Duration Of Complex Regional Pain Syndrome Research Articles

The efficacy of oral corticoids in treating complex regional pain syndrome: A retrospective cohort study.

There is growing evidence supporting the role of inflammatory mechanisms in complex regional pain syndrome (CRPS). Corticoids, as most effective anti-inflammatory drugs, are widely used in treating inflammation. The aim of this study was to retrospectively assess the efficacy of oral corticoid treatment in CRPS patients. Patients treated at the center of pain medicine in the Erasmus University Medical Centre between January 2015 and January 2020 were approached to partake in this study. Medical records were screened for age, gender, medical history, duration of CRPS, and CRPS severity score. Also, treatment effect, dose and duration, pain scores (NRS), and side effects were extracted from medical records. In addition, global perceived effect was completed in patients treated with corticoids. Between January 2015 and January 2020, twenty-nine CRPS patients received corticoids and met the inclusion criteria. One extreme outlier was excluded and treatment effect was unknown for one patient. Average daily dose was 28.9 mg (range 10-30 mg) and the mean treatment duration was 10.5 days (7-21 days). Fourteen patients (51.9%) responded positively to treatment and thirteen (48.1%) did not respond. Side effects were reported in five patients (17.9%). Corticoid treatment was effective in more than half of the patients. With only mild side effects reported the treatment also appears to be relatively safe. Further research is needed to investigate the efficacy of corticoids in treating (early) CRPS, preferably in an intervention study.

Somatotopic disruption of the functional connectivity of the primary sensorimotor cortex in complex regional pain syndrome type 1.

In complex regional pain syndrome (CRPS), the representation area of the affected limb in the primary sensorimotor cortex (SM1) reacts abnormally during sensory stimulation and motor actions. We recorded 3T functional magnetic resonance imaging resting-state data from 17 upper-limb CRPS type 1 patients and 19 healthy control subjects to identify alterations of patients' SM1 function during spontaneous pain and to find out how the spatial distribution of these alterations were related to peripheral symptoms. Seed-based correlations and independent component analyses indicated that patients' upper-limb SM1 representation areas display (i) reduced interhemispheric connectivity, associated with the combined effect of intensity and spatial extent of limb pain, (ii) increased connectivity with the right anterior insula that positively correlated with the duration of CRPS, (iii) increased connectivity with periaqueductal gray matter, and (iv) disengagement from the other parts of the SM1 network. These findings, now reported for the first time in CRPS, parallel the alterations found in patients suffering from other chronic pain conditions or from limb denervation; they also agree with findings in healthy persons who are exposed to experimental pain or have used their limbs asymmetrically. Our results suggest that CRPS is associated with a sustained and somatotopically specific alteration of SM1 function, that has correspondence to the spatial distribution of the peripheral manifestations and to the duration of the syndrome.

Experiences of diagnosis and treatment for upper limb Complex Regional Pain Syndrome: a qualitative analysis.

Complex Regional Pain Syndrome (CRPS) most frequently affects the upper limb, with high associated disability. Delays to diagnosis and appropriate treatment can adversely impact prognosis and quality of life, but little is known about the healthcare experiences of people with CRPS. This study aimed to explore lived experiences of diagnosis and treatment for people with upper limb CRPS. Participants were recruited through online support groups and multiple public and private healthcare settings in the Greater Wellington Region, New Zealand. Semi-structured interviews were conducted with participants who had experienced upper limb CRPS for more than three months and less than three years. Interviews were transcribed verbatim and analysed using reflexive thematic analysis. Thirteen participants (11 female, 2 male) aged between 43 and 68 years were interviewed. Duration of CRPS ranged from 7 months to 2.5 years. Five themes were identified. Participants initially engaged in healthcare out of a desire to return to being the person they were before having CRPS. Three interacting experiences epitomised the overall healthcare experience: (1) not knowing what is going on, (2) not being taken seriously, and (3) healthcare as adding another layer of load. Meanwhile, participants used multiple approaches in an attempt to not let CRPS stop them from continuing to live their lives. Participants in this study felt that credible information, validation, and simplification from healthcare providers and systems would support their process of navigating towards a meaningful life and self-concept in the presence of CRPS.

Effectiveness of Infliximab in Patients with Complex Regional Pain Syndrome: A Case Series.

Complex regional pain syndrome (CRPS) is a multi-mechanism disease, with an exaggerated inflammatory response as an important underlying mechanism. Auto-inflammation can theoretically be combated by anti-inflammatories, such as TNF-α inhibitors. This study's aim was to assess the effectiveness of intravenous infliximab, a TNF-α inhibitor, in patients with CRPS. CRPS patients treated with infliximab between January 2015 and January 2022 were approached to participate in this retrospective study. Medical records were screened for age, gender, medical history, CRPS duration, and CRPS severity score. Additionally, treatment effect, dose and duration, and side effects were extracted from medical records. Patients who still receive infliximab completed a short global perceived effect survey. Eighteen patients received infliximab, and all but two gave consent. Trial treatment with three sessions of 5 mg/kg intravenous infliximab was completed in 15 patients (93.7%). Eleven patients (73.3%) were categorized as responders with a positive treatment effect. Treatment was continued in nine patients, and seven patients are currently treated. Infliximab dose is 5 mg/kg, and frequency is every four to six weeks. Seven patients completed a global perceived effect survey. All patients reported improvement (median 2, IQR 1-2) and treatment satisfaction (median 1, IQR 1-2). One patient described side effects such as itching and rash. Infliximab proved effective in 11 out of 15 CRPS patients. Seven patients are still being treated. Further research is needed on the role of infliximab in the treatment of CRPS and possible predictors of response to treatment.

Complex Regional Pain Syndrome: Thalamic GMV Atrophy and Associations of Lower GMV With Clinical and Sensorimotor Performance Data.

Results on gray matter alterations in complex regional pain syndrome (CRPS) showed heterogeneous findings. Since CRPS is a rare disease, most studies included only small and heterogeneous samples resulting in a low reliability of findings between studies. We investigated 24 CRPS patients with right upper limb affection in the chronic stage of disease using structural MRI and clinical testing. We focused on gray matter volume (GMV) alterations of the brain in comparison to 33 age matched healthy controls, their association to clinical characteristics (duration of pain syndrome and pain intensity ratings) and sensorimotor performance (finger dexterity and spatiotactile resolution). When applying an explorative whole brain analysis CRPS patients showed lower GMV in the bilateral medial thalamus. No other areas showed a relevant GMV difference for the group comparisons. When applying a region of interest driven approach using anatomical masks of the thalamus, ACC/mPFC, putamen, and insula we found relevant associations of clinical and behavioral data in ACC and insula. Whereas, the GMV in ACC showed negative associations with pain intensity and CRPS duration, the GMV of the left posterior insula was negatively associated with sensorimotor performance of the affected hand side. Overall, our results are in accordance to results of others describing a thalamic reduction of GMV in patients with neuropathic pain and are also in accordance with associations of pain intensity and duration with reduced ACC in general in patients with chronic pain syndromes. Sensorimotor performance seems to be related to posterior insula GMV reduction, which has not been described yet for other patient groups.

Complex regional pain syndrome: intradermal injection of phenylephrine evokes pain and hyperalgesia in a subgroup of patients with upregulated α1-adrenoceptors on dermal nerves.

The aim of this study was to determine whether upregulated cutaneous expression of α1-adrenoceptors (α1-AR) is a source of pain in patients with complex regional pain syndrome (CRPS). Immunohistochemistry was used to identify α1-AR on nerve fibres and other targets in the affected and contralateral skin of 90 patients, and in skin samples from 38 pain-free controls. The distribution of α1-AR was compared between patients and controls, and among subgroups of patients defined by CRPS duration, limb temperature asymmetry, and diagnostic subtype (CRPS I vs CRPS II). In addition, α1-AR expression was investigated in relation to pain and pinprick hyperalgesia evoked by intradermal injection of the α1-AR agonist phenylephrine. Expression of α1-AR on nerve bundles in the CRPS-affected limb was greater in patients who reported prolonged pain and pinprick hyperalgesia around the phenylephrine injection site than in patients with transient pain after the injection. In addition, α1-AR expression in nerve bundles was greater in patients with CRPS II than CRPS I, and was greater in acute than more long-standing CRPS. Although less clearly associated with the nociceptive effects of phenylephrine, α1-AR expression was greater on dermal nerve fibres in the painful than contralateral limb. Together, these findings are consistent with nociceptive involvement of cutaneous α1-AR in CRPS. This involvement may be greater in acute than chronic CRPS, and in CRPS II than CRPS I.

Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome.

An interaction between cutaneous nerves and mast cells may contribute to pain in complex regional pain syndrome (CRPS). To explore this, we investigated the density of dermal nerve fibres, and the density and proximity of mast cells to nerve fibres, in skin biopsies obtained from the affected and unaffected limbs of 57 patients with CRPS and 28 site-matched healthy controls. The percentage of the dermis stained by the pan-neuronal marker protein gene-product 9.5 was lower in the affected limb of patients than in controls (0.12 ± 0.01% vs 0.22 ± 0.04%, P < 0.05), indicating a reduction in dermal nerve fibre density. This parameter did not correlate with CRPS duration. However, it was lower in the affected than unaffected limb of patients with warm CRPS. Dermal mast cell numbers were similar in patients and controls, but the percentage of mast cells less than 5 µm from nerve fibres was significantly lower in the affected and unaffected limbs of patients than in controls (16.8 ± 1.7%, 16.5 ± 1.7%, and 31.4 ± 2.3% respectively, P < 0.05). We confirm previous findings of a mild neuropathy in CRPS. Our findings suggest that this either develops very early after injury or precedes CRPS onset. Loss of dermal nerve fibres in CRPS might result in loss of chemotactic signals, thus halting mast cell migration toward surviving nerve fibres. Failure of normal nerve fibre-mast cell interactions could contribute to the pathophysiology of CRPS.

An exploration into the cortical reorganisation of the healthy hand in upper-limb complex regional pain syndrome

Background and aimsRecent evidence demonstrated that complex regional pain syndrome (CRPS) is associated with a larger than normal somatosensory (S1) representation of the healthy hand. The most intuitive mechanism for this apparent enlargement is increased, i.e. compensatory, use of the healthy hand. We investigated whether enlargement of the S1 representation of the healthy hand is associated with compensatory use in response to CRPS. Specifically, we were interested in whether the size of the S1 representation of the healthy hand is associated with the severity of functional impairment of the CRPS-affected hand. We were also interested in whether CRPS duration might be positively associated with the size of the representation of the healthy hand in S1. MethodsUsing functional magnetic resonance imaging (fMRI) data from our previous investigation, the size of the S1 representation of the healthy hand in CRPS patients (n=12) was standardised to that of a healthy control sample (n=10), according to hand dominance. Responses to questionnaires on hand function, overall function and self-efficacy were used to gather information on hand use in participants. Multiple regression analyses investigated whether the S1 representation was associated with compensatory use. We inferred compensatory use with the interaction between reported use of the CRPS-affected hand and (a) reported overall function, and (b) self-efficacy. We tested the correlation between pain duration and the size of the S1 representation of the healthy hand with Spearman's rho. ResultsThe relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and overall function was small and non-significant (β=−5.488×10−5, 95% C.I. −0.001, 0.001). The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and self-efficacy was also small and non-significant (β=−6.027×10−6, 95% C.I. −0.001, 0.001). The S1 enlargement of the healthy hand was not associated with pain duration (Spearman's rho=−0.14, p=0.67). ConclusionOur exploration did not yield evidence of any relationship between the size of the healthy hand representation in S1 and the severity of functional impairment of the CRPS-affected hand, relative to overall hand use or to self-efficacy. There was also no evidence of an association between the size of the healthy hand representation in S1 and pain duration. The enlarged S1 representation of the healthy hand does not relate to self-reported function and impairment in CRPS. ImplicationsWhile this study had a hypothesis-generating nature and the sample was small, there were no trends to suggest compensatory use as the mechanism underlying the apparent enlargement of the healthy hand in S1. Further studies are needed to investigate the possibility that inter-hemispheric differences seen in S1 in CRPS may be present prior to the development of the disorder.

Time Since Inciting Event Is Associated With Higher Centralized Pain Symptoms in Patients Diagnosed With Complex Regional Pain Syndrome.

We hypothesized that patients with complex regional pain syndrome (CRPS) with a longer time since their inciting event would demonstrate more symptoms of centralized pain. We conducted a cross-sectional analysis of 160 patients with CRPS using validated measures of pain, negative mood, and functioning at the time of their new patient evaluation. The 2011 Fibromyalgia Survey Criteria is a validated self-report measure of widespread body pain and comorbid symptoms (eg, trouble thinking, headaches). The measure was used as a surrogate for centralized pain symptoms. Univariate analyses and multivariate linear regression models were used to assess the associations between patient characteristics and the duration of CRPS. The cohort was divided into tertiles based on the time since the inciting event (<12 months; 1-3 years; >3 years) for univariate comparisons. Unlike the other measures of pain, mood, and function, the fibromyalgia survey score was significantly associated with a longer duration of symptoms. In a multivariate model adjusting for age and sex, each year since the inciting event was associated with an increase of 0.28 in fibromyalgia survey score (Est 0.28; 95% confidence interval, 0.11-0.46; P = 0.002). The finding was distinct from self-reported spread of CRPS symptoms, which was not different based on time since the inciting event. Our findings suggest that the longer the patients have CRPS the more likely they are to report symptoms suggestive of centralized pain. These data may explain why some patients with a longer duration of CRPS do not respond to peripherally directed therapies.

Introduction to CRPS Special Issue

The International Association for the Study of Pain (IASP) Special Interest Group on Pain and the Sympathetic Nervous System held a satellite symposium in Cardiff, Wales, ahead of the World Congress in August 2008. Papers presented at this symposium, now edited and updated, are published here. The problems facing the field of complex regional pain syndrome (CRPS) were addressed in general terms by Dr. Donald Manning, summarized below but not published here. Dr. Manning drew on his methodological experience and previewed his contributions to IMMPACT (Dworkin et al. Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 2010;140:177–93). Manning pointed out that the state of CRPS research was plagued with methodological issues, with most published studies being inadequate in one or more areas: 1. Definition of CRPS itself has not necessarily been universally accepted. 2. Duration of CRPS (avoiding the terms “acute” and “chronic”) might affect both diagnostic criteria and therapeutic stratagems. 3. Average duration of treatment is usually short. 4. Studies have too few subjects. 5. Double-blind studies are rare, placebo controls are difficult, and statistical analytic methods are controversial. 6. Objective outcome measures are rarely, if ever, used. This results in practical difficulties for clinicians and patients in applying clinical trial data to management of CRPS: 1. How does the physician know which CRPS trial applies to the particular patient? 2. Does information from “acute” CRPS or animal models apply to “chronic” CRPS? 3. How can the clinician and patient assess the risk/cost/benefit of a treatment? 4. How can the clinician and patient assess the risk/cost/benefit of “doing nothing”? 5. Why do the “best” medical centers and research groups appear to have the highest placebo effects? 6. How are CRPS recurrences, relapses, and spread prevented? 7. What are realistic treatment/intervention goals for the individual patient? With these questions in mind, Dr. R. Norman Harden reviewed his studies on …

Sensitivity and Specificity of 3-phase Bone Scintigraphy in the Diagnosis of Complex Regional Pain Syndrome of the Upper Extremity

Joint and bone alterations are seldom mentioned in the diagnostic criteria for complex regional pain syndrome (CRPS) even though they are important for long-term outcome. Altered periarticular bone metabolism can be detected by 3-phase bone scintigraphy (TPBS). Although frequently examining the diagnostic efficacy of TPBS is debatable. In all, 78 TPBS (45 CRPS/33 control group) were evaluated qualitatively and quantitatively. Sensitivity and specificity of the qualitative blinded reviewer analysis (n=57) compared with quantitative region of interest (ROI)-based analysis over the metacarpophalangeal, proximal, and distal interphalangeal joints (n=74) were evaluated. Patients' sex, age, duration of CRPS, inciting event, extent of joint alteration, and handedness were included as covariables. Qualitative blinded reviewer TPBS analysis had a high specificity (83%-100%). However, sensitivity was 31% to 50%. Interrater reliability was moderate (kappa score 0.56). Using the ROI-based evaluation, the highest sensitivity (69%) and specificity (75%) (ROI score > or =1.32) was shown for phase 3, whereas sensitivity of phases 1 and 2 rapidly declined to 50%. Duration of CRPS until TPBS was the only variable with significant impact on ROI scores of phase 3 (F=23.7; P=0.000; R=0.42). ROI scores declined with increasing duration of CRPS. In conclusion, TPBS is a highly specific tool for diagnosing CRPS of the upper limb. ROI evaluation of phase 3 within the first 5 months after onset of CRPS is an appropriate additional diagnostic tool to confirm or exclude CRPS of the upper extremity.

The important role of neuropeptides in complex regional pain syndrome.

To test the contribution of neurogenic inflammation and neuropeptide release to the pathophysiology of complex regional pain syndrome (CRPS). CRPS is characterized by edema and increased skin temperature, sympathetic dysfunction and pain, or hyperalgesia. This investigation was prompted by a recent study by the authors that suggested a facilitated neurogenic inflammation in CRPS. In addition to physical examination, calcitonin gene-related peptide (CGRP) serum concentrations were measured using a radioimmunoassay (RIA) for human CGRP in 19 patients with acute CRPS, on the affected and unaffected sides (n = 13), before and 9 months after therapy (n = 9). In addition, an age- and sex-matched group of 16 healthy controls was investigated. In blood from the cubital vein, CGRP levels in patients with CRPS (122.2 +/- 14.6 pmol/L) were increased (controls 83.8 +/- 6.7 pmol/L, p < 0.03). There was no difference between the affected and unaffected sides. There was, however, a reduction of serum CGRP after therapy (acute disease: 141.2 +/- 18.5 pmol/L, after therapy 106.7 +/- 11.3 pmol/L, p < 0.005); absolute CGRP levels then no longer differed from controls. Increased serum CGRP was correlated to the incidence of nerve lesions (p < 0.02) and hyperhidrosis (p < 0.04). There was no correlation to other clinical symptoms, duration of CRPS, or pain. However, normalization of CGRP after therapy was accompanied by clinical improvement of local inflammatory signs, but not by pain reduction. Increased systemic CGRP levels in patients with acute CRPS suggest neurogenic inflammation as a pathophysiologic mechanism contributing to vasodilation, edema, and increased sweating. However, pain and hyperalgesia, in particular in chronic stages, were independent of increased neuropeptide concentration.

Neurological findings in complex regional pain syndromes--analysis of 145 cases.

Early diagnosis is a prerequisite for a successful treatment of complex regional pain syndrome (CRPS). In order to describe neurological symptoms which characterize CRPS, we evaluated 145 patients prospectively. Two-thirds of these were women, the mean age at time of investigation was 50.4 years. CRPS followed limb trauma, surgery and nerve lesion. Employing the current IASP criteria 122 patients were classified as CRPS I and 23 as CRPS II. All patients were assessed clinically pain was quantified using the McGill pain questionnaire, skin temperature was measured by an infrared thermometer and a subgroup of 57 patients was retested in order to determine thermal thresholds (QST). Of our patients 42% reported stressful life events in a close relationship to the onset of CRPS and 41% had a history of chronic pain before CRPS. The latter group of patients gave a higher rating of CRPS pain (P<0.05). The major symptoms were pain at rest in 77% and hyperalgesia in 94%. Typical pain was deep in the limb having a tearing character. Patients getting physical therapy had significantly less pain than those without (P<0.04). Autonomic signs were frequent (98%) and often changed with the duration of CRPS. Skin temperature was warmer in acute and colder in chronic stages (P<0.001). Likewise edema had a higher incidence in acute stages (P<0.001). We found no correlation between pain and autonomic dysfunction. Motor dysfunction (present in 97%) included weakness, tremor, exaggerated tendon reflexes, dystonia or myoclonic jerks. QST revealed increased warm perception thresholds (P<0.02) and decreased cold pain thresholds (P<0.03) of the affected limb. The detailed knowledge of clinical features of CRPS could help physicians early to recognize the disease and thus to improve therapy outcome.

Pattern of autonomic dysfunction in time course of complex regional pain syndrome.

The objective of the present investigation was to describe and localize autonomic dysfunction in acute and chronic stages of complex regional pain syndrome (CRPS). Patients were investigated twice: the first investigation was performed as soon as diagnosis was established during the acute stage of CRPS and the second investigation was performed about 2 years later. Twenty-one patients completed the follow-up investigation. The median duration of CRPS was 5 (range 2-21) weeks at first investigation and 94 weeks (22-148) at follow-up. Skin temperature was recorded by thermography, sudomotor function was assessed by thermoregulatory sweat test (TST) and quantitative sudomotor axon reflex test (QSART). Skin temperature was warmer on the affected side at the first investigation (P < 0.001) and colder at follow-up (P < 0.02) compared with the contralateral limb. Sudomotor output was enhanced after both TST (P < 0.005) and QSART (P < 0.05) at the first investigation on the affected side. However, at follow-up, sweating after TST was still increased (P < 0.04) while QSART responses were not different between the affected and unaffected limbs. As compared to controls there was no statistically significant difference, neither in skin temperature nor sweating, neither on the affected nor on the unaffected side. In conclusion, the present investigation proved that vasomotor and sudomotor control are substantially altered in CRPS. In the acute stage vasomotor control is decreased in the affected limb whereas sudomotor function is enhanced. This may be the result of disturbances of thermoregulation, but different secondary peripheral mechanisms, concerning vasomotor and sudomotor function, contribute to clinical presentation of CRPS and affect autonomic function at all stages of CRPS.