Serum Soluble Interleukin-2 Receptor Does Not Differentiate Complex Regional Pain Syndrome from Other Pain Conditions in a Tertiary Referral Setting.

Previously, we showed that serum soluble interleukin-2 receptor (sIL-2R) levels, a marker for T-cell activation, were higher in complex regional pain syndrome (CRPS) patients than in healthy controls, suggesting pathogenic T-cell activation in CRPS. Additionally, sIL-2R levels discriminated well between CRPS and healthy controls with a high sensitivity (90%) and specificity (89.5%), suggesting a possible role for sIL-2R in the diagnosis of CRPS. In order to further validate this marker in the diagnostic workup of CRPS, we conducted this prospective cohort study in which we determined sIL-2R levels in patients that were referred to our tertiary referral center with a suspicion of CRPS in a limb, and subsequently compared sIL-2R levels between the patients that were diagnosed with CRPS (CRPS group) and those who were not (no CRPS group). A group of anonymous blood bank donors were used as a healthy control group. Furthermore, we explored the relationship between sIL-2R and CRPS disease severity using the CRPS severity score. Median sIL-2R levels of both the CRPS group (2809.0 pg/ml; Q3-Q1: 3913.0-1589.0) and no CRPS group (3654.0 pg/ml; Q3-Q1: 4429.0-2095.5) were significantly higher than that of the control group (1515.0 pg/ml; Q3-Q1: 1880.0-1150.0): CRPS vs. controls, p < .001; no CRPS vs. controls, p < 0.001. Serum sIL-2R levels did not differ significantly between the CRPS and no CRPS group. A statistically significant negative correlation was observed between sIL-2R levels and the CRPS severity score (r s = -0.468, p = 0.024). Our results confirm our previous findings of higher sIL-2R levels in CRPS patients than in healthy controls. We further showed that serum sIL-2R cannot differentiate between CRPS and other pain conditions of a limb in a tertiary referral setting. Interestingly, a negative correlation was found between sIL-2R and CRPS disease severity; this finding warrants further research into the relationship between sIL-2R and CRPS disease severity.

Diagnosing complex regional pain syndrome using an electronic nose, a pilot study.

OBJECTIVE: Complex regional pain syndrome (CRPS) is a complication after surgery or trauma and is characterized by a continuing regional pain in a distal extremity. The pain is disproportionate in severity and duration in relation to the preceding trauma. Currently, the diagnosis is based on the patients' signs and symptoms. There is no objective clinically applicable test available to confirm the diagnosis of CRPS, however this could contribute to a more reliable and valid diagnosis. Since the treatment of CRPS differs from that of other types of pain this could thereby lead to earlier and (more) appropriate treatment and possibly to lower medical costs. The Aeonose™ is a diagnostic test device which detects volatile organic profiles in exhaled air. Exhaled breath analysis using an electronic nose has been successfully applied to differentiate between sick and healthy persons for various indications. This study was a feasibility study in which we investigated whether the Aeonose™ is able to measure a difference in the volatome of CRPS patients compared to the volatome of healthy controls. DESIGN: Prospective observational study. SETTING: University Center for Pain Medicine. SUBJECTS: Adult patients diagnosed with CRPS according to the latest IASP criteria (n = 36) and matched healthy controls (n = 36). METHODS: Breath profiles were sampled by breathing in and out through the Aeonose™. Data were compressed using a Tucker3-like solution and subsequently used for training an artificial neural network together with the classification 'CRPS: Yes' or 'CRPS: No'. Cross-validation was applied using the leave-10%-out method. RESULTS: Data of the 72 participants were analyzed, resulting in a sensitivity of 83% (95% CI 67%-93%), specificity of 78% (95% CI 60%-89%), and an overall accuracy of 81%. CONCLUSIONS: This study suggests that the Aeonose™ can possibly distinguish patients with CRPS from healthy controls based on analysis of their volatome (MEC-2014-149).

Preferred frequencies and waveforms for spinal cord stimulation in patients with complex regional pain syndrome: A multicentre, double-blind, randomized and placebo-controlled crossover trial.

BACKGROUND: Conventional tonic spinal cord stimulation (SCS) is an effective treatment for patients with therapy-resistant complex regional pain syndrome (CRPS). Although the therapeutic effect of SCS can diminish over time due to tolerance, pain control can be regained by changing the pulse width and the amplitude and/or by increasing the stimulation frequency. This multicentre, double-blind, randomized and placebo-controlled crossover trial was conducted to investigate whether more effective pain reduction is achieved with different frequencies (trial registration, current controlled trials, ISRCTN 36655259). METHODS: The investigated settings are as follows: standard 40, 500, 1200 Hz, burst and placebo stimulation. All five were programmed in random order during the 10-week crossover period (2 weeks/setting). The primary outcome parameters were scores on the visual analogue scale (VAS), McGill Pain Questionnaire (MPQ) and the Global Perceived Effect (GPE); at the end of the crossover period, patients decided which SCS setting they preferred. A linear mixed models analysis was performed in 29 patients who completed the crossover trial. RESULTS: Significant pain reduction and GPE satisfaction was achieved with four SCS settings compared with placebo stimulation, and these four settings did not differ significantly from each other. Standard stimulation was preferred by 48% of the patients, while 52% preferred non-standard stimulation. Other than pain reduction, factors such as user-friendliness, comfort and recharging time may have influenced the patient's final decision for the preferred stimulation setting. CONCLUSIONS: Apparently, for various reasons, patients have a preference for different SCS setting. Therefore, future neuromodulation should aim to implement customized individual patient care by incorporating all stimulation options in one device. SIGNIFICANCE: This study demonstrates that standard frequency SCS is an effective therapy for patients with CRPS. However, it also demonstrates that patients can often gain better pain reduction with non-standard frequencies of SCS. Furthermore, it shows that the preferred stimulation setting is not solely driven by the amount of pain reduction, but is also influenced by which stimulation setting feels most comfortable and provides the best user-friendliness. Therefore, we strive to maximize the therapeutic effects of SCS in as many patients as possible. This can be achieved with customized individual patient care by incorporating the various frequencies and waveforms into one single device.

Randomized sham-controlled, double-blind, multicenter clinical trial on the effect of percutaneous radiofrequency at the ramus communicans for lumbar disc pain.

BACKGROUND: Investigate the effect of percutaneous radiofrequency compared to a sham procedure, applied to the ramus communicans for treatment of lumbar disc pain. METHODS: Randomized sham-controlled, double-blind, crossover, multicenter clinical trial. Multidisciplinary pain centres of two general hospitals. Sixty patients aged 18 or more with medical history and physical examination suggestive for lumbar disc pain and a reduction of two or more on a numerical rating scale (0-10) after a diagnostic ramus communicans test block. Treatment group: percutaneous radiofrequency treatment applied to the ramus communicans; sham: same procedure except radiofrequency treatment. PRIMARY OUTCOME MEASURE: pain reduction. Secondary outcome measure: Global Perceived Effect. RESULTS: No statistically significant difference in pain level over time between the groups, as well as in the group was found; however, the factor period yielded a statistically significant result. In the crossover group, 11 out of 16 patients experienced a reduction in NRS of 2 or more at 1 month (no significant deviation from chance). No statistically significant difference in satisfaction over time between the groups was found. The independent factors group and period also showed no statistically significant effects. The same applies to recovery: no statistically significant effects were found. CONCLUSIONS: The null hypothesis of no difference in pain reduction and in Global Perceived Effect between the treatment and sham group cannot be rejected. Post hoc analysis revealed that none of the investigated parameters contributed to the prediction of a significant pain reduction. SIGNIFICANCE: Interrupting signalling through the ramus communicans may interfere with the transition of painful information from the discs to the central nervous system. Methodological differences exist in studies evaluating the efficacy of radiofrequency treatment for lumbar disc pain. A randomized, sham-controlled, double-blind, multicenter clinical trial on the effect of radiofrequency at the ramus communicans for lumbar disc pain was conducted. The null hypothesis of no difference in pain reduction and in Global Perceived Effect between the treatment and sham group cannot be rejected.

Randomised sham-controlled double-blind multicentre clinical trial to ascertain the effect of percutaneous radiofrequency treatment for lumbar facet joint pain.

AIMS: The aim of this study was to compare the effect of a percutaneous radiofrequency heat lesion at the medial branch of the primary dorsal ramus with a sham procedure, for the treatment of lumbar facet joint pain. PATIENTS AND METHODS: A randomised sham-controlled double blind multicentre trial was carried out at the multidisciplinary pain centres of two hospitals. A total of 60 patients aged > 18 years with a history and physical examination suggestive of facet joint pain and a decrease of ≥ 2 on a numerical rating scale (NRS 0 to 10) after a diagnostic facet joint test block were included. In the treatment group, a percutaneous radiofrequency heat lesion (80oC during 60 seconds per level) was applied to the medial branch of the primary dorsal ramus. In the sham group, the same procedure was undertaken without for the radiofrequency lesion. Both groups also received a graded activity physiotherapy programme. The primary outcome measure was decrease in pain. A secondary outcome measure was the Global Perceived Effect scale (GPE). RESULTS: There was a statistically significant effect on the level of pain in the factor Period (T0-T1). However, there was no statistically significant difference with the passage of time between the groups (Group × Period) or in the factor Group. In the crossover group, 11 of 19 patients had a decrease in NRS of ≥ 2 at one month crossover (p = 0.65). There was no statistically significant difference in satisfaction with the passage of time between the groups (Group × Period). The independent factors Group and Period also showed no statistically significant difference. There was no statistically significant Group × Period effect for recovery, neither an effect of Group or of Period. CONCLUSION: The null hypothesis of no difference in the decrease in pain and in GPE between the treatment and sham groups cannot be rejected. Post hoc analysis revealed that the age of the patients and the severity of the initial pain significantly predicted a positive outcome. Cite this article: Bone Joint J 2016;98-B:1526-33.

Prevalence and determinants of medication non-adherence in chronic pain patients: a systematic review.

BACKGROUND: Chronic pain is commonly treated with analgesic medication. Non-adherence to prescribed pain medication is very common and may result in sub-optimal treatment outcome. The aim of this review was to investigate the prevalence of medication non-adherence and to present determinants that may help identify patients at risk for non-adherence to analgesic medication. METHODS: A search was performed in PubMed and Embase with systematic approach including PRISMA recommendations. Individual risk of bias was assessed and systematic data extraction was performed. RESULTS: Twenty-five studies were included. Non-adherence rates to pain prescriptions ranged from 8% to 62% with a weighted mean of 40%. Underuse of pain medication was more common than overuse in most studies. Factors that were commonly positively associated with non-adherence were dosing frequency, polymedication, pain intensity, and concerns about pain medication. Factors negatively associated with non-adherence were age, again pain intensity and quality of the patient-caregiver relationship. Underuse was positively associated with active coping strategies and self-medication, and negatively associated with perceived need for analgesic medication. Overuse was positively associated with perceived need, pain intensity, opioid use, number of prescribed analgesics, a history of drug abuse, and smoking. CONCLUSION: Non-adherence to analgesic medication use is very common in the chronic pain population. The choice for pharmacological therapy should not only be based upon pain diagnosis but should also take the risks of non-adherence into account. The value of adherence monitoring or adherence enhancing interventions has to be investigated in future studies.

Comparison of tonic spinal cord stimulation, high-frequency and burst stimulation in patients with complex regional pain syndrome: a double-blind, randomised placebo controlled trial.

BACKGROUND: Complex Regional Pain Syndrome (CRPS) is a disabling disease that is sometimes difficult to treat. Although spinal cord stimulation (SCS) can reduce pain in most patients with CRPS, some do not achieve the desired reduction in pain. Moreover, the pain reduction can diminish over time even after an initially successful period of SCS. Pain reduction can be regained by increasing the SCS frequency, but this has not been investigated in a prospective trial. This study compares pain reduction using five SCS frequencies (standard 40 Hz, 500 Hz, 1200 Hz, burst and placebo stimulation) in patients with CRPS to determine which of the modalities is most effective. DESIGN: All patients with a confirmed CRPS diagnosis that have unsuccessfully tried all other therapies and are eligible for SCS, can enroll in this trial (primary implantation group). CRPS patients that already receive SCS therapy, or those previously treated with SCS but with loss of therapeutic effect over time, can also participate (re-implantation group). Once all inclusion criteria are met and written informed consent obtained, patients will undergo a baseline assessment (T0). A 2-week trial with SCS is performed and, if successful, a rechargeable internal pulse generator (IPG) is implanted. For the following 3 months the patient will have standard 40 Hz stimulation therapy before a follow-up assessment (T1) is performed. Those who have completed the T1 assessment will enroll in a 10-week crossover period in which the five SCS frequencies are tested in five periods, each frequency lasting for 2 weeks. At the end of the crossover period, the patient will choose which frequency is to be used for stimulation for an additional 3 months, until the T2 assessment. DISCUSSION: Currently no trials are available that systematically investigate the importance of variation in frequency during SCS in patients with CRPS. Data from this trial will provide better insight as to whether SCS with a higher frequency, or with burst stimulation, results in more effective pain relief. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36655259.

Inflammation in cold complex regional pain syndrome.

BACKGROUND: In patients with complex regional pain syndrome (CRPS), the temperature of the affected side often differs from that of the contralateral side. In the acute phase, the affected side is usually warmer than the contralateral side, the so-called 'warm' CRPS. This thermal asymmetry can develop into a colder affected side, the so-called 'cold' CRPS. In contrast to cold CRPS, in warm CRPS, inflammation is generally assumed to be present. However, there are reports of cold CRPS patients, successfully treated with vasodilatation therapy, who subsequently displayed warm CRPS. It seems that inflammation could be 'hidden' behind vasomotor disturbance. This study was designed to test this hypothesis. METHODS: A retrospective analysis was made of patients in our CRPS database. We defined three types of CRPS: cold CRPS, neither cold nor warm (intermediate) CRPS, and warm CRPS. Of these patients, the difference between the level of the pro-inflammatory cytokines interleukin (IL)-6 (Δ IL-6) and tumor necrosis factor (TNF)-α (Δ TNF-α) in the affected extremity and that in the contralateral extremity was determined. RESULTS: The bilateral difference of the level of these cytokines did not differ among patients with cold CRPS, intermediate CRPS, or those with warm CRPS. CONCLUSION: Inflammation may be involved in cold CRPS.

Complex regional pain syndrome type I of the knee: a systematic literature review.

In our Center for Pain Medicine, a group of patients reported to have symptoms possibly attributable to complex regional pain syndrome (CRPS) of only the knee(s). Therefore, this study aimed to investigate whether the literature reports on patients with CRPS type I in the knee(s) alone and, if so, to summarize the reported diagnostics, aetiology and treatment strategies of CRPS of the knee(s). Medline, Embase, Cochrane Library, PubMed and Web of Science were searched for articles focusing on a painful disorder of the knee, most likely CRPS type I. Screening on title and abstract was followed by full-text reading and searching of reference lists to determine the final set of relevant articles. Of the 513 articles identified, 31 met the inclusion criteria. These articles reported on a total of 368 patients diagnosed with CRPS of the knee(s) based on the diagnostic criteria used at the time of publication. Knee surgery, especially arthroscopic surgery, was the most common inciting event in developing CRPS of the knee(s). Various treatment strategies were applied with variable outcomes. In conclusion, the scientific literature does report cases of CRPS type I of only the knee(s). This applies when using the diagnostic criteria prevailing at the time of publication and, obviously for a smaller number of cases, also when using the current Budapest criteria set. Arthroscopic knee surgery is described multiple times as the inciting event. We recommend to include CRPS of the knee in future research on the aetiological mechanisms of and optimal treatment for CRPS.

Interictal daily functioning in migraine.

Migraine induces disability and an impaired quality of life, even between attacks. As most studies are based on subjective reports only, this study was set up to objectively quantify the interictal daily activities and heart rate of migraine patients, in relation to their subjectively reported highest realizable level of activity and of symptoms of mood in their habitual environment. Measurements were obtained during a migraine-free 2-day period of 24 patients (age range: 21-57 years) and 24 controls (age range: 18-59 years). Accelerometry was used to quantify the time spent in different postures and movements. The subjective parameters were documented by daily log. Whereas heart rate was similar for patients and controls, migraineurs were found to be significantly less physically active than controls and reported a significantly lower realizable level of activity. In addition, when active, their body motility was less than that of controls. Migraine patients also showed a higher level of sleepiness and lower level of vigour. These interictal behavioural and subjective phenomena objectively illustrate the individual and societal burden of migraine and its chronic impact on both domains.

Towards an objective quantitative assessment of daily functioning in migraine: a feasibility study.

Migraine is a chronic disabling disorder, with migraine episodes significantly reducing quality of life and leading to impaired functioning (physically, socially, emotionally) both at home and at work. We explored whether ambulatory accelerometry can be used as an objective method to quantify the behavioral aspects of migraine-related disability. Four body mounted uni-axial piezo-resistive accelerometers were used to quantify the time spent in different body postures (lying, sitting, standing), physical activities (walking, cycling) and a general index of body motility during eight migraine attacks and subsequent recovery periods of six patients in their habitual environment. The migraine attacks and recovery periods could be monitored after about 1 h, which was the time required for the investigator to travel to the patient and for the sensors to be attached. In order to quantify the influence of a migraine episode on daily activities, we also performed measurements during a headache-free baseline period of the same patients. Overall, the procedures functioned well, indicating that ambulatory accelerometry measurements before, during and after a migraine attack are feasible to perform. Furthermore, our quantitative data revealed that migraine always influenced behavior by reducing overall body motility and that, dependent upon the severity of the attack, the effectiveness of acute treatment and the time of day, the time spent in various body positions, dynamic activities, and the number of postural transitions were affected. This feasibility study showed that ambulatory accelerometry can provide the objective behavioral effect parameters for the evaluation of migraine and its treatment on daily functioning in the habitual environment of migraine patients.

Personality traits and psychological reactions to mental stress of female migraine patients.

The purpose of this study was (i) to compare a range of stress-related personality traits, including defense and coping mechanisms, of migraine patients (n = 23) with those of tension headache patients (n = 18) and dermatologically afflicted, but otherwise healthy, controls (n = 22), and (ii) to compare their state anxiety and other moods before, during, and after the presentation of a psychological stressor (mental arithmetic). For all three groups, mental arithmetic induced a significant increase in state anxiety and mood disturbance, followed by a subsequent decrease during recovery. Migraine patients were not found to have a higher disposition for anxiety, depression, or rigidity than tension headache patients or controls. Between the headache groups no differences in the use of defense and coping mechanisms were found. Compared to the control group, however, both migraine patients and tension headache patients were more inclined to use internally focused defense mechanisms and less inclined to seek social support when confronted with a problem. The psychological reaction of migraine patients to mental stress hardly differed from tension headache and control subjects. Compared to the control subjects, however, both groups of headache patients exhibited a diminished recovery from feelings of vigour, depression, and fatigue due to the stress induced. It is suggested that this distinct psychological reaction to stress of headache patients versus healthy control subjects is related to the more internally focused defense style of the headache sufferers. Thus, in contrast to previous results, this study does not present evidence of a migraine personality. It suggests the development of specific personality characteristics as a consequence of suffering from episodic headache.

Clinical utility of the judgment of line orientation test and facial recognition test in children with acquired unilateral cerebral lesions.

In unselected adult patients with brain damage, the Judgment of Line Orientation Test and the Facial Recognition Test are considered valid instruments for detecting right cerebral hemisphere lesions. It is unknown, however, whether this applies to children as well. Performance levels on the Judgment of Line Orientation Test and the Facial Recognition Test of 18 children with acquired left cerebral lesions and 14 children with acquired right cerebral lesions were reviewed. Subjects were unselected for age, sex, or etiology. Age-related norms were obtained in 81 normal controls, aged 7 to 14 years. Judgment of Line Orientation Test and Facial Recognition Test performance levels did not predict the presence of cerebral pathology per se in our unselected groups with demonstrated unilateral cerebral lesions, nor did they contribute to the prediction of the side of the lesion within the two groups with cerebral lesions. These results cast serious doubt on an important aspect of the clinical utility of both tests in children, namely their discriminative validity in the assessment of etiologically unselected populations with brain damage.

Serotonergic, catecholaminergic, and cardiovascular reactions to mental stress in female migraine patients. A controlled study.

This study aimed at the combined assessment of the serotonergic and sympathetic nervous system reactions of migraine patients before, during, and after the induction of mental stress in order to detect the possible role of these reactions in inducing a migraine attack. The responses to mental stress of the migraine patients were compared to a group of patients suffering from tension headache and a control group. Activation of the sympathoadrenomedullary system due to mental stress was successfully induced in the migraine patients (n = 23), in the tension headache patients (n = 18), and in the control group (n = 22). The results of this study present evidence of increased cardiovascular activity in migraine patients as compared to nonmigraineurs. However, no evidence was found of a specific serotonergic, sympathoadrenomedullary, or cerebrovascular response of migraine patients to mental stress as compared to nonmigraineurs.

Psychosocial effects of skin treatment with Imedeen.

In a 3-mo. randomized double-blind placebo-controlled study, the psychosocial effects of the food supplement IMEDEEN on health-specific quality of life were examined. Participants were 45 Caucasian women with a normal skin condition in relation to their age. The variables measured were social anxiety and social skills, self-esteem, satisfaction with several parts of the body, state and trait anxiety, and psychological and social problems related to the skin. No significant effect of IMEDEEN was found on any of these psychosocial variables. Suggestions for further research are given.

Psychological consequences of genital herpes, an exploratory study with a gonorrhea control-group.

Measurements of some psychosocial variables were obtained from 27 patients with a genital herpes infection and compared with those from 12 patients with a gonorrhea infection. The measurements referred to the period before and during the infection. Evidence was found that during the infection patients were more anxious, more sexually inhibited, more bitter towards their partners, and had more psychological complaints than before the infection. Generally there was no difference between the two groups of patients, with one exception: patients with genital herpes judged themselves as having fewer psychological complaints prior to the disease than did patients with gonorrhea.

[Marked decrease in the number of hospitalizations for gonococcal infections in The Netherlands from 1981-1988]. / Sterke daling van het aantal ziekenhuisopnamen voor gonokokkeninfecties in Nederland over de periode 1981-1988.

The number of admissions for gonococcal infections in the Netherlands fell strongly over the period 1981 to 1988, in particular in the 15 to 40-year age group. The decline can only partly be explained by a change in sexual behaviour associated with the fear of AIDS. The change from clinical to outpatient treatment of these infections offers no explanation either because the number of outpatients treated dropped substantially as well.

The Dutch version of the Nottingham Health Profile: investigations of psychometric aspects.

Data on the adaptation, reliability, and validity of the Dutch version of the Nottingham Health Profile are discussed. The linguistic adaptation of the English version into Dutch is described, followed by the field-testing procedure and the analyses of data from 276 selected subjects from an average general medical group practice in a village nearby Rotterdam. The internal consistency, Cronbach alphas, of the subscales varied from .70 to .85. Test-retest measures for 51 patients with cardiac problems gave Spearman correlations from .69 to .92, while the interscale relationships yielded six relatively independent areas of discomfort and stress. By means of logistic regression analysis on differences between old versus young, male versus female, and healthy versus ill individuals, discriminant validity was satisfactory. Findings suggest that the psychometric aspects of the Dutch version, also seen from a cross-cultural point of view, are sufficient. Nevertheless, further research on reliability and validity of the Dutch version is required to establish its usefulness with different patient groups.

[Number of admissions for Reiter's disease (ICD-9-code 099.3) in Dutch hospitals in 1981-1987]. / Het aantal opnamen voor de ziekte van Reiter (ICD-9-code 099.3) in Nederlandse ziekenhuizen over de periode 1981-1987.

The number of hospitalisations of male patients for Reiter's syndrome in the Netherlands declined over the period 1981 to 1987 by almost 40%. This decline is probably connected with a change in sexual behaviour, associated with the fear of AIDS. The number of admissions of female patients is considerably smaller than that of male patients, possibly due to underdiagnosis of the disease.