Demographic and medical parameters in the development of complex regional pain syndrome type 1 (CRPS1): prospective study on 596 patients with a fracture

Limited data are available on the incidence of complex regional pain syndrome type 1 (CRPS1) and on demographic and medical risk factors for the development of CRPS1. The objective of this study was to investigate the incidence of CRPS1 in patients with a fracture using 3 sets of diagnostic criteria and to evaluate the association between demographic/medical factors and the development of CRPS1 diagnosed with the Harden and Bruehl criteria. A prospective multicenter cohort study of 596 patients (ages 18 years and older) with a single fracture of the wrist, scaphoid, ankle, or metatarsal V, recruited patients from the emergency rooms of 3 Dutch hospitals. Of the 596 participants, 42 (7.0%) were diagnosed with CRPS1 according to the Harden and Bruehl criteria, 289 (48.5%) according to the International Association for the Study of Pain criteria, and 127 (21.3%) according to the criteria of Veldman. An analysis of the medical and demographic differences revealed that patients in whom CRPS1 later developed more often had intra-articular fractures, fracture dislocations, rheumatoid arthritis, or musculoskeletal comorbidities. An ankle fracture, dislocation, and an intra-articular fracture contributed significantly to the prediction of the development of CRPS1. No CRPS1 patients were symptom free at 12 months (T3). At baseline, patients with CRPS1 had significantly more pain than patients without CRPS1 (P<.001). The incidence of the diagnosis of CRPS1 after a single fracture depends to a large extent on the diagnostic criteria used. After a fracture, 7% of the patients developed CRPS1 and none of the patients were free of symptoms at 1-year follow-up.     

Impaired self-perception of the hand in complex regional pain syndrome (CRPS)

To investigate neglect, extinction, and body-perception in patients suffering from complex regional pain syndrome (CRPS). So-called ‘neglect-like’ symptoms have been reported in CRPS, however no studies have yet analyzed this phenomenon which might substantiate the theory of the central nervous system involvement in the pathophysiology of CRPS. A total of 114 patients with CRPS of the upper limb underwent bedside neurological examination. ‘Neglect-like’ symptoms were determined by asking all patients what kind of feeling they had toward the affected hand (feeling of foreignness). Hemispatial neglect was tested with the line bisection task in 29 patients and sensory extinction to simultaneous stimulation in 40 patients. The ability to identify fingers after tactile stimulation was tested in 73 patients. Independently of the affected side and disease duration, 54.4% of the patients reported that their hand felt ‘foreign’ or ‘strange’. The ability to identify fingers was impaired in 48% on the affected hand and in 6.5% on the unaffected hand (X²=33.52, df=1, p<0.0001). These findings were related to pain intensity, illness duration and the extent of sensory deficits. No typical abnormalities indicating neglect were found in the line bisection test. Sensory extinction was normal in all patients. A large proportion of CRPS patients have disturbances of the self-perception of the hand, indicating an alteration of higher central nervous system processing. There are no indicators that classic neglect or extinction contribute to these findings. Physical therapy of such patients should take this observation into consideration.     

Impaired spatial body representation in complex regional pain syndrome type 1 (CRPS I)

Recently, a shift of the visual subjective body midline (vSM), a correlate of the egocentric reference frame, towards the affected side was reported in patients with complex regional pain syndrome (CRPS). However, the specificity of this finding is as yet unclear. This study compares 24 CRPS patients to 21 patients with upper limb pain of other origin (pain control) and to 24 healthy subjects using a comprehensive test battery, including assessment of the vSM in light and dark, line bisection, hand laterality recognition, neglect-like severity symptoms, and motor impairment (disability of the arm, shoulder, and hand). Statistics: 1-way analysis of variance, t-tests, significance level: 0.05. In the dark, CRPS patients displayed a significantly larger leftward spatial bias when estimating their vSM, compared to pain controls and healthy subjects, and also reported lower motor function than pain controls. For right-affected CRPS patients only, the deviation of the vSM correlated significantly with the severity of distorted body perception. Results confirm previous findings of impaired visuospatial perception in CRPS patients, which might be the result of the involvement of supraspinal mechanisms in this pain syndrome. These mechanisms might accentuate the leftward bias that results from a right-hemispheric dominance in visuospatial processing and is known as pseudoneglect. Pseudoneglect reveals itself in the tendency to perceive the midpoint of horizontal lines or the subjective body midline left of the centre. It was observable in all 3 groups, but most pronounced in CRPS patients, which might be due to the cortical reorganisation processes associated with this syndrome.     

Medical history and the onset of complex regional pain syndrome (CRPS)

Knowledge concerning the medical history prior to the onset of complex regional pain syndrome (CRPS) might provide insight into its risk factors and potential underlying disease mechanisms. To evaluate prior to CRPS medical conditions, a case-control study was conducted in the Integrated Primary Care Information (IPCI) project, a general practice (GP) database in the Netherlands. CRPS patients were identified from the records and validated through examination by the investigator (IASP criteria) or through specialist confirmation. Cases were matched to controls on age, gender and injury type. All diagnoses prior to the index date were assessed by manual review of the medical records. Some pre-specified medical conditions were studied for their association with CRPS, whereas all other diagnoses, grouped by pathogenesis, were tested in a hypothesis-generating approach. Of the identified 259 CRPS patients, 186 cases (697 controls) were included, based on validation by the investigator during a visit (102 of 134 visited patients) or on specialist confirmation (84 of 125 unvisited patients). A medical history of migraine (OR: 2.43, 95% CI: 1.18-5.02) and osteoporosis (OR: 2.44, 95% CI: 1.17-5.14) was associated with CRPS. In a recent history (1-year before CRPS), cases had more menstrual cycle-related problems (OR: 2.60, 95% CI: 1.16-5.83) and neuropathies (OR: 5.7; 95% CI: 1.8-18.7). In a sensitivity analysis, including only visited cases, asthma (OR: 3.0; 95% CI: 1.3-6.9) and CRPS were related. Psychological factors were not associated with CRPS onset. Because of the hypothesis-generating character of this study, the findings should be confirmed by other studies.     

Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months

There is evidence that inflammatory processes are involved in at least the early phase of complex regional pain syndrome (CRPS). We compared a panel of pro- and antiinflammatory cytokines in skin blister fluids and serum from patients with CRPS and patients with upper-limb pain of other origin (non-CRPS) in the early stage (< 1 year) and after 6 months of pain treatment. Blister fluid was collected from the affected and contralateral nonaffected side. We used a multiplex-10 bead array cytokine assay and Luminex technology to measure protein concentrations of the cytokines interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-6, IL-8, IL-10, IL-12p40, and tumor necrosis factor-alpha (TNF-α) and the chemokines eotaxin, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1β (MIP-1β). We found bilaterally increased proinflammatory TNF-α and MIP-1β and decreased antiinflammatory IL-1RA protein levels in CRPS patients compared to non-CRPS patients. Neither group showed side differences. After 6 months under analgesic treatment, protein levels of all measured cytokines in CRPS patients, except for IL-6, significantly changed bilaterally to the level of non-CRPS patients. These changes were not related to treatment outcome. In serum, only IL-8, TNF-α, eotaxin, MCP-1, and MIP-1β were detectable without intergroup differences. Blister fluid of CRPS patients showed a bilateral proinflammatory cytokine profile. This profile seems to be relevant only at the early stage of CRPS. Almost all measured cytokine levels were comparable to those of non-CRPS patients after 6 months of analgesic treatment and were not related to treatment outcome.     

Spinal cord stimulation in adolescents with complex regional pain syndrome type I (CRPS‐I)

Complex regional pain syndrome type I (CRPS‐I) is not uncommon in children, particularly in adolescent girls. Most often, the condition involves a foot and is characterized by spontaneous pain, tactile allodynia and dysautonomic signs. There is usually a history of a minor, local trauma but sometimes no reasonable cause can be identified, and there are no signs of persistent tissue injury giving rise to ongoing nociception. Common analgesics are generally of no benefit, and the standard treatment includes sociopsychological support, physiotherapy, tricyclic antidepressants and antiepileptic drugs, sympathetic blocks (SB), and cognitive‐behavioural therapy. For a minority of patients who prove to be resistant to such therapies, spinal cord stimulation (SCS) may be tried. The present study comprises seven girls, 11–14 years of age, presenting with severe, incapacitating and therapy‐resistant CRPS‐I, who were subjected to SCS. In two of them, percutaneous electrode implantation had to be performed in general anaesthesia. Trial stimulation was performed in all, but one. In two cases, it was not possible to produce paraesthesias that entirely covered the pain area. A pain relieving effect of SCS was usually not reported until after 1–2 weeks of trial stimulation. After another 2–6 weeks, pain alleviation was complete in five of the seven patients, one to eight years after the intervention. In one case, a local infection necessitated the removal of the electrode; nevertheless a few days of trial stimulation produced substantial pain relief that still persists. In four patients, the SCS use was gradually diminished and eventually the device could be removed. The favourable outcome in all seven cases with no or minor remaining symptoms and without severe recurrences illustrates that SCS may also be an efficient treatment in paediatric cases with exceptionally therapy resistant forms of CRPS I.     

Health-related quality of life in 975 patients with complex regional pain syndrome type 1

There are limited data available on health-related quality of life (QoL) in patients with complex regional pain syndrome (CRPS). In the present study we examined QoL in 975 CRPS patients attending 6 different clinics in the Netherlands. QoL was assessed using the MOS 36-Item Short-Form Health Survey (SF-36) with the Mental Health Summary Score (MHS) and the Physical Health Summary Score (PHS) as dependent variables. The influences of gender, type of affected limb, disease duration, pain scores, CRPS severity and set of diagnostic criteria used were investigated. We found the lowest scores of QoL in the physical domains of the SF-36, with lower-limb CRPS patients reporting poorer results than patients with an affected upper limb. Influence of gender on QoL was not observed, and correlations of QoL with disease duration and the CRPS severity score were weak. Pain correlated moderately with QoL. In addition, patients fulfilling stricter diagnostic criteria (ie, the Budapest criteria) had lower QoL scores than patients fulfilling less strict criteria (ie, the Orlando criteria). We conclude that loss of QoL in CRPS patients is due mainly to reduced physical health. A comparison with data available from the literature shows that CRPS patients generally report poorer QoL than patients with other chronic pain conditions, particularly in the physical domains. Pain correlated moderately with QoL and therefore deserves ongoing attention by physicians. Finally, patients meeting the diagnostic Budapest criteria have lower QoL scores than patients meeting the Orlando criteria, highlighting the impact of different sets of criteria on population characteristics.     

Bier block as a successful management of a patient with intractable complex regional pain syndrome (CRPS) type 1: A case report

Bier block was successful in the pain management of complex regional pain syndrome (CRPS) type 1.     

Longstanding complex regional pain syndrome is associated with activating autoantibodies against alpha-1a adrenoceptors

Complex regional pain syndrome (CRPS) is a limb-confined posttraumatic pain syndrome with sympathetic features. The cause is unknown, but the results of a randomized crossover trial on low-dose intravenous immunoglobulins (IVIG) treatment point to a possible autoimmune mechanism. We tested purified serum immunoglobulin G (IgG) from patients with longstanding CRPS for evidence of antibodies interacting with autonomic receptors on adult primary cardiomyocytes, comparing with control IgG from healthy and diseased controls, and related the results to the clinical response to treatment with low-dose IVIG. We simultaneously recorded both single-cell contractions and intracellular calcium handling in an electrical field. Ten of 18 CRPS preparations and only 1/57 control preparations (P < 0.0001) increased the sensitivity of the myocytes to the electric field, and this effect was abrogated by preincubation with α-1a receptor blockers. By contrast, effects on baseline calcium were blocked by preincubation with atropine. Interestingly, serum-IgG preparations from all 4 CRPS patients who had responded to low-dose IVIG with meaningful pain relief were effective in these assays, although 4/8 of the nonresponders were also active. To see if there were antibodies to the α-1a receptor, CRPS-IgG was applied to α-1a receptor-transfected rat-1 fibroblast cells. The CRPS serum IgG induced calcium flux, and fluorescence-activated cell sorting showed that there was serum IgG binding to the cells. The results suggest that patients with longstanding CRPS have serum antibodies to α-1a receptors, and that measurement of these antibodies may be useful in the diagnosis and management of the patients.     

A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome

The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8 days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS-IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS.     

Safety of "pain exposure" physical therapy in patients with complex regional pain syndrome type 1

“Pain exposure” physical therapy (PEPT) is a new treatment for patients with complex regional pain syndrome type 1 (CRPS-1) that consists of a progressive-loading exercise program and management of pain-avoidance behavior without the use of specific CRPS-1 medication or analgesics. The aim of this study was to investigate primarily whether PEPT could be applied safely in patients with CRPS-1. Twenty patients with CRPS-1 were consecutively enrolled in the study after giving informed consent. The diagnosis of CRPS-1 was defined using the Bruehl and Harden/IASP diagnostic criteria. CRPS-1 was diagnosed between 3 and 18 months after the inciting event (trauma). According to a multiple single-case design (baseline [A1], treatment [B], follow-up [A2]), multiple baseline and follow-up measurements were performed to evaluate changes in CRPS signs and symptoms and to assess functional parameters. When comparing the baseline with the follow-up phase, patients improved significantly with respect to pain on the visual analogue scale (57%), pain intensity (48%), muscle strength (52%), arm/shoulder/hand disability (36%), 10-meter walking speed (29%), pain disability index (60%), kinesiophobia (18%), and the domains of perceived health change in the SF-36 survey (269%). Three patients initially showed increased vegetative signs but improved in all other CRPS parameters and showed good functional recovery at follow-up. We conclude that PEPT is a safe and effective treatment for patients with CRPS-1.     

Nerve resection,crush and re-location relieve complex regional pain syndrome type II: A case report

This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower-limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves.     

A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I).

Exaggerated neurogenic inflammation has been recognized to be one reason for many CRPS symptoms. Since angiotensin-converting enzyme (ACE) is a key enzyme for the termination of neurogenic inflammation, it has been selected as a candidate gene for CRPS predisposition. A previous report of an insertion/deletion (I/D) polymorphism in intron 16 within the ACE gene implicated an increased risk to develop CRPS I associated with the D allele. However, in the present study the D allele frequency was not increased in CRPS I cases (0.51 for D allele, 0.49 for I allele). Furthermore, there was no co-segregation of any genotype (DD, ID, II) with the CRPS phenotype in 12 selected familial CRPS I cases from six CRPS I families. In conclusion, the results presented herein render this particular ACE gene polymorphism unlikely to be a predisposing factor for CRPS I.     

Diagnostic criteria and follow‐up parameters in complex regional pain syndrome type I – a Delphi survey

Background: Although the current clinical guideline of diagnostic criteria for the complex regional pain syndrome I (CRPS I) is a landmark endeavour to define this complex condition it does not prioritise its most important clinical manifestations. Aim: We set out to obtain an expert agreed priority list of diagnostic and follow‐up parameters in the diagnosis and management of CRPS I. Methods: A two round Delphi survey: We asked international experts to list (first round) and weight (second round) parameters (scale 1–10) they believed to be relevant in diagnosis and follow‐up. Median ratings and interquartile ranges (IQR) were calculated. Rates ≥7 and IQR ≤3 depicted important and expert agreed parameters. Results: Thirty‐two diagnostic and 23 follow‐up listings and ratings of 13 experts were available for analysis. In three domains (clinical presentation, further examinations and follow‐up) experts agreed on the following parameters, pain (10; 9–10) with its subcategories hyperesthesia (7; 5–8) hyperalgesia (8; 8–8) and allodynia (8; 7–10), signs with oedema (9; 8–10) and colour change (8; 5–8) and mobility with its categories motor change (7; 5–8) and decreased range of motion (8; 8–8). The experts agreed that no further examinations were necessary for diagnosis (10; 8–10). The agreed important follow‐up parameter was clinical course (10; 8–10) with its categories decrease in pain (8; 8–9) and hyperalgesia (8; 6–8), decreased oedema (8; 7–10) and improvements in motor function (10; 8–10) and strength (8; 6–9). Conclusion: This expert survey conveys an agreed set of relevant diagnostic parameters of CRPS I and proposes that in follow‐up examinations treatment success should be based on restoration of those manifestations.     

Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome

Complex regional pain syndrome (CRPS) is a painful, disabling, chronic condition whose etiology remains poorly understood. The recent suggestion that immunological mechanisms may underlie CRPS provides an entirely novel framework in which to study the condition and consider new approaches to treatment. Using a murine fracture/cast model of CRPS, we studied the effects of B-cell depletion using anti-CD20 antibodies or by performing experiments in genetically B-cell-deficient (μMT) mice. We observed that mice treated with anti-CD20 developed attenuated vascular and nociceptive CRPS-like changes after tibial fracture and 3 weeks of cast immobilization. In mice with established CRPS-like changes, the depletion of CD-20+ cells slowly reversed nociceptive sensitization. Correspondingly, μMT mice, deficient in producing immunoglobulin M (IgM), failed to fully develop CRPS-like changes after fracture and casting. Depletion of CD20+ cells had no detectable effects on nociceptive sensitization in a model of postoperative incisional pain, however. Immunohistochemical experiments showed that CD20+ cells accumulate near the healing fracture but few such cells collect in skin or sciatic nerves. On the other hand, IgM-containing immune complexes were deposited in skin and sciatic nerve after fracture in wild-type, but not in μMT fracture/cast, mice. Additional experiments demonstrated that complement system activation and deposition of membrane attack complexes were partially blocked by anti-CD20+ treatment. Collectively, our results suggest that CD20-positive B cells produce antibodies that ultimately support the CRPS-like changes in the murine fracture/cast model. Therapies directed at reducing B-cell activity may be of use in treating patients with CRPS.     

Thoracic sympathetic block for the treatment of complex regional pain syndrome type I: A double-blind randomized controlled study

Pain relief in complex regional pain syndrome (CRPS) remains a major challenge, in part due to the lack of evidence-based treatment trials specific for this condition. We performed a long-term randomized, double-blinded active-control study to evaluate the efficacy of thoracic sympathetic block (TSB) for upper limb type I CRPS. The study objective was to evaluate the analgesic effect of TSB in CRPS. Patients with CRPS type I were treated with standardized pharmacological and physical therapy and were randomized to either TSB or control procedure as an add-on treatment. Clinical data, pain intensity, and interference (Brief Pain Inventory), pain dimensions (McGill Pain Questionnaire [MPQ]), neuropathic characteristics (Neuropathic Pain Symptom Inventory [NPSI]), mood, upper limb function (Disabilities of Arm, Shoulder and Hand), and quality of life were assessed before, and at 1 month and 12 months after the procedure. Thirty-six patients (19 female, 44.7 ± 11.1 years of age) underwent the procedure (17 in the TSB group). Average pain intensity at 1 month was not significantly different after TSB (3.5 ± 3.2) compared to control procedure (4.8 ± 2.7; P = 0.249). At 12 months, however, the average pain item was significantly lower in the TSB group (3.47 ± 3.5) compared to the control group (5.86 ± 2.9; P = 0.046). Scores from the MPQ, evoked-pain symptoms subscores (NPSI), and depression scores (Hospital Anxiety and Depression Scale) were significantly lower in the TSB group compared to the control group at 1 and at 12 months. Other measurements were not influenced by the treatment. Quality of life was only slightly improved by TSB. No major adverse events occurred. Larger, multicentric trials should be performed to confirm these original findings.     

The role of enhanced cutaneous IL-1β signaling in a rat tibia fracture model of complex regional pain syndrome

Tibia fracture in rats initiates a syndrome resembling the complex regional pain syndrome type I. Accumulating evidence indicates that IL-1β is involved in the modulation of nociceptive information and it acts as an intermediate inflammatory mediator via up-regulation of NGF. We hypothesized that IL-1β signaling might mediate the development of the CRPS-like changes after tibial fracture, either directly or by stimulating NGF expression. Rats underwent distal tibia fracture and casting for 4 weeks and were chronically treated with an IL-1 receptor antagonist (IL-1ra). Nociceptive testing and assessment of edema and hindpaw warmth were performed at baseline and after cast removal. Bone microarchitecture was evaluated by micro-computed tomography. Confocal immunofluorescence and in situ hybridization techniques were used to evaluate changes in the cutaneous expression of IL-1β at 4 weeks post-fracture. The nociceptive and vascular effects of intraplantar IL-1β injections were evaluated in intact rats at different time points after injection. We found that: (1) IL-1ra reduced fracture-induced nociceptive sensitization, but did not decrease hindpaw edema or warmth, (2) fracture chronically up-regulated IL-1β mRNA and protein expression in hindpaw skin keratinocytes, (3) IL-1β intraplantar injection induced mechanical allodynia in a dose-dependent manner and stimulated keratinocyte NGF expression in the hindpaw skin, and (4) intraplantar injection of NGF-induced nociceptive sensitization. Collectively, these results indicate that cutaneous IL-1β signaling can contribute to chronic regional nociceptive sensitization after fracture, possibly by stimulating NGF over-expression in keratinocytes. Our data also highlight the importance of the keratinocyte as the primary source of post-traumatic IL-1β over-expression.     

Familial occurrence of complex regional pain syndrome

Genetic factors are suggested to play a role in complex regional pain syndrome (CRPS), but familial occurrence has not been extensively studied. In the present study we evaluated familial occurrence in Dutch patients with CRPS. Families were recruited through the Dutch Association of CRPS patients and through referral by clinicians. The number of affected members per family, the phenotypic expression and inheritance were assessed. Demographic and clinical characteristics of familial CRPS (fCRPS) patients were compared with those of sporadic CRPS (sCRPS) patients from a Dutch population‐based study and with a group of sCRPS patients that was proportionally matched for referral center of the fCRPS probandi to control for referral bias. Thirty‐one CRPS families with two or more affected relatives were identified, including two families with five, four with four, eight with three and 17 with two affected relatives. In comparison with sCRPS patients, fCRPS patients had a younger age at onset and more often had multiple affected extremities and dystonia. We conclude that CRPS may occur in a familial form, but did not find a clear inheritance pattern. Patients with fCRPS develop the disease at a younger age and have a more severe phenotype than sporadic cases, suggesting a genetic predisposition to develop CRPS.     

Intrathecal glycine for pain and dystonia in complex regional pain syndrome

Since glycinergic neurotransmission plays an important inhibitory role in the processing of sensory and motor information, intrathecal glycine (ITG) administration may be a potential therapy for both pain and movement disorders in patients with complex regional pain syndrome (CRPS). Aims of the current study, which is the first report on ITG in humans, were to evaluate its safety and efficacy. ITG treatment during 4 weeks was studied in CRPS patients with dystonia in the period before they received intrathecal baclofen treatment. Twenty patients were assessed and after exclusion of one patient, the remaining 19 patients were randomized in a double-blind placebo-controlled crossover study. Safety was assessed by clinical evaluation, blood examinations and electrocardiograms. Efficacy measures involved pain (numeric rating scale, McGill pain questionnaire), movement disorders (Burke–Fahn–Marsden dystonia rating scale, unified myoclonus rating scale, tremor research group rating scale), activity (Radboud skills questionnaire, walking ability questionnaire), and a clinical global impression (CGI) and patient’s global impression score (PGI). Treatment-emergent adverse events were generally mild to moderate and not different from placebo treatment. During ITG treatment growth hormone levels were slightly increased. Although there was a trend to worsening on the CGI and PGI during ITG treatment, there were no significant differences between ITG and placebo treatment in any of the outcomes. ITG given over 4 weeks was ineffective for pain or dystonia in CRPS. Although no serious adverse events occurred, further studies are required to rule out potential neurotoxicity of ITG.