STUDIES 2005-7


Our thanks to the many dedicated scientists and doctors who are working together to help find better treatments and drugs for CRPS.

As more studies become available, we will add to this page. Studies which are significant in the research field are marked with ***. You are welcome to send us any studies you have. Special thanks to Barbara Iwasiuk for her contributions.



STUDIES 2006: A-M, N-Z




11th World Congress on Pain 
AUGUST 20-26, 2005

CRPS: A CNS Disease or a Consequence of Peripheral Inflammation?

R. Baron1; F. Huygen2; C. Maier 3; M. Stanton-Hicks4
1. Dept. of Neurological Pain Research and Therapies, Neurological Clinic , University of Kiel, Kiel, Germany.
2. Pain Treatment Center, Erasmus MC, University Hospital of Rotterdam, Rotterdam, Netherlands.
3. Dept. of Pain Management , Ruhr University, Bochum, Germany.
4. Pain Management Center, Cleveland Clinics , Cleveland, OH, USA.

MINI-SYMPOSIUM: Organizer and Chair: Ralf Baron, MD

EDUCATIONAL OBJECTIVES: Participants will learn (1) the proposed clinical diagnostic criteria in CRPS, (2) the diagnostic tests which may aid the diagnosis of CRPS (3) the scientific evidence suggesting a inflammatory component to the pathophysiology, (4) the changes in the cortical somatosensory reorganization identified with imaging techniques, and (5) know the therapeutic interventions applied in CRPS.

BACKGROUND AND SUMMARY OF SESSION: Modern innovative research approaches shed some light on the pathophysiological mechanisms underlying CRPS. Evidence for a neurological disorder as well as evidence for an inflammatory disorder will be discussed in the symposium:
Autonomic abnormalities are striking clinical features that are unique for CRPS. A central unilateral inhibition of cutaneous sympathetic vasoconstrictor neurons leads to a warmer affected limb in the acute stage. This dysfunction must be due to abnormalities in the central nervous system. Using kinematic analysis as well as MEG, and fMRI-studies a pathological sensorimotor integration located in the parietal cortex was postulated that may induce an abnormal central programming and processing of sensorimotor tasks.
Some of the clinical features of CRPS particularly in its early phase (vasodilatation, swelling, pain) could be explained by an inflammatory process. The exact mechanisms of the initiation and maintenance of these inflammatory reactions in early CRPS are unclear.
The key future question to be asked in research is: What is the organizing principle leading to this complex syndrome? The changed view of pathophysiological interactions we have acquired in the last years will shift the focus of our research efforts, will bring about a diagnostic reclassification and redefinition of CRPS, and finally will have bearings on novel therapeutic approaches. The key task to be addressed in therapy is to perform controlled multicenter studies that assess the acute as well as the long term effect of drug and interventional therapies as well as physio and psychotherapy.


(Frank J.P.M. Huygen, MD, PhD)

The pathophysiology of CRPS is still a matter of debate. Afferent, efferent and central nervous system mechanisms are presumed. In artificially raised skin blisters in CRPS involved extremities, significantly higher levels of IL6 and TNF alpha were found. This is evidence for, in part, an inflammatory process. In another study significantly higher levels of tryptase in blister fluid of involved extremities were found; this demonstrates involvement of mast cells in the inflammatory process. In a case study describing one patient with an acute CRPS and another with a chronic CRPS, both patients received intravenous antiTNF. Both showed a clinical improvement and a decrease in cytokine levels in blister fluid. It is concluded that not only the nervous system but also the neuroimmune system is involved in the pathophysiology of CRPS.


(Christoph Maier, MD)

In CRPS, a widespread involvement of the CNS is suggested by a variety of clinical symptoms, such as tremor, dystonia, or hemisensory impairment. Recently, evidence for this hypothesis comes from a number of studies using different neurophysiological and functional imaging approaches. A bilateral motor cortex disinhibition similar to those found in patients with focal dystonia could be demonstrated in CRPS, as well as a shrinkage of the affected hand representation in the primary somatosensory cortex This shrinkage of the hand representation was shown to be closely related to the average pain intensity, and to be reversible after successful therapy. The latter encourage research to develop therapeutic strategies that are able to target this CNS


(Michael Stanton-Hicks, MD)

So far very few evidence based treatment regimens for CRPS are available. In the absence of more specific information about pathophysiological mechanisms treatment of the individual patient is empiric using evidence based techniques that have been proven to be effective in other neuropathic conditions. Treatment should be immediate and most importantly directed toward restoration of full function of the extremity. This objective is best attained in a comprehensive interdisciplinary setting with particular emphasis on pain management and functional restoration. Furthermore, the still hypothetical mechanism based treatment concept has to be transferred from ideas derived from animal experiments on peripheral nerve lesions to the situation in CRPS patients.

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The experience of Complex Regional Pain Syndrome: Developing an educational website

J. S. Lewis1, 2; D. R. Blake1, 3; C. S. McCabe1, 3; S. Ziebland4
1. RACE, The Royal National Hospital for Rheumatic Diseases, Bath, United Kingdom.
2. School of Health Professions and Rehabilitation Sciences, University of Southampton, Southampton, United Kingdom.
3. Department of Medical Sciences, University of Bath, Bath, United Kingdom.
4. Department of Primary Health Care, University of Oxford, Oxford, United Kingdom.

To capture, using qualitative methodology, experience of living with complex regional pain syndrome (CRPS). This data will create a CRPS module for a web based database of individual patient experiences (DIPEX), an educational resource for patients, their families and healthcare professionals (HCPs). There is a need for accurate, representative and peer reviewed information on CRPS particularly for newly diagnosed patients. The website links videoed interviews of patients 'experiences with evidence-based information about the condition and possible treatment options.It will convey common disease experiences and the impact on people's lives

Following informed consent, 20 participants from the UK who met the classification of CRPS type I and II were interviewed within their own homes. A qualitative narrative approach was utilized to encourage participants to tell their story. Follow-up questions elicited further description. These videoed semi-structured interviews were coded with qualitative analysis software then systematically analysed using content analysis. The emergent themes have been grouped into categories

The interviews, lasting approximately 2 hours produced rich descriptions as the participants were open and frank about their experiences. 12 categories emerged including; discovering a problem, symptom experience, receiving a diagnosis, treatment, body perception disturbances, impact on life and thoughts about the future. Participants describe the nature and intensity of pain and stress the frustration of obtaining a diagnosis. Emphasis was on the need for better information at diagnosis, more timely treatments and an improved awareness of the condition amongst HCPs

The findings of this study will be a unique resource for patients and HCPs. Participant's reports confirm the need for accurate and detailed information not only for patients but also in the education of HCPs treating CRPS. This DIPEX module will contribute towards meeting these needs


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T. P. DOCTOR1; C. R. Jani1; M. M. Prabhakar2
1. Anesthesia, B.J.Medical College & Civil Hospital, Ahmedabad, Gujarat, India.
2. Anesthesia, B.J.Medical College & Civil Hospital, Ahmedabad, Gujarat, India.
3. Department of Orthopedics, B.J.Medical College & Civil Hospital, Ahmedabad, Gujarat, India.

To compare and evaluate efficacy of different concentrations of Inj. Bupivacaine used for stellate Ganglion Block for Reflex Sympathetic Dystrophy of upper limb.

Total 30 patients of either sex, of age group-20-60 yrs. Diagnosed as RSD upper limb.All the patients were assessed for P/H/S/O, trauma, operation, with removal of plaster duration. Pain, blood flow, edema, . All the 30 patients after randomly selected for the block, were given stellate ganglion block with 0.375%, 0.25% and With 0.125% diluted into normal saline to make total volume of 10cc as Gr-I(n=10), II(an=10) and III(n=10) respectively under all aseptic precautions. All the patients were followed up for assessment of Pain relief, Improved blood flow, Improvement in activity, etc. were noted in follow up.

7pts. Did not require more than 2 injection in Gr-I,2pts. Required assistance for few hours and 1pt. did not benefit from the treatment. Gr-II- 2pts. Had repeated inj. up to 4 injections. Hornor syndrome was seen in with 0.375%Gr-I, than Gr-IIIand Gr-II. Paresis was observed with Gr-I-II. 0.125% gives the same results for pain relief in functional improvement without paresis. No arterial puncture was noted in any patient. Dryness of mouth, slight change in voice noted in all the groups equally.

0.125%Inj. Bupivacaine provides same effects as 0.375/0.25% for stellate ganglion block for upper limb RSD with equally good quality of analgesia with less complications and better improvement in function and symptoms.

Special thanks to the staff members of the department and resident doctors and of course to patients for completion of the study.

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K. Moriwaki1; M. Kobayashi1; K. Shiroyama1; T. Miki1; A. Sakai1; T. Ohtani1; T. Yamada1
1. Anesthesiology, National Hospital Organization Kure Medical Center, Kure, Japan.

Although basic and clinical investigations have revealed part of mechanisms underlying CRPS, the thorough pathophysiology of CRPS has not been understood. Reviewing concepts of CRPS, RSD, causalgia and related disease entities, authors aimed to update the concept of CRPS and to indicate a comprehensive conceptual framework of CRPS.

We reviewed on-line database on MEDLINE, classical literatures, textbooks of pain and personal treatment experiences of patients with CRPS (KM, 54 patients), and summarized the precedent and current concepts related with CRPS in a phylogenic tree.

Three root concepts of CRPS were identified, i.e.Mitchell's causalgia, Sudeck's bone atrophy and Evans' RSD. Until 1980s, sympathetic nervous system had been believed to play an essential role in causing RSD. Although sympathetic nervous system has close relationship with both physiological and pathological pain, the sympathetic hyperactivity theory of RSD was discarded during 1990s. Instead, concept of neuropathic pain, emerged during late 1980s and early 90s, coupled with the modified idea of autonomic dysfunction seemed to constitute current concept of CRPS. Aside from studies on neuropathic pain component in CRPS, some investigators are gradually casting lights on the peripheral tissue pathology as an essential component of CRPS, which was classically emphasized by Sudeck and Evans. Throughout the history, almost all of proposed concepts on CRPS and those on its preceding disease entities have emphasized unusual body response to the nerve or other tissue injury and resultant unusual tissue changes and pain, especially in the extremities. This indicates that healing disorder after tissue injury is a comprehensive conceptual framework of CRPS.

CRPS is not merely a neuropathic pain syndrome but more than that. The question why healing deviates from normal process in the patients should be investigated for further understanding of pathophysiological mechanisms of CRPS.
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Reorganization of the somatosensory cortex in CRPS patients

T. Ueno1; D. J. Soneji1; K. M. Kaplan1; G. H. Glover2; D. H. Ludlow1; S. C. Mackey1
1. Anesthesia, Stanford University, Palo Alto, CA, USA.
2. Radiology, Stanford University, Stanford, CA, USA.

Complex regional pain syndrome (CRPS) is a debilitating chronic neuropathic pain that affects millions of people worldwide and is thought to involve central neural mechanisms. In this study, we used fMRI to investigate somatosensory cortex reorganization in CRPS patients.

We recruited 8 healthy subjects and 7 chronic pain patients who met IASP criteria for CRPS. We used fMRI to map the somatotopic location of their hands in the primary somatosensory cortex (S1) with stimulation of the thumb for both the affected and unaffected hands, delivered via computer-controlled pneumatic plungers embedded in a foam glove. High-resolution anatomical and functional scans were collected on a 3T scanner. SPM2 software was used for co-registration and detection of activation areas in S1 (P<0.05 corrected).

All healthy subjects showed that tactile stimulation of the left and right thumb activated areas in S1 that were located at the same height. However, 4 patients' brain activation demonstrated proper somatotopic localization of the unaffected hand but significant cephalad shifting of the affected hand. One patient had the activation area of unaffected side thumb more cephalad. Additionally, two patients underwent subsequent successful inpatient treatment and were scanned post-treatment. The fMRI results demonstrated that the affected S1 activation area relocated closer to the height of the unaffected side.

Two studies using MEG have reported different somatotopic locations of hand sensation in affected/unaffected side in CRPS patients. Such reorganization was not present in our healthy subjects and occurred in 4 of our 7 patients. The reorganization may depend on clinical condition. These results indicate that cortical reorganization of S1 may play a role in the pathophysiology of CRPS and that short-term treatment can reverse some of those changes.

This research is supported by Foundation for Anesthesia Education and Research.
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Complex Regional Pain Syndrome and Post-traumatic Stress Disorder

J. Shennan1; J. Barnard2; R. Carpenter2; M. Johnson3
1. Pain Service, Waikato Hospital, Hamilton, New Zealand.
2. Anaesthesia, Waikato Hospital, Hamilton, New Zealand.
3. Health Psychology, University of Auckland, Auckland, New Zealand.

This case presentation describes concurrent Complex Regional Pain Syndrome-I (CRPS-I)and Post-traumatic Stress Disorder (PTSD) in which pain co-varies with PTSD intrusive symptoms (nightmares and flashbacks)and trauma-based cognitions.

Onset of PTSD intrusive symptoms occurred subsequent to onset of CRPS-I symptoms following a minor injury(ankle sprain). Over three years of treatment for CRPS-I the patient experienced brief episodes of near or complete remission of pain. Patient self-report of PTSD intrusive symptoms was recorded. Cognitions relating to an earlier major trauma were measured with the Post-traumatic Cognitions Inventory (Foa, 1999)

When pain relief was achieved trauma-based cognitions shifted in a non-pathological direction, and occurrence of trauma-related nightmares and spontaneous awake recall of trauma-related sensory material (flashbacks) ceased. PTSD symptoms (distorted cognitions, nightmares and flashbacks) all returned with the return of severe pain.

There has been recent interest in the relationship between pain and PTSD (Otis, Keane & Kerns, 2003) with discussion of possible shared central mechanisms. Similar interest has been expressed in the role of emotional stress and CRPS, with suggestions of common mechanisms (Geertzen et al. 1998). A recent clinical note in Pain (Grande et al.2004) described a case of concurrent CRPS-I and PTSD with anatomical parallels between the two disorders. The present case, particularly the chronological sequence of symptoms and the co-variance of cognitive symptoms, supports hypothesized shared mechanisms for these two distressing disorders.

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In chronic CRPS1 but not acute CRPS1, imagined movements can cause pain and swelling.

G. L. Moseley1, 2
1. School of Physiotherapy, University of Sydney, Lidcombe, NSW, Australia.
2. Centre for fMRI of the Brain & Department of Human Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.

Anecdotally, patients with chronic CRPS1 seem to be aggravated by imaginary movements but those with acute CRPS1 do not. This study aimed to determine whether this anecdote is true.

Twenty-one patients with CRPS1 and 18 patients with non-CRPS1 hand pain were grouped as acute (<3 months) sub acute (3-6 months) or chronic (>6 months). They performed a standardized protocol of imagined hand movements, using an in-house software program (Recognize), which involved the presentation of 18 images of left and right hands. Patients imagined twice moving their own hand to match the posture of the hand shown in the image. Muscle activity was monitored using surface electrodes placed over the flexors and extensors of the affected hand. Pain and swelling were assessed before and after ~ 5 minutes of imagined hand movements. A MANOVA compared pain and swelling between measurement occasions and between groups. Change in pain and swelling were related to duration of symptoms in each group via linear regression.

Eight CRPS1 and 3 non-CRPS1 patients reported increased pain. There was a main effect of group and time on pain. Only chronic CRPS1 patients had more pain after performance (P <0.05), although there was no effect on swelling (P >0.07). Both pain and swelling related to duration of symptoms, but only in the CRPS1 patients (r =0.36, P <0.05).

The results support the anecdotal observation that chronic CRPS1 patients are aggravated by imagined movements. Notably, some patients with non-CRPS1 hand pain also reported pain. The mechanism in not clear but may involve enhanced synaptic efficacy of cortical pain networks.

This work supported by NHMRC Grant ID 210348 and a Clinical Research Grant from NOI Australasia. GLM is Nuffield Medical Research Fellow & is on leave from The University of Sydney, Australia.

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Asymmetry of nociceptive processing in the forehead of patients with complex regional pain syndrome

P. Drummond1; P. M. Finch2
1. Psychology, Murdoch University, Perth, WA, Australia.
2. Perth Pain Management Centre, Perth, WA, Australia.

Hyperalgesia often spreads beyond the painful limb to other limbs in patients with complex regional pain syndrome (CRPS), and sensory disturbances sometimes involve the face. We examined whether hyperalgesia extends to the forehead in patients with chronic limb pain associated with features of CRPS.

The mechanical pain threshold to pressure applied by an algometer and the heat pain threshold to radiant heat were assessed in the painful and contralateral limbs and on each side of the forehead in 32 CRPS patients. Ratings of sharpness to a firm bristle were also obtained at each test site, and the touch threshold to thin nylon monofilaments was assessed in the symptomatic and contralateral limbs.

The mechanical pain threshold in the forehead was lower ipsilateral to limb pain than contralaterally (p<0.001), irrespective of whether pain originated in the arm or leg and irrespective of the nature of symptoms in the painful limb. Although sharpness and heat pain thresholds did not differ between the two sides of the forehead in the group as a whole, sharpness and sensitivity to heat pain in the painful limb extended ipsilaterally to the forehead. Conversely, loss of tactile and thermal sensitivity in the symptomatic limb were associated with ipsilateral loss of tactile and thermal sensitivity in the forehead.

Disturbances in nociceptive processing extend beyond the symptomatic limb to the forehead in CRPS, consistent with a disturbance in central nociceptive processing.

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Immune responses to Campylobacter and serum auto antibodies in patients with Complex Regional Pain Syndrome

A. Goebel2, 1; H. Vogel3, 1; O. Caneris4, 5; Z. Bajwa6; L. Clover1; R. Schedel3; H. Karch7; G. Sprotte3; A. Vincent1
1. Neurosciences group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford , United Kingdom.
2. Nuffield Department of Anaesthetics, University of Oxford, Oxford, United Kingdom.
3. Klinik fuer Anaesthesiologie, Universitaet Wuerzburg, Wuerzburg, Germany.
4. North East Rehabilitation Network, Comprehensive Pain Management Clinic, Salem, NH, USA.
5. Department of Anesthesia, Pain Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
6. Department of Anesthesia, Arnold Pain Center, Beth Israel Hospital, Harvard Medical School, Boston, MA, USA.
7. Institut fuer Hygiene und Microbiologie, Universitaet Wuerzburg, Wuerzburg, Germany.

We previously reported profound pain relief in some patients with CRPS after treatment with intravenous immunoglobulin (PainMed 2002). Furthermore, in passive-transfer experiments of patient serum to mice we presented evidence for pathogenic serum antibodies (AnnNeurol 2005). We now hypothesize, that some cases of CRPS may be post infectious and/or autoimmune in origin and, therefore, may show immune-activation in early disease. Furthermore, we propose that those patients with spreading disease or minor preceding injury may show evidence of a distinct autoimmune reactivity.
As infection with Campylobacter jejuni can lead to an inflammatory peripheral neuropathy, we first measured antibodies to this pathogen. Secondly we looked for serum auto reactivity towards rodent tissues.

Serum was obtained after ethics approval from 92 patients with CRPS and age/sex-matched healthy controls. A Campylobacter IgA and IgG ELISA (strains Penner 19 and Lior 11) was performed. mmunohistochemistry was performed on mouse total body tissues as previously described (Amyes et al., JNeuroimmunoy 2001).

The median serum IgA levels were significantly higher in patients with disease duration (DD)<1.5 years, as compared with the remaining patients or control subjects (p<0.02 for Lior, p=0.0041 for Penner). 32 CRPS patient and 8 control sera showed some binding to mouse sections. The median composite score in the group of 23 patients with a DD<1.5 years was 1.0, versus 0.5 in the group with longer DD (p<0.002). Sera of patients with minor trauma (n=6) stained mouse tissue significantly stronger than other patients or controls (<0.0002).

These results provide evidence for two distinct immune mechanisms in CRPS. One relates to involvement of the immune system in the early stages of disease, consistent with an immune precipitating actor in some (CRPS 1 and 2) cases. The other, relates to patients with minor injury as a putative autoimmune subgroup.

Research support from ZLB(CH) to AG

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Dysynchiria Feeling the virtual limb in CRPS1 patients

N. E. Acerra1, 2; T. Souvlis2; G. L. Moseley3, 2
1. School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, QLD, Australia.
2. Department of Physiotherapy, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
3. Centre for fMRI of the Brain and Department of Human Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.

Synchiria, or bilateral sensation following unilateral touch, is observed in phantom limb pain (PLP) and post-stroke and may be the result of cortical changes. Since complex regional pain syndrome type 1 (CRPS1) has similar cortical changes and clinical findings as PLP, synchiria should also occur with CRPS1.

Ten patients with CRPS1 and nine patients with each of neck-related arm symptoms, localized arm symptoms and symptomatic controls participated. Sensory assessment included light touch, punctuate touch, and cold application to the unaffected limb while the patient watched the mirror-image, or virtual limb. Patients reported the quality and location of the sensation(s) evoked by each stimulus.

In patients with CRPS1, four phenomena were observed: (i) normal sensation; (ii) synchiria to cold; (iii) paraesthesia, or; (iv) pain on the affected limb solely following stimulation of the unaffected limb. The last two phenomena only occurred in response to stimulation at sites on the affected limb that corresponded to areas of paraesthesia and pain on the affected limb. We collectively termed these phenomena dysynchiria. Synchiria and dysynchiria were not produced in non-CRPS1 patients or controls, nor in RPS1 patients with eyes closed.

Synchiria and a new phenomenon, dysynchiria, were consistently evoked with CRPS1 but not with other patients or controls. The mechanisms are unclear, but cortical changes are probably involved. These results provide further evidence of similarities between CRPS1, PLP and stroke, which may have implications for assessment and management of each.

GLM is a Nuffield Medical Research Fellow, currently on leave from the University of Sydney. This work supported by NHMRC grant ID 210348 and RBWH Foundation Grants (GLM).

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Therapeutic benefits of peripheral nerve blocks in CRPS

C. Jean Luc1; L. Daniel2; P. Bernard2; P. Sebastien1; T. Yves2; B. Annie1; S. Emmanuel1
1. Anesthesie Reanimation, CHU Jean Minjoz-Universite de Franche Comte, Besancon, France.
2. Orthopedie-Traumatologie, CHU Jean Minjoz-Universite de Franche-Comte, Besancon, France.
3. Explorations fonctionnelles neuro-musculaires, CHU Jean Minjoz-Universite de Franche Comte, Besancon, France.

During the sympathetically independent phase (SIP) of the complex pain regional syndrome (CRPS) I and II, no therapeutic method used alone is effective. The aim of this open and prospective study is to assess the benefits of peripheral nervous blockade in a multi modal approach.

All consecutive patients with refractory post-traumatic and post surgical CRPS I and II at the SIP were eligible for the study. After consent, 8 ml of ropivacaine 0,025% were injected to obtain a sensory differential blockade of each nerve involved in the nociceptive process (neurostimulation : Stimuplex HNS 11, Braun). Clinical symptoms (spontaneous pain, hyperalgesia and mechanical allodynia) were evaluated before and daily after the block (visual analogic scale). Duration of effectiveness for pain symptoms and improvement in range of motion during and after active physical therapy, were also observed.

25 patients were included in the study (20 females and 5 males, mean age of 50 years [min=31; max=77]. No motor blockade was observed. Average time of effectiveness was 3,36+/-1,25 days. Pain scores were significantly improved during this period and painless physical therapy was obtained for 4/25 patients. 23 patients increased their range of motion for a period exceeding the duration of the sensory blockade.

Sensory differential blockade of peripheral nerve is effective to control neurogenic pain at the SIP of CRPS I and II. Such long benefits of peripheral nerve blocks obtained with low concentration of ropivacaine put its pharmacological interaction with nervous fibers into question.

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M. Mizutani1; T. Kimura2
1. Graduate School of Education and Human Development, Nagoya University, Nagoya-city, Aichi-ken, Japan.
2. Multidisciplinary Pain Center, Aichi Medical University, Aichi-gun Nagakute-cho, Japan.

Pain relief for Complex Regional Pain Syndrome (CRPS) remains still challenging. We evaluated the efficacy of autogenic training (AT) on pain relief for CRPS in terms of subjective numerical pain rating and changes of skin temperature.

We made a series of hypnotically-structured AT for four CRPS-I patients ranging 27 to 52 yrs for more than 6 months. Skin temperatures in each limb were continuously measured by infrared thermography. No suggestion for altering pain or for distraction was given during AT. Subjective numerical pain rating ranges on a scale of zero (free from pain) to ten (maximum pain).

Numerical pain rating decreased in the range from 2 to 7 points reduction in each session of three patients: Two patients showed decreased pain rating at an early stage, while one patient required several months for pain relief. Other one patient showed no changes of pain rating. The mean skin temperature in diseased limbs increased from 28.2 to 31.3C, while from 32.2 to 33.7C in normal limbs after six-month training. In addition, we measured heart rate variability for two patients during AT. High frequency component (0.04-0.15Hz) as a marker of parasympathetic activity, increased in the range from 137 to 994% of the control values and the ratio of low frequency (0.15-0.4Hz) to high frequency as a marker of sympathetic activity extremely decreased in the range from 4 to 36% of the control values.

There are sparse published data about the clinical application of AT for CRPS patients. The current data indicated that AT surprisingly increased the temperatures even in diseased limbs by 3.1 C, in addition to increased HF and decreased LF/HF ratio, suggesting that AT might be related to the sustained reduction in central sympathetic outflows. Hypnotically-structured AT for CRPS patients seem worth a try to normalize the central autonomic perturbations arising from intractable pain, thus AT might give rise to long-term sympatholytic changes in the late stage of CRPS.

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The usefulness of three-phase bone scan and thermography in the diagnosis of complex regional pain syndrome

S. Park1; M. Seo1; P. Lee1; Y. Oh1; S. Lee2
1. Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seong-Nam, South Korea.
2. Seoul National University Hospital, Seoul, South Korea.

Complex regional pain syndrome(CRPS) is a painful and disabling problem, the diagnosis of which can be difficult to confirm by objective measures. Three-phase bone scan(TPBS) and thermography have been recommended for use in the diagnosis of the CRPS. The purpose of the study was to determine the usefulness of the TPBS and thermography in the diagnosis of CRPS.

A retrospective chart review conducted of 17 patients who had TPBS and thermography as part of a work-up for unexplained extremity pain. All patients were injected with technetium-99m methylene diphosphonate and scanned using established criteria. Phase I is a radionuclide angiogram. Phase II is the blood pool or tissue phase. Phase III consists of delayed images obtained 3 to 4 hours after radionuclide injection. The diffuse increased tracer uptake in the delayed image(phase III) is diagnostic for CRPS. Also, all patients underwent thermography under a baseline condition. Degree of temperature asymmetry between affected and non-affected limbs were measured. There was considered positive for CRPS if it showed temperature asymmetries between affected and non-affected extremities was more han 1.00 degree C.

Review of the TPBS for 17 patients indicated the 5 patients (29%) had diffusely positive scans. And thermographic abnormalities were noted in 16 of 17 CRPS patients (94%).

The use of thermography in clinical settings to assess autonomic dysfunction can be an important part of CRPS diagnosis. However, this study demonstrated that only 29% of CRPS patients had bone scan abnormalities. Therefore, TPBS alone cannot provide a completely accurate diagnosis and that it is imperative that bone scan data be integrated with a thorough clinical evaluation and other relevant testing.

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Sensory abnormalities in Complex Regional Pain Syndrome show a bilateral distribution and a distinct time course

W. Magerl2; S. Foerderreuther3; W. Kaufhold1; M. Steinberger1; S. C. Azad1; M. Valet4; A. Beyer1; V. Huge1
1. Department of Anaesthesiology; Pain Clinic, Ludwig-Maximilians-University, Munich, Germany.
2. Institute of Physiologie and Pathophysiology, Johannes Gutenberg University , Mainz, Germany.
3. Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
4. Department of Neurology, Klinikum Rechts der Isar, Technical University, Munich, Germany.

Beyond autonomic, trophic, and motor disturbances, sensory abnormalities are a key symptom of Complex Regional Pain Syndrome (CRPS). These sensory changes are typically not restricted to the innervation area of a peripheral nerve or nerve root. They sometimes even show a hemisensory spread indicating central mechanisms. It is not known whether sensory changes also affect the contralateral side, and so far no study has investigated the time course of the sensory changes.

61 patients presenting with CRPS of the upper extremity according to the revised diagnostic criteria of the IASP by Bruehl, were enrolled in the study. Patients with CRPS symptoms for 2-9 months were categorized as acute CRPS, patients with a longer history were classified as chronic CRPS. 56 healthy patients, matched for gender and age served as a control group. Warm and cold detection thresholds WDT/CDT), as well as heat and cold pain threshold (HPT/CPT) and the incidence of paradoxical heat sensations were assessed in both hands using a TSA 2001 Thermal Sensory Analyzer (Medoc, Israel).

In acute CRPS, patients displayed significant sensory loss (increase of both WDT and CDT), combined with a thermal hyperalgesia (decrease in CPT and HPT) as compared to controls. Paradoxical heat sensation was registered in a significant percentage of acute CRPS patients, but not chronic CRPS or controls. In chronic CRPS there was further sensory loss, but thermal hyperalgesia was partially resolved. All sensory abnormalities occurred bilaterally, but were more pronounced at the affected limb.

These results show for the first time, that neurological sensory changes in CRPS develop with a distinct time dependent pattern. The bilateral distribution of sensory changes is another indicator for central mechanisms in the pathophysiology of CRPS.

This work was supported by the Bundesministerium fuer Bildung und Forschung (German Research Network Neuropathic Pain (Project B.C.2.3.3)

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A Multicenter, Open-Label, 12-Week Study with Extension to Evaluate the Safety and Efficacy of Lenalidomide (CC-5013) in the Treatment of Complex Regional Pain Syndrome Type-1.

G. Irving2; R. Schwartzman1; M. Wallace3; R. Rauck4; S. Dogra5; S. Raja6; A. Cooper7; H. Faleck7; J. Zeldis7; D. Manning7
1. Neurology, Drexel University College of Medicine, Philadelphia, PA, USA.
2. Pain Management, Swedish Hospital, Seattle, WA, USA.
3. Anesthesiology, University of California San Diego, San Diego, CA, USA.
4. Center for Clinical Research, Winston-Salem, NC, USA.
5. Anesthesiology, University of North Carolina Hospitals, Chapel Hill, NC, USA.
6. Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
7. Celgene Corporation, Summit, NJ, USA.

Lenalidomide, an immunomodulator, was evaluated for safety and efficacy in subjects with unilateral chronic CRPS type I.

In this 6-center, open-label study, subjects received lenalidomide 10mg/day orally for 12 wks following a 1-wk baseline evaluation. Completers could extend treatment for a total of 40 additional wks. Assessments included pain intensity numerical rating scale (NRS-PI), Short-Form McGill Pain Questionnaire (SF-MPQ), Brief Pain Inventory (BPI), Sleep dysfunction NRS (NRS-S) and a survey of CRPS symptoms. Subject and Clinician Global Impression of Change were assessed on a 7-point scale (PGIC and CGIC) with < 3 = worsening, 4= no change, >5 = improvement.

40 chronic CRPS (6 yrs avg) subjects, (75% F) at least partially refractory to conventional therapy with high pain scores (7.1 +/-1.3) enrolled (BL) and 31 completed the core phase (C). 28 subjects entered the extension (Ex), 18 completed all 52 wks and continued treatment for a second 52 wks. Mean scores (SD) for those completing the Ex(prelim. analysis): Pain BL 7.0(1.1), C 5.2 (2.6), Ex 4.9 (2.5) p<0.01; Sleep BL 6.0 (2.5), C 4.2 (2.6), Ex 4.2 (2.5) p<0.01; SF-MPQ total BL 24.2 (8.8), C 16 (9.4), Ex 17 (8.5) p<0.01; BPI pain and functional scores were significantly improved at C and remained significant to Ex p<0.05 except for general activity (Ex p=0.1). CRPS symptoms demonstrated sustained improvement over 52 wks. PGIC C 5.8(1.0), Ex 5.5 (1.3) p<0.01; CGIC C 6.0 (0.8), Ex 5.7 (1.3) p<0.01. Adverse events were mild and time-limited. Rash, pruritis, dizziness, headache, nausea, increased sweating and decreased TSH were the most common. Seven serious adverse events (3 thromboembolic, 3 cytopenias, 1 rectal bleeding) were suspected to be related to lenalidomide and 10 were considered not suspected.

Lenalidomide is a potentially meaningful therapy for Type 1 CRPS with symptom reduction sustained over 52 wks of treatment. A well-controlled clinical study is underway.

Supported by Celgene Corporation

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***Birklein, F MD CRPS J Neurol 2005 252;131-138

Abstract: CRPS may develop after limb trauma and is characterized by pain, sensory-motor and autonomic symptoms. Most important for the understanding of the pathophysiology of CRPS are recent results of pathophysiological research. Major mechanisms for CRPS symptoms, which might be present subsequently or in parallel during the course of CRPS are trauma-related cytokine release, exaggerated neurogenic inflammation, sympathetically maintained pain and cortical reorganization in response to chronic pain ( neuroplasticity), The recognition of these mechanisms in individual CRPS patients is the prerequisite for a mechanism-oriented treatment.

"Besides clinical examination, several technical diagnostic tools can support the diagnosis. Nevertheless, CRPS cannot be proven by any diagnostic measure. A negative result in these tests should not question a clinically typical CRPS and should by no means delay treatment."


Harke, H Gretenkort Ladleif HU Rahman S Spinal Cord Stimulation in sympathetically maintained CRPS type 1 with severe disability:A prospective clinical study Eur Journal of Pain 9 2005 363-73

We assessed the long-term effects of SCS on the improvement of functional status in CRPS 1.As a result of permanent pain relief under long-term SCS combined with physiotherapy, the functional status and quality of life could be significantly improved in SMP CRPS 1.


****Quisel, Anne MD, Gill James M MD, Witherell Peter MD CRPS Underdiagnosed Journal of Family Practice Vol 54 No 6 June 2005

"CRPS may be diagnosed by history and physical exam with no further testing."

Several different diagnostic criteria have undergone validity testing; the 1993 IASP, Bruehl's criteria and Veldman's criteria....Some cases of CRPS type 1 may be preventable. Some cases of CRPS 1 in post-stroke upper extremity hemiplegia (aka shoulder-hand syndrome) may be prevented by early inpatient rehabilitation and avoidance of shoulder trauma to the affected arm. Some cases of post-fracture CRPS 1 may be prevented by 500 mg vitamin C daily started upon diagnosis of fracture and continued through healing."

"Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free?....The key is to remain alert to deviation from the normal course of recovery. Studies have shown that 9 weeks post-injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrists) and sweating or temperature changes in the injured limb may have CRPS 1. In a prospective case series (n=109) no new cases of CRPS 1 developed beyond 9 weeks post-injury."

"It is important to consider patients' report of typical signs even when these signs are not present on examination"

PARC NOTE: Every family physician should read this article on how to recognize and diagnose CRPS in a clinical setting.


***Schwartzman, RJ MD CRPS: Sympathetic inhibition as a diagnostic marker Clin Auton Res 2005 15;13-14

"Nerve injury may induce the sprouting of sympathetic fibers at the dorsal root ganglia level where they form baskets around large touch neurons and this could fire then contributing to mechanoallodynia. After partial nerve injury, cutaneous nociceptors develop noradrenergic sensitivity which can be demonstrated by intradermal injection of norephinephrine. These patients have a reucrrence of allodynia, hyperalgesia and spontaneous pain after their former pain had been relieved by sympathetic blockade. In patients with demonstrated SMP, who then had stimulation of their cutaneous sympathetic afferent system by body cooling, pain increased.....In most patients with severe CRPS of longstanding, there is clinical evidence of coupling of sympathetic outflow with both muscle, joint and deep tissue nociceptors."

Vaneker M, Wilder-Smith OH, Schrombges P, de Man-Hermsen I, Oerlemans HM. 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. 2005 May;115(1-2):204-11. Department of Anaesthesiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

We used quantitative sensory testing (QST) to gain further insight into mechanisms underlying pain in CRPS 1. Specific goals were: (1) to identify altered patterns of sensory processing some 8 years after diagnosis, (2) to document differences in sensory processing between 'warm' and 'cold' diagnostic subgroups, (3) to determine relationships between changed sensory processing and disease progression regarding pain. The study was performed on a cohort of patients (n=47) clinically diagnosed with CRPS 1 of one upper extremity approximately 8 years previously. Pain was quantified by VAS and MacGill Pain Questionnaire (MPQ), and all subjects underwent electrical and mechanical QST. Cold patients (n=13) had poorer MPQ scores than warm ones (n=34), and more pain on electrical stimulation. Their evoked pain increased with disease progression and correlated with clinical pain measures. For both diagnostic subgroups, thresholds to pressure pain were lower on the affected extremity and with disease progression. Eight years after original diagnosis, cold CRPS 1 patients have poorer clinical pain outcomes and show persistent signs of central sensitisation correlating with disease progression. The latter is not the case for warm CRPS 1 patients. Both diagnostic subgroups show greater pressure hyperalgesia on the affected limb and with disease progression. QST may prove useful in the subdiagnosis of CRPS 1 and in quantifying its progression, with both applications warranting further investigation for clinical and research use.





For immediate release: January 30, 2006

Study finds nerve damage in previously mysterious chronic pain syndrome Reduction in small-fiber nerves may underlie complex regional pain syndrome-I (reflex sympathetic dystrophy)

BOSTON - Researchers at Massachusetts General Hospital (MGH) have found the first evidence of a physical abnormality underlying the chronic pain condition called reflex sympathetic dystrophy or complex regional pain syndrome-I (CRPS-I). In the February issue of the journal Pain, they describe finding that skin affected by CRPS-I pain appears to have lost some small-fiber nerve endings, a change characteristic of other neuropathic pain syndromes

"This sort of small-fiber degeneration has been found in every nerve pain condition ever studied, including postherpetic neuralgia and neuropathies associated with diabetes and HIV infection," says Anne Louise Oaklander, MD, PhD, director of the MGH Nerve Injury Unit, who led the study. "The nerve damage in those conditions has been much more severe,

Complex regional pain syndrome is the current name for a baffling condition first described in the 19th century in which some patients are left with severe chronic pain and other symptoms - swelling, excess sweating, change in skin color and temperature - after what may be a fairly minor injury. The fact that patients' pain severity is out of proportion to the original injury is a hallmark of the syndrome, and has led many to doubt whether patients' symptoms are caused by physical damage or by a psychological disorder. Pain not associated with a known nerve injury has been called CRPS-I, while symptoms following damage to a major nerve has been called CRPS-II.

Because small-fiber nerve endings transmit pain messages and control skin color and temperature and because damage to those fibers is associated with other painful disorders, the MGH research team hypothesized that those fibers might also be involved with CRPS-I. To investigate their theory they studied 18 CRPS-I patients and 7 control patients with similar chronic symptoms known to be caused by arthritis. Small skin biopsies were taken under anesthesia from the most painful area, from a pain-free area on the same limb and from a corresponding unaffected area on the other side of the body. The skin biopsies showed that, the density of small-fiber nerve endings in CRPS-I patients was reduced from 25 to 30 percent in the affected areas compared with unaffected areas. No nerve losses were seen in samples from the control participants, suggesting that the damage was specific to CRPS-I, not to pain in general. Tests of sensory function performed in the same areas found that a light touch or slight heat was more likely to be perceived as painful in the affected areas of CRPS-I patients than in the unaffected areas, also indicating abnormal neural function. "The fact that CRPS-I now has an identified cause takes it out of the realm of so-called 'psychosomatic illness.' One of the great frustrations facing CRPS-I patients has been the lack of an explanation for their symptoms. Many people are skeptical of their motivations, and some physicians are reluctant to prescribe pain medications when the cause of pain is unknown," says Oaklander.

"Our results suggest that CRPS-I patients should be evaluated by neurologists who specialize in nerve injury and be treated with medications or procedures that have proven effective for other nerve-injury pain syndromes."

She adds that the next research steps should investigate why some people are left with CRPS after injuries that do not cause long-term problems for most patients, determine the best way of diagnosing the syndrome and evaluate potential treatments. "Investigations that identify the causes of disease are only possible if patients are willing to come to the lab and allow researchers to study them," she adds. "We are tremendously grateful to these CRPS patients, whose willingness to let us study them - despite their chronic pain - allowed us to make an important step in helping those who suffer from this condition." Oaklander is an assistant professor of Anaesthesia and Neurology at Harvard Medical School.

The study was supported by grants from The Mayday Fund, the National Institute for Neurological Disorders and Stroke, and the American Federation for Aging Research. Coauthors are Julia Rissmiller, Lisa Gelman, Li Zheng, MD, PhD; Yuchiao Chang, PhD; and Ralph Gott, all of the MGH. Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School.

Contact: Sue McGreevey (617) 724-2764

PAIN PRACTITIONER Volume 16 No. 1 Spring 2006

The entire issue is devoted to "CRPS: Grappling with the Mysteries", Special Edition

"The treatment of pain is all about suffering..."

List of Articles:

  • CRPS: New Hope after a decade of dispelling myths. Dr. Bradley Galer
  • Exploring Psychosocial Issues in CRPS by Dr. Covington
  • When Children Hurt Too Much by Dr David Sherry MD
  • Emerging Treatment and Diagnosis by Dr. D. Manning
  • New Rechargeable Spinal Cord Stimulators Systems offer Advantages in CRPS Treatment by Dr. J Prager MD
  • The Use of Thermography in the Diagnosis of CRPS: A Physician’s Opinion by Dr Phillip Getson
  • Theory of Suffering by Dr Moscovitz MD
  • Three Stories about CRPS patients and RSDSA article.

Published by American Academy of Pain Management, 13947 Mono Way #A Sonora CA 95370.



Burns AW, Parker DA, Coolican MR, Rajaratnam K.Complex regional pain syndrome complicating total knee arthroplasty. J Orthop Surg (Hong Kong). 2006 Dec;14(3):280-3.
Sydney Orthopaedic Arthritis and Sports Medicine, Chatswood, New South Wales, Australia.

PURPOSE. To compare the long-term outcome of patients diagnosed with complex regional pain syndrome-type 1 (CRPS-1) after total knee arthroplasty (TKA) with those of uncomplicated TKA knees and preoperative osteoarthritic knees. METHODS. Medical records of 1280 patients who underwent TKA for osteoarthritis were retrospectively reviewed; 8 were diagnosed as having symptoms and signs consistent with CRPS after TKA. Patients with primary inflammatory arthritis, signs of component loosening, malpositioning, or of infected arthroplasty were excluded. No patient had signs of CRPS prior to operative intervention. The 8 patients were compared with 2 groups of age- and sex-matched controls: uncomplicated TKA knees and preoperative osteoarthritic knees. Patients were followed up for a mean of 54 (range, 13-111) months and their range of movement, Western Ontario and McMaster Universities Osteoarthritis Index, SF-36 questionnaire scores, and Knee Society scores were assessed and compared. RESULTS. After appropriate treatment, most CRPS complicated patients had similar scores on SF-36, Western Ontario and McMaster Universities Osteoarthritis Index, and Knee Society scores when compared with uncomplicated TKA patients. Scores for CRPS complicated patients were significantly improved when compared with preoperative osteoarthritic patients. The incidence of CRPS after TKA was 0.7%. CONCLUSION. When managed early, patients complicated with CRPS after TKA have a similar prognosis to patients with uncomplicated TKA.


******* Bruehl S, Chung OY.
Psychological and behavioral aspects of complex regional pain syndrome management. Clin J Pain. 2006 Jun;22(5):430-7. Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.

Psychological and behavioral factors can exacerbate the pain and dysfunction associated with complex regional pain syndrome (CRPS) and could help maintain the condition in some patients. Effective management of CRPS requires that these psychosocial and behavioral aspects be addressed as part of an integrated multidisciplinary treatment approach. Well-controlled studies to guide the development of a psychological approach to CRPS management are not currently available. A sequenced protocol for psychological care in CRPS is therefore proposed based on available data and clinical experience. Regardless of the duration of the condition, all CRPS patients and their families should receive education about the negative effects of disuse, the pathophysiology of the syndrome, and possible interactions with psychological/behavioral factors. Patients with acute CRPS (<6-8 weeks) may not need additional psychological care. All patients with chronic CRPS should receive a thorough psychological evaluation, followed by cognitive-behavioral pain management treatment, including relaxation training with biofeedback. Patients making insufficient overall treatment progress or in whom comorbid psychiatric disorders/major ongoing life stressors are identified should additionally receive general cognitive-behavioral therapy to address these issues. The psychological component of treatment can work synergistically with medical and physical/occupational therapies to improve function and increase patients' ability to manage the condition successfully.

*****Groeneweg JG, Huygen FJ, Heijmans-Antonissen C, Niehof S, Zijlstra FJ.
Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. 1.BMC Musculoskelet Disord. 2006 Nov 30;7:91.
Department of Anesthesiology, subdivision Pain Treatment Center, Erasmus MC Rotterdam, The Netherlands.

BACKGROUND: In complex regional pain syndrome type 1 (CRPS1) pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) during early chronic CRPS1. METHODS: Included were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-alpha, ET-1 and nitrate/nitrite (NOx). RESULTS: The levels of IL-6, TNF-alpha and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased. CONCLUSION: The NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution.

***de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC.
The incidence of complex regional pain syndrome: A population-based study. Pain. 2006 Nov 3; [Epub ahead of print]
Erasmus Medical Center, Pharmaco-epidemiology Unit, Departments of Medical Informatics and Epidemiology and Biostatistics, PO BOX 2040, 3000 CA Rotterdam, The Netherlands.

The complex regional pain syndrome (CRPS) is a painful disorder that can occur in an extremity after any type of injury, or even spontaneously. Data on the incidence of CRPS are scarce and mostly hospital based. Therefore the size of the problem and its burden on health care and society are unknown. The objective of the present study was to estimate the incidence of CRPS in the general population. A retrospective cohort study was conducted during 1996-2005 in the Integrated Primary Care Information (IPCI) project, a general practice research database with electronic patient record data from 600,000 patients throughout the Netherlands. Potential CRPS cases were identified by a sensitive search algorithm including synonyms and abbreviations for CRPS. Subsequently, cases were validated by electronic record review, supplemented with original specialist letters and information from an enquiry of general practitioners. The estimated overall incidence rate of CRPS was 26.2 per 100,000 person years (95% CI: 23.0-29.7). Females were affected at least three times more often than males (ratio: 3.4). The highest incidence occurred in females in the age category of 61-70 years. The upper extremity was affected more frequently than the lower extremity and a fracture was the most common precipitating event (44%). The observed incidence rate of CRPS is more as four times higher than the incidence rate observed in the only other population-based study, performed in Olmsted County, USA.Postmenopausal woman appeared to be at the highest risk for the development of CRPS.

Fishman SM.: The role of the pain psychologist, trigger point injections, reflex sympathetic dystrophy.J Pain Palliat Care Pharmacother. 2006;20(4):93-7. Division of Pain Medicine, Department of Anesthesiology and Pain Medicine, University of California at Davis, CA, USA.

This feature presents information for patients in a question and answer format. It is written to simulate actual questions that many pain patients ask and to provide answers in a context and language that most pain patients will comprehend. Issues addressed in this issue are the role of the pain psychologist, trigger point injections, and reflex sympathetic dystrophy.


Fishman SM.
Pain medicine specialists imaging the brain for pain.
Department of Anesthesiology and Pain Medicine, University of California at Davis, CA, USA.

This feature presents information for patients in a question and answer format. It is written to simulate actual questions that many pain patients ask and to provide answers in a context and language that most pain patients will comprehend. Issues addressed in this issue are pain medicine as a specialty and how the brain can be imaged for pain.


********Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, Huygen FJ, van der Meijden P, Hop WC, Hooijkaas H, Zijlstra FJ. Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1.Mediators Inflamm. 2006; 2006(1):28398.
Department of Anaesthesiology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Inflammatory processes are known to be involved at least in the early phase of complex regional pain syndrome type 1 (CRPS1). Blister fluid obtained from the involved extremities displayed increased amounts of proinflammatory cytokines IL-6 and TNFalpha compared with the noninvolved extremities. The aim of this paper is to investigate the involvement of mediators by measurement of several other cytokines using new detection techniques that enable multiple cytokine measurement in small samples. The use of a multiplex-25 bead array cytokine assay and Luminex technology enabled simultaneous measurement of representative (1) proinflammatory cytokines such as GM-CSF, IL-1beta, IL-1RA, IL-6, IL-8, and TNF-alpha; (2) Th1/Th2 distinguishing cytokines IFN-gamma, IL-2, IL-2R, IL-4, IL-5, and IL-10; (3) nonspecific acting cytokines IFN-alpha, IL-7, IL-12p40/p70, IL-13, IL-15, and IL-17; and (4) chemokines eotaxin, IP-10, MCP-1, MIP-1alpha, MIP-1beta, MIG, and RANTES. Although minimal detection levels are significantly higher in the bead array system than those in common ELISA assays, in blister fluid, IL-1RA, IL-6, IL-8, TNF-alpha, IL-12p40/p70, MCP-1, and MIP-1beta were detectable and increased in CRPS1 affected extremities. Levels of IL-6 and TNF-alpha simultaneously measured by ELISA (Sanquin Compact kit) and by multiplex-25 bead array assay (Biosource) were highly correlated (r = 0.85, P < .001 for IL-6 and r = 0.88, P < .001 for TNF-alpha). Furthermore, IP-10 and eotaxin were detectable but diminished in CRPS1, whereas detectable amounts of IL-10 were similar in involved and noninvolved extremities. Multiplex bead array assays are useful systems to establish the involvement of cytokines in inflammatory processes by measurements in blister fluids of CRPS1. Ten representative cytokines were detectable. However, detection levels and amounts measured are at least 3 times higher in the multiplex-25 array assay than in the ELISA assays used simultaneously for the measurement of cytokines.

Harden RN, Bruehl SP. Diagnosis of complex regional pain syndrome: signs, symptoms, and new empirically derived diagnostic criteria.Clin J Pain. 2006 Jun;22(5):415-9.
Center for Pain Studies, Rehabilitation Institute of Chicago, Chicago, IL, USA.

This review will discuss the relevant history of the taxonomy and eventual development of diagnostic criteria of what is currently called complex regional pain syndrome. The authors will take their discussion through the early days (at which time the disorder was called reflex sympathetic dystrophy) through consensus-developing conferences to the current conceptualization of the criteria as published by the International Association for the Study of Pain's Task Force on Taxonomy in 1994. The authors will also mention the recent work of the closed workshop held in Budapest in 2004, where clinical and research criteria were proposed; these criteria were published in 2005. The review will also address issues of staging and subtyping the syndrome, as well as a discussion of the salient signs, symptoms, and tests appropriate for use in the diagnosis.


****Harden RN, Swan M, King A, Costa B, Barthel J.
Treatment of complex regional pain syndrome: functional restoration.Clin J Pain. 2006 Jun;22(5):420-4.
Center for Pain Studies, Chicago, IL 60610, USA.

In this review, the authors discuss the development of consensus-based treatment guidelines in 1997. They also synthesize the recommendations of a closed workshop held in Budapest in late 2004 that reexamined these treatment guidelines and made further and more detailed recommendations. They explore and develop the rationale for making functional restoration the pivotal treatment algorithm in the management of complex regional pain syndrome, around which all other treatments, such as psychotherapy, drugs, and interventions, revolve. The authors discuss in detail the process of functional restoration and the modalities appropriate to accomplishing that--specifically, the role of the occupational therapist, physical therapist, recreational therapist, and vocational rehabilitation specialist. Medications, interventions, and psychotherapy will be covered in other sections of this series.


Larbig W, Montoya P, Braun C, Birbaumer N.
Abnormal reactivity of the primary somatosensory cortex during the experience of pain in complex regional pain syndrome: a magnetoencephalograhic case study. Neurocase. 2006 Oct;12(5):280-5.
Institute of Medical Psychology and Behavioral Neurobiology, University of Tubingen, Germany.

A 49-year-old male worker developed persistent pain in his left wrist after work strain injuries. Clinical symptoms met with criteria for Complex Regional Pain Syndrome (CRPS) type I. In the present study, the effect of the experience of pain on the somatotopy of the primary cortical hand representation was investigated. Somatosensory evoked magnetic fields (SEF) elicited by non-painful tactile stimulation at the index finger of the affected and the unaffected hand were recorded when experiencing pain elicited by a moderate physical load condition (holding a 1.6 kg object in the hand). It was shown that MEG and subjective responses to innocuous tactile stimuli were reduced when simultaneous nociceptive stimulation was applied. These findings suggest a gating effect in the central nervous system elicited by concurrent simultaneous information from two different somatosensory modalities (pain and tactile). The results revealed the existence of nociceptive-induced plastic changes in the central nervous system associated with CRPS type I.

Marinus J, Van Hilten JJ.
Clinical expression profiles of complex regional pain syndrome, fibromyalgia and a-specific repetitive strain injury: more common denominators than pain?
Disabil Rehabil. 2006 Mar 30;28(6):351-62.
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.

PURPOSE: To systematically evaluate and compare the clinical manifestations, disease course, risk factors and demographic characteristics of Complex Regional Pain Syndrome type 1 (CRPS), fibromyalgia (FM) and a-specific Repetitive Strain Injury (RSI). METHOD: A literature search was performed using terms related to the aforementioned topics and diseases. Only original clinical studies that included at least 20 subjects were eligible. RESULTS: Fifty-nine studies on CRPS, 73 on FM and 7 on a-specific RSI were identified. The diseases show similarities in age distribution, male-female ratio, pain characteristics and sensory signs and symptoms. Motor, autonomic and trophic changes are frequently reported in CRPS, but only occasionally in FM and RSI. Systemic symptoms are found in patients with CRPS and FM, and in a subgroup of patients with RSI. In all three disorders, symptoms usually start locally, but may spread to other body regions later, which, in the case of FM, is a prerequisite for diagnosis. Disease onset is always, usually, or occasionally of traumatic origin in RSI, CRPS and FM, respectively. Anxiety and depression are more frequent in patients compared to controls, but probably not very different from patients with other pain conditions or chronic diseases. CONCLUSIONS: Apart from some obvious differences between CRPS, FM and RSI, the similarities are conspicuous. The common features of CRPS, FM and a-specific RSI may suggest that a common pathway is involved, but until patients with these type of symptoms are assessed with a uniform assessment procedure, a thorough comparison cannot be made. A systematic evaluation of patients with a suspected diagnosis of CRPS, FM or RSI, may lead to a better appreciation of the differences and similarities in these diseases and help to unravel the underlying mechanisms.

Studies 2006 N-Z

.Nelson DV, Stacey BR. Interventional therapies in the management of complex regional pain syndrome Clin J Pain. 2006 Jun;22(5):438-42.
Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR, USA.

Invasive procedures have long held a place in the therapeutic armamentarium for the management of complex regional pain syndrome (CRPS). However, this has evolved considerably, particularly as research into the mechanisms of CRPS has called into question long-held presumptions about the key role of sympathetic dysfunction in the syndrome. This review summarizes some of the key information currently available about interventional treatments, including nerve blocks, spinal cord and peripheral nerve stimulation, chemical and surgical sympathectomies, and deep brain stimulation. The potential roles for these procedures in facilitating functional rehabilitation goals that are primary to the treatment of CRPS are emphasized.

********Niehof SP, Huygen FJ, van der Weerd RW, Westra M, Zijlstra FJ.
Thermography imaging during static and controlled thermoregulation in complex regional pain syndrome type 1: diagnostic value and involvement of the central sympathetic system. Biomed Eng Online. 2006 May 12;5:30.
Department of Pain Treatment, Erasmus MC, University Medical Center, Dr, Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

BACKGROUND: Complex Regional Pain Syndrome type 1 (CRPS1) is a clinical diagnosis based on criteria describing symptoms of the disease.The main aim of the present study was to compare the sensitivity and specificity of calculation methods used to assess thermographic images (infrared imaging) obtained during temperature provocation. The secondary objective was to obtain information about the involvement of the sympathetic system in CRPS1. METHODS: We studied 12 patients in whom CRPS1 was diagnosed according to the criteria of Bruehl. High and low whole body cooling and warming induced and reduced sympathetic vasoconstrictor activity. The degree of vasoconstrictor activity in both hands was monitored using a videothermograph. The sensitivity and specificity of the calculation methods used to assess the thermographic images were calculated. RESULTS: The temperature difference between the hands in the CRPS patients increases significantly when the sympathetic system is provoked. At both the maximum and minimum vasoconstriction no significant differences were found in fingertip temperatures between both hands. CONCLUSION: The majority of CRPS1 patients do not show maximal obtainable temperature differences between the involved and contralateral extremity at room temperature (static measurement). During cold and warm temperature challenges this temperature difference increases significantly. As a result a higher sensitivity and specificity could be achieved in the diagnosis of CRPS1. These findings suggest that the sympathetic efferent system is involved in CRPS1.

****************Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R. Pain. 2006 Feb;120(3):235-43. Epub 2006 Jan 19.

Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy).
Comment in:
Pain. 2006 Aug;123(3):334-5.
Pain. 2006 Feb;120(3):227-9.

Nerve Injury Unit, Departments of Anesthesiology, Neurology, and Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

CRPS-I consists of post-traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS-I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP-defined CRPS-I affecting their arms or legs. We studied three sites on subjects' CRPS-affected and matching contralateral limb; the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5-immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom-matched controls. CRPS-I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P<0.03) and heat-pain hyperalgesia (P<0.04) at the CRPS-affected site. Axonal densities were highly correlated between subjects' ipsilateral and contralateral control sites (r=0.97), but were diminished at the CRPS-affected sites of 17/18 subjects, on average by 29% (P<0.001). Overall, control subjects had no painful-site neurite reductions (P=1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS-associated neurite losses.

These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI affecting nociceptive small-fibers. This type of nerve injury will remain undetected in most clinical settings.

Pankaj A, Kotwal PP, Mittal R, Deepak KK, Bal CS.Diagnosis of post-traumatic complex regional pain syndrome of the hand: current role of sympathetic skin response and three-phase bone scintigraphy. J Orthop Surg (Hong Kong). 2006 Dec;14(3):284-90.
Department of Orthopedics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. PURPOSE. To evaluate the role of sympathetic skin response (SSR) and three-phase bone scintigraphy (TPBS) in the diagnosis of complex regional pain syndrome (CRPS). METHODS. 60 patients with CRPS of the hand were recruited. TPBS was performed using a bolus injection of 20 mCi of Tc-99m methylene diphosphonate in an antecubital vein and blood flow (first phase) image, blood pool (second phase) image, and delayed (third phase) image obtained. Patients were considered to have CRPS when the blood pool and blood flow images showed diffuse asymmetric uptake, or when the delayed image indicated increased asymmetric periarticular uptake. SSR was measured simultaneously in the affected and unaffected hands. Standard surface electromyogram disc electrodes were applied to the palm and dorsum of both hands. Electrical stimuli were applied to the skin at the base of little and ring fingers of the unaffected hand. Patients were considered abnormal when response was absent or the peak-to-peak amplitude was <50% of the contralateral hand in at least 2 readings. RESULTS. The delayed phase of TPBS tested positive in all; the first and second phases tested positive in 54 (90%) and 56 (93%) of the patients, respectively. Four of the 6 patients with a negative first phase had had symptoms persisting for more than 6 months, and the other 2 for about 3 to 6 months. No patient presenting within 3 months had a negative scan. SSR was absent in 16 (27%) patients and normal in 44 (73%). 11 (79%) of 14 patients who presented more than 6 months after symptom onset displayed an abnormal SSR, while only 10% of those presenting within 3 to 6 months and 11% of those presenting within 3 months had an abnormal SSR. 12 (75%) of the 16 patients with abnormal SSR had associated decreased sweating, compared with 2 (4.5%) of the 44 patients with a normal SSR. CONCLUSION. TPBS is a very sensitive corroborative test to confirm the clinical suspicion of CRPS during the initial stages, but not in late cases. SSR can be used to document the sympathetic dysfunction in cases having an associated sweating abnormality and may have some diagnostic value in late cases of CRPS, when TPBS is less reliable.


Paraskevas KI, Michaloglou AA, Briana DD, Samara M.
Treatment of complex regional pain syndrome type I of the hand with a series of intravenous regional sympathetic blocks with guanethidine and lidocaine.Clin Rheumatol. 2006 Sep;25(5):687-93.
Department of Vascular Surgery, Athens University Medical School, Athens, Greece.

The aim of this study was to evaluate the efficacy of guanethidine and lidocaine in the treatment of complex regional pain syndrome (CRPS) type I of the hand. Seventeen patients, aged between 33 and 72 years, suffering from CRPS type I of the hand received two series of intravenous regional sympathetic block (Bier's block) sessions with guanethidine and lidocaine according to the following therapeutic protocol: (1) 5 sessions (once every second day) composed of intravenous regional administration of 15 mg guanethidine and 1 mg lidocaine/kg body weight each and (2) 20 sessions (twice a week) composed of intravenous regional administration of 10 mg guanethidine and 1 mg lidocaine/kg body weight each. Complete disappearance of pain and return of the normal function and movement of the extremity were achieved. No side effects were observed. The above-described therapeutic protocol method resulted in excellent pain relief and full restoration of both function and range of movement of the affected extremity in 17 patients suffering from CRPS type I of the hand.


Rowbotham MC. Pharmacologic management of complex regional pain syndrome. Clin J Pain. 2006 Jun;22(5):425-9. UCSF Pain Clinical Research Center, Departments of Neurology and Anesthesia, University of California, San Francisco, School of Medicine, USA.

Few randomized controlled trials of oral pharmacotherapy have been performed in patients with complex regional pain syndrome (CRPS). The prevalence of CRPS is uncertain. Severe and advanced cases of CRPS are easily recognized but difficult to treat and constitute a minority compared with those who meet minimum criteria for the diagnosis. Unsettled disability or liability claims limit pharmaceutical industry interest in the disorder. Many studies are small or anecdotal, or are reported on only via posters at meetings. Targeting the process of bone resorption with bisphosphonate-type compounds such as calcitonin, clodronate, and alendronate has shown efficacy in three published randomized controlled trials. Intravenous phentolamine has been studied both alone and in comparison to intravenous regional blockade or stellate ganglion block. Steroids continue to be administered by multiple routes without large-scale placebo-controlled trials. Topical medications have received little attention. There has been considerable interest in the use of thalidomide and TNF-alpha blockers for CRPS, but no published controlled trials as of yet. Numerous other oral drugs, including muscle relaxants, benzodiazepines, antidepressants, anticonvulsants, and opioids, have been reported on anecdotally. Some therapies have been the subject of early controlled studies, without subsequent follow-up (eg, ketanserin) or without an analogous well-tolerated and equally effective oral treatment (eg, intravenous ketamine). Gabapentin, tricyclic antidepressants, and opioids have been proven effective for chronic pain in disorders other than CRPS. Each has shown a broad enough spectrum of analgesic activity to be cautiously recommended for treatment of CRPS until adequate randomized controlled trials settle the issue. The relative benefit of oral medications compared with the widely used treatments of intensive physical therapy, nerve blocks, sympathectomy, intraspinally administered drugs, and neuromodulatory therapies (eg, spinal cord stimulation) remains uncertain. In summary, treatment of CRPS has received insufficient study and remains largely empirical.

*****Schattschneider J, Binder A, Siebrecht D, Wasner G, Baron R.
Complex regional pain syndromes: the influence of cutaneous and deep somatic sympathetic innervation on pain. Clin J Pain. 2006 Mar-Apr;22(3):240-4.
Klinik fur Neurologie, Sektion fur Schmerzforschung und therapie, Univeritatsklinikum Schleswig-Holstein, Campus Kiel, Germany.

OBJECTIVES: Complex regional pain syndromes (CRPS) can be relieved by sympathetic blockade. Different sympathetic efferent output channels innervate distinct effector organs (ie, cutaneous vasoconstrictor, muscle vasoconstrictor. and sudomotor neurons, as well as neurons innervating deep somatic tissues like bone, joints, and tendons). The aim of the present study was to elucidate in CRPS patients the sympathetically maintained pain (SMP) component that exclusively depends on cutaneous sympathetic activity compared with the SMP depending on the sympathetic innervation of deep somatic tissues. METHODS: The sympathetic outflow to the painful skin was modulated selectively in awake humans. High and low cutaneous vasoconstrictor activity was produced in 12 CRPS type 1 patients by whole-body cooling and warming (thermal suit). Spontaneous pain was quantified during high and low cutaneous vasoconstrictor activity. By comparing the cutaneous SMP component with the change in pain that was achieved by modulation of the entire sympathetic outflow (sympathetic ganglion block), the SMP component originating in deep somatic structures was estimated. RESULTS: The relief of spontaneous pain after sympathetic blockade was more pronounced than changes in spontaneous pain that could be induced by selective sympathetic cutaneous modulation. The entire SMP component (cutaneous and deep) changes considerably over time. It is most prominent in the acute stages of CRPS. CONCLUSIONS: Sympathetic afferent coupling takes place in the skin and in the deep somatic tissues, but especially in the acute stages of CRPS, the pain component that is influenced by the sympathetic innervation of deep somatic structures is more important than the cutaneous activation. The entire sympathetic maintained pain component is not constant in the course of the disease but decreases over time.

Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist E, Schuermann M.
Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.
Clin J Pain. 2006 Mar-Apr;22(3):235-9. Department of Surgery, Ruhr University, Bochum, Germany. .

OBJECTIVES: Complex regional pain syndrome type 1 (CRPS 1) is a disorder that can affect an extremity after minor trauma or surgery. The pathogenesis of this syndrome is unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response, but neurogenic dysregulation also may contribute to it. METHODS: For further insights into the pathogenesis of CRPS 1, the authors investigated inflammatory and neurogenic mediators-C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), soluble tumor necrosis factor receptor I/II (sTNFR I/II), sE-selectin, sL-selectin, sP-selectin, substance P, neuropeptide Y, and calcitonin gene-related peptide-in venous blood from both the healthy arm and the arm with acute CRPS I from 25 patients and from 30 healthy volunteers. RESULTS: Levels of IL-8 and sTNFR I/II were significantly elevated in patients, whereas all soluble forms of selectins were significantly suppressed. There was no significant difference in white blood cell count (WBC), CRP, and IL-6. Substance P was significantly elevated in patients. The other two neuropeptides were unchanged. None of the parameters studied showed any differences between the CRPS I-affected arm and the normal arm. CONCLUSIONS: Elevated IL-8 and sTNFR I/II levels indicate an association between CRPS I and an inflammatory process. Normal WBC, CRP, and IL-6 give evidence for localized inflammation. The hypothesis of neurogenic-induced inflammation mediated by neuropeptides is supported by elevated substance P levels.

*********Schwartzman RJ. Alexander GM, Perreault MJ, Reichenberger ER, Changes in immune and glial markers in the CSF of patients with Complex Regional Pain Syndrome. Brain Behav Immun. 2006 Nov 25; [Epub ahead of print]
Department of Neurology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.

Complex Regional Pain Syndrome is a severe chronic pain condition characterized by sensory, autonomic, motor and dystrophic signs and symptoms. The pain in CRPS is continuous, it worsens over time, and it is usually disproportionate to the severity and duration of the inciting event. This study compares cerebrospinal fluid (CSF) levels of pro- and anti-inflammatory cytokines, chemokines and several biochemical factors (glial fibrillary acidic protein (GFAP), the nitric oxide metabolites (nitrate plus nitrite), the excitatory amino acid neurotransmitter glutamate, calcium, total protein and glucose) in patients afflicted with CRPS to levels found in patients suffering with other non-painful or painful conditions. The aim of the study is to determine the degree of involvement of glial cells and immune system mediators in the pathophysiology of CRPS. There was no elevation or reduction of a CSF marker that was specific for CRPS patients. However, there were several patterns of markers that could be helpful in both elucidating the mechanisms involved in the disease process and supporting the diagnosis of CRPS. The most common pattern was found in 50% (11 out of 22) of the CRPS patients and consisted of; elevated IL-6, low levels of IL-4 or IL-10, increased GFAP or MCP1 and increases in at least two of the following markers NO metabolites, calcium or glutamate. The results from this and other similar studies may aid in elucidating the mechanisms involved in the pathophysiology of CRPS. A better understanding of these mechanisms may lead to novel treatments for this very severe, life-altering illness.

****** Schwartzman RJ, Alexander GM, Grothusen J.
Pathophysiology of complex regional pain syndrome. Expert Rev Neurother. 2006 May;6(5):669-81. Drexel University College of Medicine, Department of Neurology, 245 N. 15 Street, MS 423 hiladelphia, PA 19102, USA.

Complex regional pain syndrome (CRPS) most often follows injury to peripheral nerves or their endings in soft tissue. A combination of prostanoids, kinins and cytokines cause peripheral nociceptive sensitization. In time, the Mg(2+) block of the N-methyl-D-aspartate receptor is removed, pain transmission neurons (PTN) are altered by an influx of Ca(2+) that activates kinases for excitation and phosphatases for depression, activity-dependent plasticity that alters the firing of PTN. In time, these neurons undergo central sensitization that lead to a major physiological change of the autonomic, pain and motor systems. The role of the immune system and the sickness response is becoming clearer as microglia are activated following injury and can induce central sensitization while astrocytes may maintain the process.


Sinis N, Birbaumer N, Schwarz A, Gustin S, Unertl K, Schaller HE, Haerle M.
Memantine and Complex Regional Pain Syndrome (CRPS): effects of treatment and cortical reorganisation][Article in German]Handchir Mikrochir Plast Chir. 2006 Jun;38(3):164-71.
Klinik fur Hand-, Plastische, Rekonstruktive und Verbrennungschirurgie, BG-Unfallklinik, Eberhard-Karls-Universitat Tubingen.

BACKGROUND: In recent studies a central nervous system involvement in the pathogenesis of Complex Regional Pain Syndrome (CRPS) was suggested, stimulating the introduction of central acting drugs. Animal studies have demonstrated an increased expression of the N-methyl-D-aspartate (NMDA) receptors in experimental neuropathic pain. PURPOSE: The aim of this study was to investigate the relationship between NMDA receptor blockers and CRPS. METHOD: Three patients suffering from CRPS of one upper extremity where treated with oral NMDA antagonist Memantine for eight weeks. Patients expressed their pain levels with a visual analog scale ranging from zero to ten at rest and after fist clenching. Furthermore, the range of movement of the fingers and the wrist were documented. To assess force, a pinchmeter and a dynamometer were used. Cortical reorganisation was studied with functional Magnetic Resonance Imaging (fMRI) and Magnetoencephalography (MEG). RESULTS: Six months after treatment with Memantine no rest pain was present in any of the patients. Furthermore, an increase in finger movement was observed after six-month follow-up with no deficits and free movement ranges. Additionally, wrist movement was improved and an increase of force was measured after six months with the dynamometer and the pinchmeter. Moreover the functional impairment, cortical reorganisation was observed in all patients before treatment. These changes returned to a normal pattern after eight weeks of treatment with Memantine. CONCLUSION: These first results demonstrate central nervous system involvement in the development and maintenance of CRPS. The results (functional, pain, fMRI, MEG) after treatment with Memantine indicate the importance of the NMDA receptor system in neuropathic pain syndromes and provide a promising approach for the treatment of CRPS.


Shehab D, Elgazzar A, Collier BD, Naddaf S, Al-Jarallah K, Omar A, Al-Mutairy M.
Impact of three-phase bone scintigraphy on the diagnosis and treatment of complex regional pain syndrome type I or reflex sympathetic dystrophy. Med Princ Pract. 2006;15(1):46-51.
Department of Medicine, Faculty of Medicine, Kuwait University.

OBJECTIVE: To determine the impact of three-phase bone scintigraphy (TPBS) on the diagnosis and management of complex regional pain syndrome type I (CRPSI) or reflex sympathetic dystrophy (RSD). SUBJECTS AND METHODS: Twenty consecutive patients with a recent clinical evidence of CRPSI were referred for TPBS as part of their routine management plan. All patients underwent neurological examinations with special attention to the evaluation of clinical features of vasomotor, sudomotor, motor and sensory dysfunction. Patients were followed prospectively. When both the clinical and TPBS results supported the diagnosis of CRPSI, patients were started on treatment. RESULTS: Of the 20 patients, TPBS supported the diagnosis of RSD in 9 who were treated with steroids and physiotherapy. Complete follow-up was available for 7 of them and all had a satisfactory response to treatment. For the remaining 11 patients RSD was diagnosed clinically but not confirmed by TPBS. On follow-up there was no evidence that TPBS failed to identify RSD in these 11 patients. CONCLUSION: The results indicate that TPBS confirmed the clinical diagnosis of RSD, and, more importantly, had a significant impact on its management.

Shiraishi S, Kobayashi H, Nihashi T, Kato K, Iwano S, Nishino M, Ishigaki T, Ikeda M, Kato T, Ito K, Kimura T. Cerebral glucose metabolism change in patients with complex regional pain syndrome: a PET study. Radiat Med. 2006 Jun;24(5):335-44.
Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Nagoya 466-8550, Japan.

PURPOSE: The aim of this study was to examine abnormalities of the central nervous system in patients with chronic pain who were diagnosed with complex regional pain syndrome (CRPS). MATERIALS AND METHODS: Brain activity was assessed using (18)F-fluorodeoxyglucose positron emission tomography. The data collected from 18 patients were compared with data obtained from 13 normal age-matched controls. RESULTS: Our results showed that glucose metabolism was bilaterally increased in the secondary somatosensory cortex, mid-anterior cingulated cortex (ACC) or posterior cingulated cortex (PCC) (or both), parietal cortex, posterior parietal cortex (PPC), and cerebellum as well as in the right posterior insula and right thalamus in our patients. In contrast, glucose metabolism was reduced contralaterally in the dorsal prefrontal cortex and primary motor cortex. Glucose metabolism was bilaterally elevated in the mid-ACC/PCC and the PPC, which correlated with pain duration. CONCLUSION: These data suggested that glucose metabolism in the brains of patients with CRPS changes dramatically at each location. In particular, glucose metabolism was increased in the areas concerned with somatosensory perception, possibly due to continuous painful stimulation.

**Stanton-Hicks M MD
Complex regional pain syndrome: manifestations and the role of neurostimulation in its management..J Pain Symptom Manage. 2006 Apr;31(4 Suppl):S20-4.
Department of Pain Management, The Cleveland Clinic Foundation, Ohio, USA.

The hallmark of complex regional pain syndrome (CRPS) is excruciating pain (aching, burning, pricking, or shooting). Diagnosis should be established as soon as possible, as response to treatment is adversely affected by any delay. Treatment of CRPS is aimed at improving function, using an interdisciplinary, time-dependent, patient-dependent approach that encompasses rehabilitation, psychological therapy, and pain management. If no response to conventional treatment (e.g., pharmacotherapy) is noted within 12-16 weeks, a more interventional technique such as spinal cord stimulation (SCS) should be used. SCS has been shown to be highly effective in the treatment of CRPS type I, resulting in a significant, long-term reduction in pain and improvement in quality of life. SCS is particularly effective at helping to restore function in affected extremities, especially if applied early in the course of the disease. SCS is also cost effective and improves health-related quality of life.

Toda K, Muneshige H, Asou T.
Intravenous regional block with lidocaine for treatment of complex regional pain syndrome.
Clin J Pain. 2006 Feb;22(2):222-4. Department of Rehabilitation, Hiroshima University Hospital, Hiroshima, Japan.

OBJECTIVES: The goal of this article is to report the successful treatment of a patient with complex regional pain syndrome (CRPS) type 1 involving the hand with the use of an intravenous regional block. METHODS: The patient was a 35-year-old woman who developed CRPS during conservative therapy for a metacarpal fracture. An intravenous regional block with lidocaine alone, using a two-tourniquet technique, was delivered 10 times for at least 40 minutes. The first five treatments were given twice a week and the next five were delivered weekly. All affected joints, including the wrist, were manipulated without undue force. Functional physical measurements were assessed, including range of motion and performance of fine and gross motor tasks. RESULTS: The visual analog scale scores for pain declined from 10 to 0 after treatment. Use of a pen, a pair of chopsticks, and a hammer improved, and edema decreased. CONCLUSIONS: Intravenous regional block with lidocaine was well tolerated and associated with relief in this case of CRPS type 1.

******Vaneker M, Wilder-Smith OH, Schrombges P, Oerlemans HM.Impairments as measured by ISS do not greatly change between one and eight years after CRPS 1 diagnosis. Eur J Pain. 2006 Oct;10(7):639-44. Epub 2005 Nov 21.

Pain Centre, Department of Anaesthesiology, Radboud University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

BACKGROUND: Complex Regional Pain Syndrome type 1 (CRPS 1) is a potentially incapacitating complication in which pain seems to be the most disabling factor. We performed a late follow up study of a well-defined CRPS 1 population more than eight years after diagnosis. The relationships between early and late impairments were studied with a view to outcome prediction and to investigate possible differences in long-term impairments according to initial CRPS 1 subdiagnosis (i.e. "warm" or "cold", diagnosed according to skin temperature measured via infrared thermometer). METHODS: We again measured patients using the Impairment Level SumScore (ISS) (T8). These data were compared with earlier ISS measurements at CRPS diagnosis (T0) and after one year's treatment (T1). Correlations were determined between these measures. RESULTS: Forty-five patients participated in the present study. Total median ISS improved by 55% (statistically/clinically significant) after one year's treatment (T1), and worsened (non-significantly) by 14% from T1 to T8 - without differences according to original subdiagnosis. ISS correlations were stronger for T1 vs. T8 than for T0 vs. T1 or T0 vs. T8, being strongest for the ISS factors related to pain. CONCLUSIONS: Considerable impairments, as measured by ISS, are still present over eight years after first CRPS 1 diagnosis. These do not greatly change between one and eight years post-diagnosis. ISS outcomes are similar for "cold" and "warm" CRPS 1 diagnostic subgroups. Component ISS scores associated with pain appear to possess greatest predictive power.

Varrassi G, Paladini A, Marinangeli F, Racz G. Neural modulation by blocks and infusions.Pain Pract. 2006 Mar;6(1):34-8. Department of Anesthesiology and Pain Management, University of L'Aquila, L'Aquila, Italy.

Neural blockade is widely used in clinical practice to alleviate acute or chronic pain, including neuropathic pain. However, to date there is little controlled evidence to confirm the efficacy of nerve blocks in neuropathic pain. The most common indication for nerve blocks, especially sympathetic blockade, is complex regional pain syndrome, in which success rates of up to 38% have been achieved, depending on the type of the block used. Greater efficacy has been achieved by combining a nerve block with patient-controlled analgesia. Sympathectomy is recommended for the treatment of neuropathic pain only after careful consideration of its usefulness, effectiveness, and risk of adverse effects. Current evidence and clinical experience suggest that neural blockade could be a useful adjunct in the management of refractory neuropathic pain, but further well-controlled studies would be of great benefit to support this type of therapy.

******Webster LR, Walker MJ. Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain.Am J Ther. 2006 Jul-Aug;13(4):300-5. Lifetree Pain Clinic, Salt Lake City, Utah, USA.

Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients. Thirteen outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point verbal analog score (VAS), 11 of 13 patients (85%) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The results demonstrate that ketamine may provide a reasonable alternative treatment for nonresponsive neuropathic pain in ambulatory outpatients.

Wilder RT. Management of pediatric patients with complex regional pain syndrome.
Clin J Pain. 2006 Jun;22(5):443-8. Mayo Clinic Mayo Eugenio Litta Children's Hospital, Rochester, MN 55902, USA.

This review summarizes current information about diagnosis and treatment of complex regional pain syndrome (CRPS) in children. Although it has been widely held that CRPS in children is intrinsically different from adults, there appear to be relatively few differences. However, there is a marked preponderance of lower extremity cases in children. Historically, psychological factors have been invoked to explain the genesis and persistence of CRPS in children, but the evidence is not compelling. Treatment outcome studies are limited but indicate that children generally respond to a primary focus on physical therapy. Multidisciplinary treatment reports are particularly encouraging. The general perception that children have a milder course may relate to the potentially greater willingness of children to actively participate in appropriately targeted treatment rather than to innate differences in the disease process itself. Recurrence rates appear higher than in adults, but response to reinitiation of treatment seems to proceed efficiently. Clinical judgment dictates the extent of medication or interventional therapy added to the treatment to facilitate rehabilitation. In many ways, the approach to the treatment of children mirrors that of adults, with perhaps greater restraint in the use of medications and invasive procedures. The rehabilitation of children with CRPS, like that of adults with CRPS, needs further rigorous investigation.

Yen LD, Bennett GJ, Ribeiro-da-Silva A.
Sympathetic sprouting and changes in nociceptive sensory innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injury. J Comp Neurol. 2006 Apr 20;495(6):679-90.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.

Previous studies have suggested that sympathetic sprouting in the periphery may contribute to the development and persistence of sympathetically maintained pain in animal models of neuropathic pain. In the present study, we examined changes in the cutaneous innervation in rats with a chronic constriction injury to the sciatic nerve. At several periods postinjury, hind paw skin was harvested and processed by using a monoclonal antibody against dopamine-beta-hydroxylase to detect sympathetic fibers and a polyclonal antibody against calcitonin gene-related peptide to identify peptidergic sensory fibers. We observed migration and branching of sympathetic fibers into the upper dermis of the hind paw skin, where they were normally absent. This migration was first detected at 2 weeks, peaked at 4-6 weeks, and lasted for at least 20 weeks postlesion. At 8 weeks postlesion, there was a dramatic increase in the density of peptidergic fibers in the upper dermis. Quantification revealed that densities of peptidergic fibers 8 weeks postlesion were significantly above levels in sham animals. The ectopic sympathetic fibers did not innervate blood vessels but formed a novel association and wrapped around sprouted peptidergic nociceptive fibers. Our data show a long-term sympathetic and sensory innervation change in the rat hind paw skin after the chronic constriction injury. This novel fiber arrangement after nerve lesion may play an important role in the development and persistence of sympathetically maintained neuropathic pain after partial nerve lesions.


Asokumar Buvanendran, M.D., *Scott S. Reuben, MD, Maruti Kari, MD, Jeffrey S. Kroin, PhD, Craig Della Valle, MD, Rush University Medical Center, *Baystate Medical Center.

Perioperative Pregabalin Reduces Neuropathic Pain at 3 Months after Total Knee Arthroplasty (TKA)


Introduction: Pregabalin (Lyrica) has been shown to be effective for the treatment of chronic neuropathic pain (Pain Res Manag 2006; 11:16A-29A). Pregabalin administered before and after surgery reduced opioid use following spinal fusion surgery (Anesth Analg 2006;103:1271). This study examines the hypothesis that pregabalin administered perioperatively for patients’ undergoing total knee arthroplasty (TKA) can reduce chronic long-term pain syndromes.

Methods: Following IRB approval, a total of 146 patients having primary TKA were enrolled in this randomized, placebo-controlled, double-blind study. Patients were randomly assigned to 2 drug groups. Half of the patients received pregabalin 300 mg orally 2 hours prior to surgery, and the other half received matching placebo, at the same time point. In the operating room, patients were sedated with midazolam and a combined spinal-epidural procedure performed. At completion of surgery, epidural infusion of fentanyl/bupivacaine was initiated using continuous basal infusion with superimposed patient-controlled bolus. Patients subsequently received repeated doses of pregabalin 150 mg b.i.d. or placebo starting the day after surgery, with drug dosing continued up until day 14 post-surgery. The incidence of neuropathic pain was assessed 3 months post-surgery using the S-LANSS score, a valid diagnostic tool to assess neuropathic pain, with patients scoring ³12 considered to have neuropathic pain (J Pain 2005;6:149). The incidence of mechanical allodynia (stroking) or hyperalgesia (pressure) was also recorded. Comparison between the 2 groups was by chi-squared test.

Results: There was no difference in demographics (age, weight, etc.) between the 2 groups. At 3 months post-TKA, the incidence of patients with neuropathic pain post-TKA was lower in the pregabalin (1.49%) group compared to the placebo (11.39%) (P=0.018). The incidence of allodynia in the operated leg (fig) was also lower (P=0.0337) at 3 months for the pregabalin group (14%) than the placebo group (37%). The incidence of hyperalgesia in the operated leg was lower (P=0.0346) for the pregabalin group (20%) than the placebo group (34%). Patients who received pregabalin also had lower VAS pain scores in the operated leg at 3 months post-TKA compared to placebo (P=0.047).

Discussion: Perioperative administration of pregabalin decreased the incidence of neuropathic pain from 11.39% to 1.49% at 3 months after TKA. This suggests that pregabalin may be a useful perioperative medication for decreasing the incidence of chronic pain for patients undergoing this surgical procedure.

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