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From the Departments of *Anesthesiology and Neuroscience and Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
Address correspondence and reprint requests to Dr Zijlstra, Assoc. Prof., Department of Anesthesiology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Address e-mail to f.zijlstra{at}erasmusmc.nl.
Abstract
BACKGROUND: In patients with complex regional pain syndrome type 1 (CRPS1), some improvement can be achieved by the administration of ketanserin, a 5-HT2A receptor antagonist. We measured plasma levels of serotonin (5-HT) during CRPS1 and correlated these levels with disease characteristics.
METHODS: Plasma 5-HT was measured in 35 patients who had CRPS1 for 3 yr and compared with 35 age-matched healthy controls.
RESULTS: The plasma 5-HT levels were 411 ± 263 nmol/L and 29 ± 18 nmol/L, respectively (P < 0.001). No correlations with disease characteristics were observed.
CONCLUSIONS: The markedly elevated levels of plasma 5-HT in CRPS1 patients suggest a role for 5-HT during the course of this disease. However, because of the lack of correlations with distinct disease characteristics, 5-HT is probably one of a number of mediators in CRPS1.
Complex regional pain syndrome type 1 (CRPS1) is a complication that follows trauma or surgery in an extremity, leading to a dramatic loss of function, disability, and chronic pain. Therapeutic options are limited and insufficient to provide complete recovery.1–4 In an animal model, prolonged disturbance of the microcirculation by ischemia/reperfusion causes pain and other signs of CRPS1, such as edema and changes in skin temperature.5 Similar signs have been observed after cardiac catheterization via the radial artery.6,7
In blood vessels, serotonin (5-hydroxy-tryptamine; 5-HT) evokes vasoconstriction through activation of the 5-HT2A receptor. Important actions and functions of 5-HT are: (i) vascular constriction and contraction of other smooth muscles; (ii) increased microvascular permeability; (iii) induction of blood platelet aggregation; (iv) stimulation of peripheral nociceptive nerve endings; and (v) excitation/inhibition of neurons in the central nervous system. Clinical conditions associated with disturbed 5-HT function include migraine, carcinoid syndrome, mood disorders, and anxiety.8,9
Specific 5-HT2A receptor antagonism by ketanserin results in a pronounced vasodilatation, which was demonstrated in CRPS1 patients two decades ago. Two case reports indicated that ketanserin was an effective vasodilator in sympathetic dystrophy or causalgia (currently known as CRPS1),10,11 and a double-blind, placebo-controlled, crossover trial of 16 patients with chronic peripheral burning pain demonstrated the beneficial effect of ketanserin.12 Based on that report, ketanserin is also recommended for clinical use in chronic CRPS1.13 However, no studies investigating 5-HT levels in the CRPS1-affected limb or in the circulation that would justify this type of pharmaceutical intervention have been performed.14
We investigated whether CRPS1 patients had detectable increases in plasma 5-HT concentrations during the course of the disease. Some patients with CRPS1 exhibit the described physical limitations and psychological dysfunction,15 and this phenomenon could be associated with increased 5-HT.16 The co-occurrence of increased 5-HT with chronic pain suggests that 5-HT could be a common causative factor in chronic pain and psychological dysfunction.17 Therefore, we also compared plasma 5-HT levels with pain, disease activity (skin surface temperature, edema, and mobility), and a self-report inventory.
METHODS
The protocol was approved by the Medical Ethics Committee of the Erasmus MC Rotterdam (MEC no. 1989.780/2001/24), and written informed patient consent was obtained. Guidelines according to the Declaration of Helsinki (amended version of 2002) and Good Clinical Practice (ICH/GCP version 1996) were followed. Data collection and calculations were performed according to guidelines for registration of personal data.
Subjects
Thirty-five patients diagnosed as having CRPS1 in one extremity according to the criteria of Bruehl et al.18 were recruited for this study.
A group of 35 age-matched healthy controls were asked to give blood for plasma 5-HT analysis. Demographic data and characteristics of the patients and controls are presented in Table 1, including any disease-related medication. None of the patients used ketanserin.
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Blood Samples
EDTA blood samples (7 mL) were collected from the patients and healthy controls. In 29 patients with CRPS1 in the upper extremity, blood was obtained from both the CRPS1 and the contralateral extremity by venapuncture. In six patients with CRPS1 in the lower extremity, blood was drawn from the CRPS1 extremity, and a control sample taken from the contralateral upper extremity by venapuncture. For the healthy controls, one sample of blood was drawn from an upper extremity by venapuncture.
Blood was centrifuged at 2650gmax for 10 min at 20°C and plasma was stored at –80°C until assay.
Plasma 5-HT Determinations
Measurement of plasma 5-HT concentration, and its break-down product 5-hydroxyindoleacetic acid (5-HIAA), was performed using the reversed-phase high-performance liquid chromatography method of Bax et al.19 The detection limit for both compounds was approximately 3 fmol at a signal-to-noise ratio of 3. The mean recoveries (±sd) of 5-HT and 5-HIAA added to the platelet poor plasma samples were 95% ± 7% (n = 76) and 72% ± 8% (n = 35), respectively.
Pain Measurements
The maximal intensity of disease-related pain during the last 24 h was determined using a visual analog scale (VAS)20,21 and the McGill pain questionnaire Dutch-Language Version.22 The VAS is measured in millimeters (0–100, no pain to most intensive pain), and the McGill pain questionnaire Dutch-Language Version score is measured by counting the total number of words chosen (0–20).
Measurements of Disease Activity
Skin Temperature Measurements
Skin surface temperature also reflects blood tissue distribution. It is generally accepted that vasoconstriction or vasodilatation, respectively, leads to cold or warm extremities.1
We measured skin temperature on the dorsal aspect of the hand or foot in a matrix of five points using an infrared tympanic probe thermometer (First Temp Genius®; Sherwood Medical Crawley, Sussex, UK),23 and calculated the difference in mean temperature between the CRPS1 and the contralateral extremity.
Determination of Edema
We measured differences in the volume (in grams) of the CRPS1 and contralateral extremities using a volumeter, which measures the amount of water displaced by the immersion of a body part.24
Determination of Mobility
We assessed mobility in the upper and lower extremity, by measuring the active range of motion (AROM) according to the American Society of Hand Therapists clinical assessment recommendations.25–27 The AROM on the CRPS1 extremity was multiplied by 100 and divided by the AROM on the contralateral extremity, resulting in percentage of normal mobility (100%).
Self-Report Inventory
Patients completed the Dutch-Language Version of the SCL-90.28 The SCL-90 is a multidimensional, self-report inventory composed of 90 items that measures dimensions such as anxiety, agoraphobia, depression, somatization, inadequacy, sensitivity, hostility, and insomnia. The total score (between 90 and 450) is a measure of psychoneuroticism or emotional instability.
Statistical Analysis
Data were analyzed with SPSS for Windows, version 12.0. The one-sample Kolmogorov-Smirnov test was used to determine whether or not the sample data were consistent with the normal distribution function. Data of temperature difference, volume difference, AROM, VAS pain, MPQ pain, SCL-90, and the plasma 5-HT concentration were reported as mean ± sd. Between subjects, differences in plasma 5-HT concentrations between extremities were analyzed using the Wilcoxon signed-ranks test, and the correlation between parameters was calculated using the Pearson’s correlation coefficient. Differences in plasma 5-HT between patients and controls were tested by the Mann–Whitney test. The 
of the tests was set at the traditional 0.05 level.
RESULTS
5-HT
Plasma 5-HT levels in CRPS1-affected extremities (491 ± 280 nmol/L) and the contralateral extremities (433 ± 260 nmol/L) were in the same range and correlated well with one another (r = 0.97; P < 0.001). However, we observed a marked difference between the plasma 5-HT levels of healthy controls and patients (Table 2), both in CRPS1-hands (441 ± 250 nmol/L; n = 29) and CRPS1-feet (265 ± 300 nmol/L; n = 6) in comparison with healthy controls. No differences were observed between males (390 ± 255 nmol/L; n = 9) and females (418 ± 270 nmol/L; n = 26). Plasma 5-HT levels were not correlated with disease duration (correlation coefficient 0.152, P value 0.384). 5-HIAA was slightly and significantly decreased in CRPS1 patients (Table 2). Again, no differences were observed between males (26 ± 15 nmol/L; n = 6) and females (25 ± 10 nmol/L; n = 17).
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Pain
The mean VAS pain in this patient group (n = 35) was 54 ± 28 mm on a scale of 0–100 mm, whereas the MPQ pain intensity (measured in n = 26) was 12 ± 5 words of 20 possible chosen words. Neither VAS pain nor MPQ pain intensity correlated with plasma 5-HT (Table 3). Figures 1A and B show the distribution of plasma 5-HT concentrations plotted against VAS pain and MPQ pain intensity.
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Objective Disease Activity Variables and Plasma 5-HT Correlations
Functional disease variables were measured effectively in a proportion of the patients. The temperature difference (n = 29), the volume difference (n = 22) and the AROM (n = 22) did not correlate with plasma 5-HT levels (Table 3 and Figs. 1C–E, respectively).
Self-Report Inventory
The total score of the SCL-90 (n = 35) as a measure of psychoneuroticism or emotional instability in this group of patients was 145 ± 50, which is not significantly increased in comparison with earlier published total scores from a normal population, and is in the same range as the CRPS1 patients from that study.15 Subscale scores and the total score did not correlate with plasma 5-HT levels (Table 3 and Fig. 1F).
DISCUSSION
Our results show that plasma 5-HT concentrations are an order of magnitude higher in CRPS1 patients than in an age-matched (not gender), healthy control group. However, we detected no significant correlation between 5-HT levels and pain, disease activity, or the results of a self-reported inventory.
The marked high 5-HT levels in platelet poor plasma from CRPS1 patients are in the range normally found for platelet rich plasma. Platelets are considered to be the most important source of 5-HT in blood. No data have been presented regarding such high plasma 5-HT levels associated with a disease state. The simultaneously measured 5-HIAA plasma levels, which are in the normal range and even diminished in CRPS1 patients, suggests a diminished breakdown of 5-HT in these patients.
The role of 5-HT in the course of CRPS1 remains unknown. Is 5-HT only one of a number of mediators formed in a cascade of processes, or should it be considered as one of a number of key mediators in the cascade of consecutive processes? In the search for other key mediators of the processes that follow the initial traumatic event, several bioactive substances have been suggested and investigated. Neuropeptides released after damage to nerve endings initiate the release of a cascade of vasoactive mediators.29 In patients who have recently developed CRPS1, increased proinflammatory cytokines were found to be increased in skin blister fluid taken from the CRPS1 extremity in comparison with the contralateral extremity.30,31 After 2 yr, skin blister fluid cytokine levels are still increased32; however, during the course of the disease a pronounced decline in cytokine levels is observed.33 Other vasoactive mediators, such as nitric oxide (NO)34 and presumably 5-HT, could play a role in the cell–cell interaction and activation of other mediators.
Based on the primary effects of 5-HT, in CRPS1 patients, ischemia resulting in pain would be expected; furthermore, a diminished mobility, changing temperature and volume of the affected extremity could occur. Besides centrally affected pain perception, psychological dysfunction (depression) could develop. In patients with psychological dysfunction, mean plasma 5-HT levels in a range from 33 to 62 nmol/L have been reported; however, in some patients, plasma 5-HT levels reached 200–250 nmol/L, similar to our observations.35 In one study, plasma 5-HT levels of psychiatric patients and controls were 78 ± 58 nmol/L and 33 ± 38 nmol/L, respectively. Again, some individual patients showed levels of >150 nmol/L.36
From the pharmaceutical point of view, inhibition of 5-HT release from blood platelets and antagonizing the 5-HT2A receptor could counteract vasoactive effects associated with CRPS1 and promote recovery. This phenomenon has not been observed with therapies other than ketanserin. A beneficial effect of ketanserin on chronic peripheral burning pain has been suggested.12 Furthermore, peripheral 5-HT2A receptor antagonism has been shown to attenuate primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury.37 However, this allodynia-suppressing effect was attributed to the addition of l-carnitine, which affects ischemia and oxygen transport in the tissues, resulting in diminished pain intensity.38,39 In open studies, a number of CRPS1 patients have been treated with both ketanserin and l-carnitine. One study40 suggests that pretreatment with ketanserin is necessary to obtain the beneficial effects of l-carnitine. Alternatively, treating CRPS1 patients with NO donors could improve tissue blood distribution evoked by vasodilatation through increased cyclic guanosine monophosphate levels.34 Moreover, NO has been shown to inhibit platelet 5-HT release.41 Treatment with the antidepressant fluoxetine was associated with a significant decline in plasma 5-HT levels.42 Until now, however, in CRPS1 patients only increased levels of catecholamines have been associated with psychological dysfunction.43 The role of 5-HT in psychological dysfunction44 in CRPS1 patients still has to be confirmed.
In conclusion, markedly increased plasma 5-HT concentrations suggest a role for 5-HT in patients with CRPS1. However, because of the lack of correlation with distinct disease characteristics, 5-HT is probably one of a number of mediators in the cascade of consecutive processes that occur in the course of this painful and debilitating disease.
ACKNOWLEDGMENTS
The skilful help of George Groeneweg, BSc, and Sjoerd Niehof, BSc, (Dept. of Anesthesiology) who performed the measurements of mobility, volume, and skin surface temperature, was highly appreciated. The authors also thank Dr. Dirk Stronks (Pain Knowledge Centre) for statistical analysis.
The study was performed within TREND (Trauma Related Neuronal Dysfunction), a knowledge consortium in the Netherlands that integrates research on Complex Regional Pain Syndrome type 1.
Footnotes
Accepted for publication February 7, 2008.
The material costs of the HPLC-performed plasma analyses were funded by the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA, USA). The personnel costs of Feikje Wesseldijk were covered by a grant from the Dutch government (BSIK03016). The other authors were paid by departmental and institutional funds.
REFERENCES
and interleukin-6 are not correlated with characteristics of complex regional pain syndrome type 1 in 66 patients. Eur J Pain 2007;[Epub ahead of print]
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