbate pain in some patients, independent of the peripheral sympathetic nervous system. This may account for the lack of effect of peripheral sympathetic blockade on pain in some CRPS patients.

PMID: 14707316

Forouzanfar T, Kemler MA, Weber WE, Kessels AG, van Kleef M.

Spinal cord stimulation in complex regional pain syndrome: cervical and lumbar devices are comparably effective.
Br J Anesth 2004 Mar;92(3):348-53. Epub 2004 Jan 22.

Department of Anaesthesiology, University Hospital Maastricht, Maastricht, The Netherlands.

BACKGROUND: Spinal cord stimulation (SCS) has been used since 1967 for the treatment of patients with chronic pain. However, long-term effects of this treatment have not been reported. The present study investigated the long-term effects of cervical and lumbar SCS in patients with complex regional pain syndrome type I. METHODS: Thirty-six patients with a definitive implant were included in this study. A pain diary was obtained from all patients before treatment and 6 months and 1 and 2 years after implantation. All patients were asked to complete a seven-point Global Perceived Effect (GPE) scale and the Euroqol-5D (EQ-5D) at each post-implant assessment point. RESULTS: The pain intensity was reduced at 6 months, 1 and 2 years after implantation (P<0.05). However, the repeated measures ANOVA showed a statistically significant, linear increase in the visual analogue scale score (P=0.03). According to the GPE, at least 42% of the cervical SCS patients and 47% of the lumbar SCS patients reported at least 'much improvement'. The health status of the patients, as measured on the EQ-5D, was improved after treatment (P<0.05). This improvement was noted both from the social and from the patients' perspective. Complications and adverse effects occurred in 64% of the patients and consisted mainly of technical defects. There were no differences between cervical and lumbar groups with regard to outcome measures. CONCLUSION: SCS reduced the pain intensity and improves health status in the majority of the CRPS I patients in this study. There was no difference in pain relief and complications between cervical and lumbar SCS.

PMID: 14742334

Gorodkin R, Moore T, Herrick A.

Assessment of endothelial function in complex regional pain syndrome type I using iontophoresis and laser Doppler imaging.

Rheumatology (Oxford). 2004 Mar 16

University of Manchester Rheumatic Disease Centre, Hope Hospital, Salford, UK.

OBJECTIVES: To assess microvascular endothelial function in patients with complex regional pain syndrome type I (CRPS) compared with healthy controls, as measured by iontophoresis of vasoactive chemicals and laser Doppler imaging. METHODS: Microvascular blood flow was stimulated locally in affected and contralateral limbs of patients with CRPS (n = 17) and in control subjects (n = 16) using iontophoresis of the endothelial-dependent vasodilator acetylcholine (ACh) and the endothelial-independent vasodilator sodium nitroprusside (NaNP). Changes in blood flow were measured using laser Doppler imaging. Comparisons were made between right and left limbs and between patients and controls. RESULTS: No significant differences in blood flow [expressed as a median percentage increase from baseline (interquartile range)] were detected between affected and contralateral limbs in patients with CRPS for ACh [affected 237 (95-344); unaffected 251 (152-273)] or for NaNP [affected 102 (49-300); unaffected 190 (53-218)]. In addition, there were no significant differences between patients and healthy controls [controls, ACh 216 (119-316); controls, NaNP: 122 (48-249)]. CONCLUSIONS: In this pilot study, CRPS was not associated with impairment of microvascular endothelial function. This may be a true result or may reflect the diversity of the CRPS disease process.

PMID: 15026582

Clark, Triesman GJ Pain and Depression An Interdisciplinary Patient-Centered Approach Adv Psychosom Basel Karger 2004 Vol. 25 pp 89-101

Grabow T, MD Raja, MD S Christo, P.
CRPS: Diagnostic Controversies, Psychological Dysfunction and Emerging Concepts

Division of Pain Medicine, Dept. of Anesthesia and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore MD USA

ABSTRACT: Complex regional pain syndrome types I and II are neuropathic pain disorders that involve dysfunction of the peripheral and central nervous system. CRPS type I and II are formerly known as reflex sympathetic dystrophy and causalgia, respectively. Most experts believe that a multidisciplinary approach including pharmacotherapy, physiotherapy, and psychotherapy is warranted. Historically, there has been considerable controversy regarding this disease entity. In particular, the precise mechanism of the sympathetic dysfunction as well as the nature of the psychological dysfunction commonly observed in patients with CRPS has been the subject of considerable debate. Current strides in our understanding of the pathophysiology of this disease have improved treatment options.


Complex regional pain syndrome (CRPS) types I and II formerly known as reflex sympathetic dystrophy and causalgia, are neuropathic pain disorders likely involving dysfunction of the both the peripheral and central nervous system. The pathophysiology is poorly understood and treatments often are directed at managing signs and symptoms of the disease. A significant number of patients exhibit comorbid psychological dysfunction which has led some clinicians to believe incorrectly that it is entirely a psychiatric disease. Animal research has improved our mechanistic understanding of neuropathic pain and this awareness hay facilitate our understanding of CRPS (particularly type II). Recent clinical investigation has resulted in an improved understanding of the biological dysfunction observed in patients with CRPS. This review will (1) summarize the historical arguments and controversy surrounding the disease, (2) describe the psychological dysfunction often observed in patients with CRPS and (3) discuss recent trends in the neurobiological understanding of CRPS.

CRPS Controversy and Misunderstanding

CRPS History
Several authors have questioned the validity of CRPS type I as an actual organically based neurological disease and have doubted the involvement of the sympathetic nervous system in the maintenance of the pain. Many aspects of the disease, including nomenclature, etiopathogenesis, diagnosis and treatment have generated considerable controversy. As a result, CRPS type I (RSD), has been considered by some experts an expression of somatoform disease and therefore has been designated as pseudoneuropathy of psychogenic origin. A brief discussion of several of these arguments is warranted.

Causalgia was first described in 1864 as a distinct disease entity by Silas Weir Mitchell who noted extreme pain, autonomic abnormalities, trophic changes and involuntary movements in Civil War soldiers who suffered from traumatic injury to peripheral nerves.

Renee Leriche later postulated in 1916 that the sympathetic nervous system was involved in pain states involving major tissue or nerve injury, the term RSD was coined nearly half a century later in 1946 by JA Evans to describe patients who exhibited causalgia-like symptoms but without evidence of major tissue or nerve injury. Several other terms have been used to describe this disease such as minor causalgia, algodystrophy, shoulder-hand syndrome, posttraumatic dystrophy, and Sudeck’s atrophy. In general, the disease was given different names based on the personal assumptions, frame of reference, institutional background, or country of origin of the investigators who were describing the disease process.

In 1994, a task force commissioned by the IASP introduced the present day descriptive terminology to standardize the nomenclature, remove obsolete mechanistic understandings, and improve disease recognition, Until this time, scholars had argued that the term RSD erroneously implied an underlying “reflexive” mechanism presumably related to aberrant function (ex. hyperactivity) of the sympathetic nervous system that if left untreated, would inevitably lead to permanent dystrophic change. Today, most authorities recognize that sympathetic (overactivity) is not observed and that sympathetic dysfunction and dystrophic changes occur only in a subset of patients with CRSP. Furthermore, certain therapies specifically aimed at the sympathetic nervous system may be unwarranted. (1,2). Despite the efforts of the IASP, many clinicians are unfamiliar with the modern taxonomy and the majority of contemporary investigations fail to utilize the diagnostic criteria proposed by the IASP.

According to the IASP, the diagnosis of CRPS requires (1) an initiating noxious event or cause of immobilization (2) continuing pain, allodynia or hyperaglesia disproportionate to any inciting event (3) evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity and (4) the exclusion of a medical condition that would otherwise account for the degree of pain and dysfunction. the presence on an initiating noxious event or cause of immobilization was not required according to the original publication by the IASP in 1994; however, this statement was omitted from the more widely available and Meddling-indexed summary statement from the consensus meeting published in 1995.. Importantly, a precipitating inciting event may not be detected in approximately 10% of patients with CRPS(6). This definition is entirely descriptive and does not imply etiology or specific pathophysiology. This lack of mechanism based specificity in the proposed diagnostic criteria has detracted somewhat from its universal acceptance by the scientific community.


Patients with CRPS exhibit signs of emotional duress and psychological dysfunction. Consequently, it was tempting for early investigators to conclude that much of the pain and symptomatology was the results of untreated psychiatric disease or caused by exaggerated sympathoarousal secondary to underlying stress. The term RSD helped to maintain this cause and effect link between the sympathetic nervous system, and the pain. As a result, many patients underwent therapies designed to mitigate sympathetic nervous system dysfunction. Today there is convincing evidence in animals and humans that nerve injury and tissue inflammation may be associated with aberrant functioning of the sympathetic nervous system. (7) (Table 1) Despite this link, the pathophysiology of CRPS is incompletely understood and several mechanisms may be operating simultaneously. Furthermore, it is commonly recognized that only a subset of patients with CRPS have sympathetically maintained pain ((SMP) which is defined as pain that is modulated by sympathetic block or pharmacological antagonism of alpha adrenoreceptor function.

Psychological Dysfunction

Psychiatric Comorbid Conditions in Chronic Pain

Chronic pain patients frequently have associated comorbid psychiatric disease.(8). When ranked form most frequent to least frequent, the following comorbid conditions likely are associated more with chronic pain patients than with the general population: affective disorders (depression), psychoactive substance, use-related disorders, somatoform disorders, and anxiety disorders. Moreover, a significant number of chronic pain patients may have more than one axis I psychiatric comorbidity. Psychiatric comorbidities can have a negative impact on chronic pain and functional status. In addition, there are a group of conditions commonly observed in chronic pain patients that are not necessarily psychiatric in nature which in addition, do not satisfy formal Diagnostic and Statistical Manual (DSM) criteria. These observations include such things as pain behaviours, sleep disturbance, somatization, nonorganic physical findings, and impaired functional status out of proportion to physician expectations based on objective findings(8). The prognostic implication of these conditions is unknown.

Psychiatric Disease in CRPS

Patients with CRPS commonly suffer from psychological dysfunction. In fact, patients with CRPS experience a significant amount of depression, anxiety and phobia. However, attempts to establish a unique “CRPS personality” have been unsuccessful. In general, early studies lacked validity due to various flaws in methodological design. For example, studies failed to examine premorbid personality data, investigators used heterogenous definitions of psychiatric terminology and psychometric instruments had nor been normed on pain populations(9). Nevertheless, reported prevalence of psychiatric disorders in patient with CRPS ranges from 18-64%(10). Psychological examination using the Structured Clinical Interview (SCID) of the DSM-IV demonstrates a high frequency of affective disorder (46%), anxiety disorder (27%), and substance abuse disorder (14%) in patients with CRPS.(11). However, the prevalence of psychiatric disorders in patients with CRPS may not be much different from chronic pain patients in general. For example, the prevalence of major depression (1.5-54.5%), anxiety disorders (7-62.5%) and substance abuse disorders (3.2-18.9%).in chronic pain patients is reported in similar rates as CRPS patients (8) Finally Breuhl and Carlson (10) reviewed data strictly from studies which used the MMPI and concluded that patients with CRPS like patients with chronic pain in general, are somatically preoccupied, depressed and use repression as a psychological defense mechanism.

There has been historical debate whether chronic pain or psychiatric illness is the primary process. The reciprocal relationship between pain and psychological dysfunction in patient with CRPS is evident from a recent study of daily diaries which demonstrated that yesterday’s depressed pain also contributed to today’s depression, anxiety and anger.(12)> Several literature reviews have examined whether psychological dysfunction was the cause or effect of CRPS. (9,10,13). In general, the majority of historical studies suffered from flaws in methodology such as lack of consistent and homogenous diagnostic groups, lack of control groups and significant statistical tests, lack of objective measures of psychological disease, poorly defended behavioural criteria, and incorrect use of psychiatric or psychological terminology(13). As a result, Lynch (13) concluded there is no valid evidence that certain personality traits or psychological factors predispose one to the development of CRPS. Similarly, due to the methodological weakness of the literature, Breuhl and Carlson (10) concluded that there is insufficient data to draw meaningful conclusions whether or not pre-existing psychological factors predispose to the development of CRPS.

In summary, most authors have concluded that cormorbid psychological disease in patients with CRPS is a consequence of the chronic pain rather than its cause. (9, 13). Further more, there is no evidence that individuals with certain personality types are predisposed to developing CRPS. Finally there are no consistent psychological differences between CRPS and non-CRPS pain patients (14-22).
Table 2)

Factitious Disorder
The overall prevalence of factitious disorder in chronic pain patients is between 0,14 and 2% (8). Patients with conversion disorder and factitious illness my have similar clinical presentation to patients with CRPS. In Fact, certain sensory sign (ex. Non-anatomical and expansive areas of hypoesthesia or hyperalgesia with normal peripheral sensory nerve conduction of somatosensory evoked potentials) or features (e.g. normalization of hypoesthesia by nerve blocks) identified in patients with CRPS type 1 likely are psychogenic in origin. Moreover, neurophysiological investigation suggest that certain positive motor signs (dystonia, tremors, spasms, irregular jerks) identified in patients with CRPS type I are in fact psychogenic in origin and represent psuedoneurological illness(23).

Strain and Distress in Caregivers

Caregivers of patients with CRPS experience significant levels of strain and susceptibility to depression measured by the Caregiver Strain Index (CSI) and General Health Questionnaore012 (GHQ 12), respectively(24). Caregiver health can have a significant impact on recipient care. Thus, physicians should not only implement psychosocial interventions directed at patients but also caregivers of patient with CRPS.

Other Issues (Legal, Disability)

Allen et al (25) recently performed a retrospective chart review of the epidemiology of CRPS. They reported that 54% of patients had a worker compensation claim and that 17% had a lawsuit related to the CRPS. The effect of litigation on pain severity and clinical outcomes for patients with CRPS is unknown.

Neglect-like Symptoms

Patients with CRPS often display signs of motor dysfunction that appear to be related to voluntary guarding in order to avoid exacerbation of pain. However, recent evidence suggest that motor dysfunction may be related to neglect-like symptoms ( e.g. cognitive neglect, motor neglect)in a subset of patients with CRPS(26.) Of note, self-reported motor dysfunction is the second most commonly reported groups of symptoms after sensory dysfunction in patient with CRPS. (27).

Quality of Life

A pilot study demonstrated substantial interference with quality of like measured by modified Brief Pain Inventory (mBPI) as well as significant sleep disturbance in patient with CRPS(27).

Stressful Life Events
Stressful life events were more common in patients with CRPS than in a control group of patients with hand pathology measured by the Social Readjustment Rating Scale (SRRS) (20). However, these authors concluded that there was no direct casual relationship between these stressful life events or any underlying psychological dysfunction measured by SCL-90 and the onset of CRPS. In a retrospective study, Geertzen et al (28) concluded that stressful life events and psychological dysfunction measured by the SRRS and RAND-36 item health Survey (RAND-36), respectively, already existed at the time of diagnosis of CRPS and did not results from CRPS.


Sympathetic Nervous System

In animals, there is overwhelming evidence that nerve injury and inflammation can result in functional coupling between the sympathetic efferents and primary sensory afferent neurons within the peripheral nervous system (7).The site of this aberrant sympathetic-sensory coupling involves the dorsal root ganglia (DRG) the area of injury itself (e.g. neuroma site) or within the tissue innervated by the injured nerve.
Several of these correlates exist in humans and these findings have been summarized in recent reviews (7). For example, peripheral nerve injury results in sympathetic sprouting and functional coupling between sympathetic efferents and primary sensory afferent neurons in the DRG (29). An increase of alpha-adrenoreceptors have been observed in the hyperalgesic skin of patients with CRPS type 1 (30). Patients with CRPS I have decreased sympathetic outflow but increased ?-adrenergic responsiveness in the affected limbs suggesting adrenergic supersensitivity. This supersensitivity is reversed with CRPS symptoms resolve. Pharmacological or surgical sympathectomy can decrease pain in patient with CRPS and patients with neuropathic pain report increased pain during stress or after intradermal injection of a physiological dose of norepinephrine(NE)(31). In addition, injections of NE can rekindle pain and mechanical hyperalgesia in patient who have had a previous sympathetic block. Finally, inflammatory pain and hyperalgesia produced by topical capsaicin is decreased by a-adrenoceptor antagonists and increased by NE(32).
Despite this evidence, systematic reviews have failed to demonstrate the efficacy of therapies designed to inhibit sympathetic function and question their unity (1,2).In fact, some investigators have challenged the validity of pharmacological tests to establish the diagnosis of SMP. The pain can be challenging even for clinicians with considerable expertise. (33).
Recent studies have examined the effect of the natural stimulation of the subject’s own sympathetic nervous system on spontaneous pain and hyperalgesia rather than the effect of pharmacological treatment such as sympathetic blocks or injections of NE. Sympathetic arousal increased pain and vasoconstriction in the affected extremity of patients with CRPS I and II. (34). Also sympathetic activation increased spontaneous pain and spatial distribution of mechanical hyperalgesia in patients with CRPS I who have SMP. (34). These two investigations were the first to demonstrate that physiological activation of the sympathetic nervous system can modulate the pain experience in humans through endogenous release of NE from sympathetic nerve endings. These findings provide evidence in support of the concept of SMP or pain as the result of sympathetic efferent activity.


In the acute stage of CRPS I there is complete functional loss of cutaneous sympathetic vasoconstrictor activity as well as decreased venous plasma levels of NE (presumably secondary to decreased postganglionic release from sympathetic terminals) confined to the affected extremity (36). This autonomic impairment may recover within weeks and likely reflects dysfunction within the CNS. During chronic CPRS sympathetic vasoconstrictor neurons are still inhibited but adrenoreceptor supersensitive in vascular tissue results in ongoing vasoconstriction and subsequent cold skin. These vascular abnormalities are dynamic and more pronounced when examined over the entire range of the thermoregulatory cycle (37).
Patients with acute CRPS I also demonstrate a-adrenergic super sensitivity of sudomotor nerves that is reversible with disease progression (38). Unilateral disturbances in sudomotor function determined by quantitative sudomotor axon reflex test (QSART) and thermoregulatory sweat test (TST) also have been reported in patients with chronic CRPS (39).

Sensory Dysfunction
Sensory disturbances are common in patients with CRPS I and II and predominately consist of hyperalgesia, allodynia, and spontaneous pain (6). Quantitative sensory testing (QSART) demonstrates an increase in warm perception thresholds and a decrease of cold pain thresholds in patient with CRPS I and II. Sensory impairments frequently extend beyond the affected area and may involve quadratic or hemilateral regions of the body (41).

Motor Dysfunction

Motor disturbances are prevalent in patients with CRPS I and II.(6) and are independent of sensory and autonomic complaints (40). The most frequently described motor disturbance is loss of function of the affected extremity. Detailed neurological examination may detect objective evidence of isolated motor weakness, muscle atrophy, tremor, dystonia, or ataxia. Furthermore, electrodiagnostic and nerve conduction velocity can be used to document muscle and large fiber abnormalities, respectively. Decrease in active range of motion can be assessed by goniometer. Similarly, muscle power can be assessed by measuring grip force strength or by manual muscle testing. More complex motor tasks can be measured by kinematic analysis. A recent study has demonstrated neurophysiological evidence of impairment of central sensor motor integration in patients with CRPS I (42). These motor deficits may be secondary to abnormal integration of visual and sensory inputs to the parietal cortex (43).

CNS Dysfunction

Evidence suggests that certain autonomic, motor and sensory disturbances in patients with CRPS are caused by dysfunction within the CNS whereas certain aspects of the pain itself may be related to aberrant peripheral mechanisms. Potential peripheral and central mechanisms are described elsewhere (7,44). Occasionally, dysfunction of the sensory, motor, or autonomic nervous system, may involve bilateral structures after unilateral nerve or tissue injury (45). In addition, several investigators have described CNS abnormalities by fMRI, MRS, or SPECT. Recent investigation suggests that patients with CRPS may develop function or structural reorganization and change in central representation of sensory maps. However it is unclear whether these abnormalities are as a result of the chronic pain or whether they represent specific regions of primary dysfunction within the CNS.

Treatment Algorithm for CRPS

The therapeutic strategy for patients with CRPS involves the concurrent utilization of pharmaoco-,physio- and psychotherapy. However, randomized controlled trials (RCT) investigating the impact of psychological intervention on homogenous groups of patient with neuropathic pain, including patients with CRPS have not been undertaken (46) Nevertheless, principles derived from operant and cognitive behaviour theory are useful to treat chronic pain patient in general and these strategies should be used for patients with CRPS. The goal of pharmacological therapy is to reduce pain in order to facilitate functional restoration. In general medications that are effective for the treatment of neuropathic pain are used for patients with CRPS. The goal of physiotherapy is to improve functional status. In general desensitization and physical rehabilitation cannot proceed without adequate pain control. Most authorities believe that active participation in physical therapy is instrumental for improvement in patient with CRPS. To date, only the short term efficacy of physical therapy has been demonstrated by a RCT specifically for CRPS patients (47). The use of these interventional techniques should be considered in the treatment algorithm when other therapies have failed. A summary of current therapeutic strategies has been published. (48).

Low doses of a common intravenous anesthetic may relieve debilitating pain syndrome
Harbut R MD

23 Sep 2004

Limited, low-dose infusions of a widely used anesthetic drug may relieve the often intolerable and debilitating pain of Complex Regional Pain Syndrome (CRPS), a Penn State Milton S. Hershey Medical Center researcher found.

"This pain disorder is very difficult to treat. Currently-available therapies, at best, oftentimes only make the pain bearable for many CRPS sufferers," said Ronald E. Harbut, M.D., Ph.D., assistant professor of anesthesiology, Penn State Hershey Medical Center. "In our retrospective study, some patients who underwent a low-dose infusion of ketamine experienced complete relief from their pain, suggesting that this therapy may be an option for some patients with intolerable CRPS."

The study, titled "Subanesthetic Ketamine Infusion Therapy: A Retrospective Analysis of a Novel Therapeutic Approach to Complex Regional Pain Syndrome," was published in the September 2004 issue of Pain Medicine, the official journal of the American Academy of Pain Medicine.

CRPS (type I), also known as Reflex Sympathetic Dystrophy Syndrome (RSD), affects between 1.5 million and 7 million people in the United States and is oftentimes marked by a severe, burning pain that can be very resistant to conventional therapies. The pain frequently begins after a fall or sprain, a fracture, infections, surgery, or trauma. Often present in the limbs with possible later spreading to other parts of the body, patients also may experience skin color changes, sweating abnormalities, tissue swelling, and an extreme sensitivity to light touch or vibrations. The McGill Pain Index rates CRPS as 42 on the scale of 50, with 50 being most severe.

Although much is unknown about CRPS, the pain experienced by patients appears to be caused by over-stimulation of a nerve receptor complex involved in the process of feeling pain. Therefore, efforts have been made to treat CRPS by blocking these receptors. Whereas most pain medications do not effectively block these receptor complexes (often referred to as NMDA-receptors), ketamine does.

The study was initiated by Graeme E. Correll, B.E., M.B.B.S., and involved reviewing the medical records of 33 patients with CRPS treated by Correll. The patients, some of whom had failed to obtain pain relief from conventional therapies, were treated with low-dose inpatient intravenous infusions of ketamine between 1996 and 2002 in Mackay, Queensland, Australia. Ketamine infusions were started at very low rates and were slowly increased in small increments as tolerated by selected patients. The therapy was then continued as long as the patient tolerated the drug and continued to benefit from it. Treatment cycles generally continued until the patient experienced complete pain relief; until initially-obtained relief would not improve any further; or for no more than 48 hours if there was no improvement in pain severity.

Pain was completely relieved for 25 (76 percent) patients, partially relieved for six (18 percent) patients, and not relieved for two (6 percent) patients. Although the relief obtained did not last indefinitely, 54 percent remained completely pain-free for three months or more and 31 percent for six months or more. For 12 patients who received a second treatment, 58 percent experienced relief for one year or more with 33 percent remaining pain-free for more than three years.

The most frequent side effect reported was a feeling of inebriation. Hallucinations occurred in six patients with less frequent side effects including complaints of light-headedness, dizziness and nausea. Liver enzymes were altered in four patients but resolved after therapy.

The exact mechanism of sustained pain relief is unknown, but is currently under study at Penn State Hershey Medical Center. Harbut likened the ketamine treatment to the healing of a broken bone. "If someone breaks a bone and you simply put the two pieces back together, they won't immediately heal. However, if you add a splint and hold the bones steady for a period of time, and then later take away the splint the bone is healed. I believe that the ketamine treatment does something similar that lends support and allows the nerve cells to heal themselves, so that when you take away the ketamine, the pain is reduced or gone."

Harbut began studying CRPS with Correll during a work assignment Harbut volunteered to take in far northern Queensland, Australia, in the late 1990s. Correll was developing a therapy for CRPS but wanted a collaborator to formally research the effectiveness of the therapy. Harbut brought Correll's method back to the U.S. where he developed an FDA-approved study protocol (used at the Mayo Clinic Scottsdale) using this method to attempt to treat post herpetic neuralgia, another pain disorder with symptoms somewhat similar to CRPS. At the same time, Harbut met a patient who had suffered with intolerable CRPS for nine years who wanted to try this new therapy. That patient became the first successful treatment of intractable CRPS in the U.S. (A Case Report of this treatment appeared in the June 2002 issue of Pain Medicine.)

"Ultimately, we want to find a way to improve the quality of life for those who suffer with intolerable CRPS, some of whom at times contemplate suicide because of their endless pain," Harbut said. "Although optimistic about these early findings, certainly more study is needed to further establish the safety and efficacy of this novel approach." (A large clinical study is currently planned and under development at Penn State Hershey Medical Center.)

In addition to Harbut and Correll, the team involved in this study included: Jahangir Maleki, M.D., Ph.D., and Edward J. Gracely, Ph.D., Drexel University College of Medicine; and Jesse J. Muir, M.D., Mayo Clinic Scottsdale.


***Huygen FJ, Ramdhani N, Van Toorenenbergen A, Klein J, Zijlstra FJ.
Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type 1.
Immunol Lett. 2004 Feb 15;91(2-3):147-154.

Pain Treatment Center, Department of Anesthesiology, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Background: The Complex Regional Pain Syndrome type 1 (CRPS1) is a complication of surgery or trauma but spontaneous development is also described. Although the pathogenesis remains debatable, afferent, efferent and central nervous system mechanisms are proposed. Recently we showed involvement of the proinflammatory cytokines IL-6 and TNFalpha which is direct evidence for an inflammatory process. Many types of cells, such as activated T lymphocytes, monocytes,macrophages and skin resident cells like mast cells, could contribute to the production of cytokines. Involvement of mast cells is relatively easy to detect by measurement of tryptase. Aim: To establish whether mast cells are involved in the inflammatory reactions during CRPS1. Methods: Twenty patients fulfilling the Bruehl criteria with CRPS1 in one extremity were studied. Impairment was assessed by registration of pain and measurement of differences in temperature, volume and mobility between the involved and uninvolved extremity. Blisters were made with a suction method in order to determine cytokines and mast cell derived tryptase in the involved and uninvolved extremity. Results: In the blister fluid a significant difference ( [Formula: see text] range, Wilcoxon signed-ranks test [Formula: see text] ) was found between the involved and uninvolved extremity in IL-6 {53.5 (17.3-225) versus 6.2 (2-20.3) pg/ml}, TNFalpha {31 (15.5-131.5) versus 8 (4-39) pg/ml}, and tryptase {37 (20.5-62.3) versus 12.5 (6.7-23.5)ng/ml}. There was a significant correlation (0.455) between the intensity of pain and tryptase levels in the involved extremity (Spearman's test, [Formula: see text] ). Conclusion: Mast cells are involved in inflammatory reactions during the CRPS1. Mast cells could play a role in the production of cytokines such as TNFalpha.

PMID: 15019283


***Huygen FJ, Niehof S, Klein J, Zijlstra FJ.

Computer-assisted skin videothermography is a highly sensitive quality tool in the diagnosis and monitoring of complex regional pain syndrome type I.
Eur J Appl Physiol. 2004 Jan 21

Department of Anesthesiology, Pain Treatment Centre, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

The use of thermography in the diagnosis and evaluation of complex regional pain syndrome type 1 (CRPS1) is based on the presence of temperature asymmetries between the involved area of the extremity and the corresponding area of the uninvolved extremity. The interpretation of thermographic images is, however, subjective and not validated for routine use. The objective of the present study was to develop a sensitive, specific and reproducible arithmetical model as the result of computer-assisted infrared thermography in patients with early stage CRPS1 in one hand. Eighteen patients with CRPS1 on one hand and 13 healthy volunteers were included in the study. The severity of the disease was determined by means of pain questionnaires [visual analogue scale (VAS) pain and McGill Pain Questionnaire], measurements of mobility (active range of motion) and oedema volume. Asymmetry between the involved and the uninvolved extremities was calculated by means of the asymmetry factor, the ratio and the average temperature differences. The discrimination power of the three methods was determined by the receiver-operating curve (ROC). The regression between the determined temperature distributions of both extremities was plotted. Subsequently the correlation of the data was calculated. In normal healthy individuals the asymmetry factor was 0.91 (0.01) (SD), whereas in CRPS1 patients this factor was 0.45 (0.07) (SD). The performance of the arithmetic model based on the ROC curve was excellent. The area under the curve was 0.97, the P value was <0.001, the sensitivity 92% and specificity 94%. Furthermore, the temperature asymmetry factor was correlated with the duration of the disease and VAS pain. In conclusion, in resting condition, videothermography is a reliable additive diagnostic tool of early stage CRPS1. This objective tool could be used for monitoring purposes during experimental therapeutic intervention.

PMID: 14735366

Karacan I, Aydin T, Ozaras N.

Bone loss in the contralateral asymptomatic hand in patients with complex regional pain syndrome type 1.
Metab. 20 J Bone Miner 04;22(1):44-7.

SSK Vakif Gureba Hospital Physical Medicine and Rehabilitation Clinic, Istanbul, Turkey.

Regional osteoporosis was seen radiographically in clinically affected areas in patients with complex regional pain syndrome type 1 (CRPS1). The aim of the this study was to investigate whether bone loss developed in the contralateral hand in patients with unilateral CRPS1 of the hand. Thirty-two patients with CRPS1 of the hand were included in this study. Bone mineral density was measured in the left proximal femur and both ultradistal radiuses, using dual-energy X-ray absorptiometry. The subjects were classified as grades 1 to 3 according to the T-score of both ultradistal radiuses (densitometric grades): grade 1, both radiuses were normal; grade 2, bone loss was determined only in the affected radius; and grade 3, there was bone loss in both radiuses. Twenty (62.5%) patients had bone loss in the affected hand; 11 patients (34.4%) had bone loss only on the affected side and 9 patients (28.1%) had bone loss on both sides. The mean duration of the period between the diagnosis of the injury and the measurement of bone density was 1.9 +/- 0.6 months in patients with grade 1, 3.1 +/- 1.0 months in patients with grade 2, and 5.5 +/- 2.2 months in patients with grade 3. The Spearman test showed a significant correlation between the period of injury and the densitometric grade ( R = 0.774; P = 0.0001). In conclusion, the current study of patients with CRPS1, showed that the bone loss in the asymptomatic contralateral hand developed at a later stage than that in the affected hand. This bone loss was less frequent and of a lower degree in the asymptomatic contralateral hand than in the affected hand. The bone loss in the asymptomatic contralateral hand could be explained by the loss of sympathetic tone in CRPS1 and contralateral sympathetic innervation.

PMID: 14691686

Lake AP.

Intravenous regional sympathetic block: past, present and future?
Pain Res Manag. 2004 Spring;9(1):35-7.

Glan Clwyd Hospital, Bodelwyddan, Denbighshire, United Kingdom.

Intravenous regional sympathetic block is a valued component of the pain clinician's armamentarium for the management of the complex regional pain syndrome type 1. Treatment of this multifaceted condition is multimodal, and despite a lack of convincing supporting evidence from clinical trials, the author makes the case for retaining the technique while recommending both appropriate guidance and further study.


PMID: 15007401

Mense S.

Neurobiological basis for the use of botulinum toxin in pain therapy.
J Neurol. 2004 Feb;251 Suppl 1:1-7.

Institut fur Anatomie und Zellbiologie III, Universitat Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.

The various serotypes of botulinum toxin (BoNT) exert their action by inhibiting the exocytosis of acetylcholine (ACh) on cholinergic nerve endings. BoNT cleaves proteins (e.g. SNAP-25 or VAMP) that are necessary for the docking of the ACh vesicle to the presynaptic membrane. Without docking, no ACh can be released into the synaptic cleft and the innervated structure is paralyzed. This article focuses on the neuromuscular endplate. The main targets of BoNT therapy are states of muscle hyperactivity such as contractures (in the physiological sense), or spasm and focal dystonias. CONTRACTURES: The "integrated hypothesis" of the formation of myofascial trigger points suggests that a lesion of a muscle damages the endplate so that excessive ACh is released. This causes a local contracture (partial contraction of a muscle fiber) underneath the endplate. The contracture compresses small blood vessels, and the tissue becomes ischemic. Ischemia leads to the release of bradykinin (BKN) and sensitization or excitation of nociceptors. BoNT is a causal therapy in these cases, because it stops the excessive ACh release. SPASM: Reflex spasm in a given muscle can be induced by nociceptive input from neighboring joints or muscles. If the force generated by a spasm is relatively high, it will compress the large blood vessels supplying the muscle. The final effect again is ischemia. In this case a drop in pH may accompany the ischemia and BKN are known to be effective stimulants for muscle nociceptors. DYSTONIA: In cases of weak dystonias, a compression of blood vessels is unlikely. However, the tonic contraction will cause a lowering of pH and a release of ATP. Muscle cells contain ATP at concentrations sufficient to excite muscle nociceptors. In cases of spasm and dystonia, BoNT can abolish the pain by relaxing the muscle. Since many patients report alleviation of their pain before the muscle relaxing effect of BoNT has set in, a direct analgesic action of BoNT is being discussed. Most hypotheses rest on the assumption that BoNT inhibits not only the exocytosis of ACh but also of their neurotransmitters. Such an action could be analgesic if the release of neuropeptides from nociceptive nerve endings is prevented. This way, BoNT could alleviate the pain of neuropathies and various types of headache where neurogenic inflammation plays a role. Another site of an analgesic action could be the postganglionic sympathetic nerve ending that uses norepinephrine and ATP as transmitters. Norepinephrine is known to increase cases of chronic pain, and ATP is a stimulant of muscle nociceptors. If BoNT inhibits the release of these transmitters, it could be analgesic in cases of sympathetically maintained pain including the complex regional pain syndrome.

PMID: 14991335


For a copy of this or any CRPS article, visit McMaster Health Sciences Library. Search Pub Med using the PMID number listed.

Pleger B, Tegenthoff M, Schwenkreis P, Janssen F, Ragert P, Dinse HR, Volker B, Zenz M, Maier C.
Mean sustained pain levels are linked to hemispherical side-to-side differences of primary somatosensory cortex in the complex regional pain syndrome I.
Exp Brain Res. 2004 Mar;155(1):115-9. Epub 2004 Jan 27.

Department of Neurology, BG-Kliniken Bergmannsheil, Ruhr University Bochum, Buerkle-de-la-Camp Platz 1, 44789, Bochum, Germany.

Chronic back pain as well as phantom-limb pain is characterized by a close relationship between the amount of cortical reorganization and the magnitude of pain. In patients with positively assessed complex regional pain syndrome type I (CRPS I), we found a positive correlation between representational changes of primary somatosensory cortex (SI) and mean sustained pain levels. We investigated seven right-handed patients with CRPS I of one upper limb by means of somatosensory evoked potential (SSEP) mapping. Cortical representation of the CRPS-affected hand was significantly smaller than that of the contralateral healthy hand, giving rise to a substantial side difference. Subjective pain levels experienced over the last 4 weeks were estimated according to the visual analogue scale (VAS). Individual expansion of hand representation contralateral to the CRPS-affected limb was significantly correlated with mean pain intensity. Accordingly, low pain levels were linked to small representational side-to-side differences, while subjects with a distinctive hemispherical asymmetry reported the highest pain levels. Follow-up studies using functional imaging methods might be instrumental in providing a better understanding of this issue.

PMID: 15064892

Pleger B, Janssen F, Schwenkreis P, Volker B, Maier C, Tegenthoff M.

Repetitive transcranial magnetic stimulation of the motor cortex attenuates pain perception in complex regional pain syndrome type I.
Neurosci Lett. 2004 Feb 12;356(2):87-90.

Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany.

In complex regional pain syndrome (CRPS) many clinical symptoms suggest involvement of the central nervous system. Neuropathic pain as the leading symptom is often resistant to therapy. In the present study we investigated the analgesic efficiency of repetitive transcranial magnetic simulation (rTMS) applied to the motor cortex contralateral to the CRPS-affected side. Seven out of ten patients reported decreased pain intensities. Pain relief occurred 30 s after stimulation, whereas the maximum effect was found 15 min later. Pain re-intensified increasingly 45 min after rTMS. In contrast, sham rTMS did not alter pain perception. These findings provide evidence that in CRPS I pain perception can be modulated by repetitive motor cortex stimulation.

Rizzo M, Balderson SS, Harpole DH, Levin LS.

Thoracoscopic sympathectomy in the management of vasomotor disturbances and complex regional pain syndrome of the hand.
Orthopedics. 2004 Jan;27(1):49-52.

Division of Orthopedic, Duke University Medical Center, Box 3945, Durham, NC 27710, USA.

Complex regional pain syndrome, vasospastic disorders, and hyperhidrosis are chronic and debilitating upper extremity problems. Twenty-nine consecutive patients treated with thoracoscopic sympathectomy are presented. Diagnoses included complex regional pain syndrome, hyperhidrosis, Buerger's disease, Raynaud's disease, and peripheral vascular disease. All patients with hyperhidrosis had complete symptom resolution. Patients with Buerger's and Raynaud's disease had excellent/good results. Six patients with complex regional pain syndrome had excellent or good relief; the remaining six patients had varying degrees of recurrence. A statistically significant association was noted between duration of complex regional pain syndrome prior to sympathectomy and outcome. Thoracoscopic sympathectomy is an effective treatment for hyperhidrosis and vasospastic disorders. Although the results for complex regional pain syndrome are not uniformly excellent, this technique offers promise in the treatment of this difficult problem.

PMID: 14763530




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