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Feline FJA ter Bruggen,1 W Ken Redekop,2 Dirk L Stronks,1 Frank JPM Huygen1 1Department of Anesthesiology, Center for Pain Medicine, Erasmus MC, Rotterdam, the Netherlands; 2Department of Health Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, the NetherlandsCorrespondence: Feline FJA ter Bruggen Tel +31 6 40962334Email ftbruggen@gmail.com; f.terbruggen@erasmusmc.nlObjective: The success of neurostimulation depends partly on the amount of coverage of the neurostimulation-induced paresthesia of the painful area. This is often achieved by asking feedback from patients intraoperatively. If sedation analgesia is used, it is important that the patient is comfortable during sedation and easily arousable. If the patient is not well sedated or experiences residual effects of the sedation during testing, this can directly influence the ideal placement of the leads and indirectly the long-term effect of the treatment. It is our hypothesis that the quality of the sedation is directly coupled to the adequacy of lead placement and in this way in the result of the treatment. Dexmedetomidine is known for its easy production of arousable sedation. The aim of the present study was to compare the long-term effect of using dexmedetomidine versus propofol during the implantation of a neurostimulator.Materials and Methods: This is a post-trial follow-up analysis of the DexMedPro cohort. The primary outcome was global perceived effect (GPE). The secondary outcomes were the course of pain intensity, the emotional and physical functioning at the time of follow-up, and the course of neurostimulation treatment. In this study, we used the patient satisfaction with sedation as a measure for sedation quality.Results: Regarding the GPE, no statistically significant differences were found between the experimental groups in either subscale (ie, recovery (p=0.82) and satisfaction with the neurostimulation treatment at follow-up (p=0.06)). The same was found regarding the secondary parameters. A correlation was found between patient satisfaction with sedation during the lead implantation (side effects and procedural recall) and satisfaction at follow-up.Conclusion: Regarding the long-term efficacy of neurostimulation treatment, no statistically significant differences were found between the dexmedetomidine and the propofol group. We observed a trend towards greater satisfaction with the neurostimulation treatment at follow-up in the dexmedetomidine group, compared to the propofol group.Keywords: dexmedetomidine, propofol, chronic pain, neurostimulation, follow-up, retrospective studies

Objectives: Approximately 10% of patients who undergo inguinal hernia repair or Pfannenstiel incision develop chronic (> three months) postsurgical inguinal pain (PSIP). If medication or peripheral nerve blocks fail, a neurectomy is the treatment of choice. However, some patients do not respond to this treatment. In such cases, stimulation of the dorsal root ganglion (DRG) appears to significantly reduce chronic PSIP in selected patients., Materials and Methods: In this multicenter, randomized controlled study, DRG stimulation was compared with conventional medical management (CMM) (noninvasive treatments, such as medication, transcutaneous electric neurostimulation, and rehabilitation therapy) in patients with PSIP that was resistant to a neurectomy. Patients were recruited at a tertiary referral center for groin pain (SolviMáx, Eindhoven, The Netherlands) between March 2015 and November 2016. Suitability for implantation was assessed according to the Dutch Neuromodulation Association guidelines. The sponsor discontinued the study early owing to slow enrollment. Of 78 planned patients, 18 were randomized (DRG and CMM groups each had nine patients). Six patients with CMM (67%) crossed over to DRG stimulation at the six-month mark., Results: Fifteen of the 18 patients met the six-month primary end point with a complete data set for a per-protocol analysis. Three patients with DRG stimulation had a negative trial and were lost to follow-up. The average pain reduction was 50% in the DRG stimulation and crossover group (from 6.60 ± 1.24 to 3.28 ± 2.30, p = 0.0029). Conversely, a 13% increase in pain was observed in patients with CMM (from 6.13 ± 2.24 to 6.89 ± 1.24, p = 0.42). Nine patients with DRG stimulation experienced a total of 19 adverse events, such as lead dislocation and pain at the implantation site., Conclusions: DRG stimulation is a promising effective therapy for pain relief in patients with PSIP resistant to conventional treatment modalities; larger studies should confirm this. The frequency of side effects should be a concern in a new study., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02349659., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to assess the effectiveness of a low-dose intravenous S-ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS)., Methods: In this retrospective study, patients with CRPS who received intravenous S-ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S-ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful., Results: Forty-eight patients were included. Mean disease duration was 5 years (interquartile range [IQR] = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03)., Conclusion: In a group of patients with CRPS with refractory pain, low-dose intravenous S-ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow-up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S-ketamine infusions and to ascertain possible predictors of response to the treatment., (© 2021 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Objectives: Ketamine is used to treat chronic refractory pain. However, there are no scientific guidelines for ketamine use in the Netherlands. The aim of this survey was to provide an overview of the use of ketamine for chronic pain in the Netherlands., Methods: All pain clinics in the Netherlands were contacted. A digital survey, available from June 2019 to January 2020, was sent to 68 pain clinics. The survey was completed by one pain physician as a representative of the entire pain department. The survey included questions about ketamine treatment indications, administration, dose, duration, treatment repetition and the inpatient or outpatient setting., Results: The survey was completed by 51 pain clinics (75.0%). Thirty-one clinics used ketamine for chronic pain treatment. The most common indication was Complex Regional Pain Syndrome (83.9%). Pain clinics administered ketamine via intravenous infusions (96.8%), iontophoresis (61.3%), subcutaneous (3.2%) or oral administration (3.2%). Intravenous ketamine treatment was offered in an inpatient setting in 14 pain clinics, in both an inpatient and outpatient setting in 11 pain clinics and in six pain clinics in an outpatient setting. In the outpatient setting, the median starting dose was 5 mg/h (IQR=17.5-5). The median maximum dose was 27.5 mg/h (IQR=100-11.9). The median infusion duration was 6 h (IQR=8-4). In the inpatient setting, the median starting dose was 5 mg/h (IQR=5-1.5) and the median maximum dose was 25 mg/h (IQR=25-14). Patients were admitted to hospital for a median of 4 days (IQR=5-1)., Conclusions: The results of this Dutch nationwide survey study show that there are heterogeneous treatment protocols with different indications, treatment setting and dosing regimen for the treatment of chronic pain with ketamine. This study encourages the formulation of a broader consensus and the development of evidence based guidelines for ketamine treatment., (© 2021 Thomas J.P. Mangnus et al., published by De Gruyter, Berlin/Boston.)

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., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 K. D. Bharwani et al.)

Objectives: Nonadherence to prescribed pain medication is common in chronic noncancer pain patients. Beliefs about pain medication have been reported to be associated with nonadherence behavior in cross-sectional studies. The aim of this study was to prospectively investigate the relationship between patients' beliefs about pain medication and their medication adherence and treatment outcome., Methods: Chronic noncancer pain patients completed a baseline questionnaire including the 47-item Pain Medication Attitudes Questionnaire, consisting of 7 subscales with regards to beliefs on prescribed medication. After 11 weeks, medication underuse and overuse were assessed by self-report. In addition, patient satisfaction with regards to the effect of prescribed pain medication and satisfaction as regards prescribed medication and care, and the burden of side effects were assessed., Results: A total of 133 participants completed the baseline questionnaire, and 99 patients completed the follow-up questionnaire. Concerns over side effects at baseline were positively associated with underuse and the presence of side effects after 11 weeks. The perceived need was positively associated with overuse, whereas concerns over addiction were negatively associated with overuse. Concerns over tolerance were negatively associated with patient satisfaction with medication effects after 11 weeks. Concerns over tolerance and mistrust in the prescribing doctor were negatively associated with satisfaction about medication and care., Conclusion: Attitudes and concerns toward pain medication are associated with adherence patterns and outcome parameters. To improve medication adherence and therapy outcome, patient beliefs about pain medication should be taken into account by providing tailored education, adequate follow-up, or alternate therapy.

Background: During the lead implantation of most spinal cord neurostimulators, the patient has to be comfortable and without pain. However, the patient is expected to provide feedback during electrical mapping. Titrating sedatives and analgesics for this double goal can be challenging. In comparison with our standard sedative agent propofol, the pharmacological profile of dexmedetomidine is more conducive to produce arousable sedation. The latter, however, is associated with hemodynamic side effects. We investigated whether dexmedetomidine is preferable over propofol during neurostimulator implantation., Methods: This single-center single-blinded randomized controlled trial included 72 patients with an indication for a neurostimulator, randomized to sedation with either propofol (0.5 mg/kg for 10 minutes, followed by 2.0 mg/kg/h) or dexmedetomidine (1 μg/kg for 10 minutes, followed by 0.6 μg/kg/h). The primary outcome was patient satisfaction with the sedation. The secondary outcomes were patient's and operator's comfort, number of titration adjustments, standard intraoperative hemodynamic and respiratory parameters and side effects., Results: Data of 69 patients (dexmedetomidine n = 35; propofol n = 34) were analyzed. Those receiving dexmedetomidine were more satisfied with the sedation than those receiving propofol; i.e. with sedation delivery (median 100.0 vs 83.3, P < .01), procedural recall (median 95.8 vs 83.3, P = .03), and sedation side effects (median 90.0 vs 83.3, P = .01). Fewer changes in the dexmedetomidine titration were necessary to maintain arousable sedation. Over time, mean arterial pressure and heart rate were significantly lower in the dexmedetomidine group. Hemodynamic side effects were comparable across groups., Conclusions: Dexmedetomidine sedation resulted in higher patient satisfaction and allowed for better arousable sedation than sedation with propofol. Although differences in hemodynamic parameters were found between the groups, these differences were not regarded as clinically relevant., (© 2019 Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background and Aims: During implantation of most spinal cord neurostimulators, patients need to be cooperative to give feedback during lead placement, and also be comfortable. Sedation and analgesia can support these conditions. This survey aimed to provide an overview of the sedation-analgesia regimens currently used among Dutch pain specialists. The survey focused on the sedative agent "dexmedetomidine" due to its attractive pharmacological profile and its promising results during awake procedures., Methods: A 27-item survey was sent to the 65 pain specialists involved in neurostimulation in the Netherlands. The survey consisted of questions related to different aspects of sedation and analgesia during neurostimulation, e.g. the current regimen, the opinion on and experience with dexmedetomidine as a sedative agent, and preferences regarding different aspects of sedation (i.e. production of arousable sedation, pain management, quality of patient's feedback and overall preference)., Results: Of 65 pain specialists, 45 (69%) completed the survey. Most commonly used sedative was propofol (91%) and most common used analgesic was remifentanil (78%). Of the 45 respondents, 21 (47%) considered the use of dexmedetomidine, whereas 13 (29%) had experience with dexmedetomidine during neurostimulation. The most frequently mentioned positive property of dexmedetomidine was the easy production of arousable sedation. Most respondents who used dexmedetomidine preferred dexmedetomidine sedation over propofol sedation regarding all aspects of sedation., Conclusions: The most commonly used sedation-analgesia regimen is the combination of propofol-remifentanil during the implantation of a neurostimulator among Dutch pain specialists. Only a small percentage of respondents had experience with the use of dexmedetomidine, despite its reported advantages., Implications: When implanting a spinal cord neurostimulator, dexmedetomidine could be considered as a sedative, given its allowance for and preservation of a state of easy arousable sedation., (©2019 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.)

Objective: Although complex regional pain syndrome (CRPS) of the knee is comparable to CRPS of the ankle/foot at time of diagnosis, no reports are available concerning the course of knee CRPS. Therefore, this study investigated the clinical course in terms of the symptoms and signs, health-related quality of life (HR-QoL), and work status of patients diagnosed with CRPS of the knee., Design: Observational, descriptive study., Setting: Single-center study., Subjects: Patients with CRPS of the knee., Methods: Patients self-reported their past and current CRPS symptoms, HR-QoL, and work status; all underwent a physical examination. A comparison was made of changes in symptoms over time between patients with CRPS of the knee and those with CRPS of more distal locations., Results: In total, 32 patients were enrolled. The follow-up time was 11.5 ± 6.29 years since diagnosis, and symptoms and signs showed a significant decrease over time. Twelve patients (37.5%) rated their health as (generally) positive. Patients who were still able to work (31.3%) stated that their physical health gave them at least some problems in the performance of their job. A change in symptoms occurred significantly less often in CRPS of the knee., Conclusions: CRPS of the knee changes in terms of symptoms over time, but significantly less than CRPS of other locations. A change in work status was reported in 82% of the patients due to their CRPS, and in 91%, the pain interfered with their daily life. CRPS of the knee is a painful condition with persistent symptoms causing a diminished HR-QoL., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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).

Background and aims Anterior cutaneous nerve entrapment syndrome (ACNES) may result in chronic abdominal pain. Therapeutic options include local injection therapy. Data on the efficacy of adding corticosteroids to these injections is lacking. Methods Patients ≥18 years with ACNES were randomized to receive an injection of lidocaine with (LC-group) or without (LA-group) the addition of methylprednisolone into the point of maximal abdominal wall pain. Pain was recorded using a numeric rating scale (NRS: 0-10) and a verbal rating scale (VRS: 0=no pain, 5=unbearable pain) at baseline and 6 weeks after the start of a bi-weekly injection regimen consisting of a total of three injections. A minimal 50% reduction on NRS and/or two points on VRS were considered successful responses. Results Between February 2014 and August 2016, 136 patients (median age 46 year, range 18-79, 75% females) were randomized (68 vs. 68). The proportion of patients demonstrating a successful response after 6 weeks did not significantly differ between groups (LA 38%, LC 31%, p=0.61). At 12 weeks, the number of patients still experiencing a minimal 50% pain relief had decreased but no group difference was observed (LA 20%, LC 18%, p=0.80). Minor side effects included temporary increase of pain, tenderness at injection sites or transient malaise (LA23/68, LC 29/68, p=0.46). Conclusions Adding corticosteroids to a lidocaine does not increase the proportion of ACNES patients with a successful response to injection therapy. Lidocaine alone can provide long term pain relief after one or multiple injections, in approximately 1 of 5 patients.

Background and Objectives: Patients with complex regional pain syndrome (CRPS) confined to the knee are often therapy resistant. Neurostimulation is an accepted treatment for CRPS. Although results with dorsal column (DC) stimulation in patients with CRPS confined to the knee are often disappointing, the availability of dorsal root ganglion (DRG) stimulation may provide new opportunities for this complaint. Therefore, this study explores patients' preference for DC stimulation vs. DRG stimulation in treating chronic pain due to CRPS confined to the knee., Methods: A prospective, observational crossover cohort study was conducted comparing 2 methods of neurostimulation, in randomized order, in patients with CRPS confined to the knee. After receiving DC and DRG stimulation during a trial period of 16 days, patients were asked which of the 2 methods they preferred. Patients with a successful trial period with one or both stimulation methods received a fully implantable system., Results: Twelve patients were included. After finishing the trial period, 10 patients (83.3%) preferred DRG stimulation and 2 (16.7%) preferred DC stimulation (P = 0.04)., Conclusion: To our knowledge, this is the first study to compare these 2 neurostimulation methods in patients with CRPS confined to the knee. Results show that the probability of the preference for either neurostimulation treatment significantly deviates from chance in favor of DRG stimulation., (© 2017 World Institute of Pain.)

Objective: Complex regional pain syndrome (CRPS) is characterized by continued pain disproportional to the inciting event, sensory abnormalities, vasomotor and sudomotor disturbances, and motor and trophic changes. Inflammatory involvement has been demonstrated in past CRPS studies resulting in pain, swelling, and warmth. Currently, it is unknown whether spinal cord stimulation (SCS) has immunomodulatory properties. The aim of this study was to determine whether SCS has immunomodulatory properties in CRPS patients., Methods: The primary outcome parameters are cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-15, IL-17, TNF-α, IFN-γ), chemokines (IP-10 and Eotaxin), and growth factors (VEGF, PDGFbb, and basic FGF) from interstitial fluid of artificial skin blisters before (T0-baseline without SCS) and after SCS therapy (T1-40 Hz standard frequency stimulation and T2-preferred frequency stimulation). Secondary outcome parameters were baseline demographics, CRPS signs, symptoms, and phenotype (inflammatory, vasomotor, dystonia, or neuropathic). Results were analyzed by means of a MANOVA repeated measures design., Results: After SCS, the expression of both pro- and anti-inflammatory cytokines decreased over time in both the CRPS affected extremity and the contralateral extremity. The levels of IP-10, Eotaxin, VEGF, and PDGFbb were also significantly reduced bilaterally. There were no significant changes in IL-6 and TNF-α before and after SCS. The sensory signs, symptoms, and phenotype improved after SCS., Discussion: SCS in CRPS patients attenuates T-cell activation, improves peripheral tissue oxygenation and decreases anti-angiogenetic activity which results in diminished endothelial dysfunction and improved bloodflow. The possible immunomodulatory effects of SCS opens new therapeutic possibilities in diseases with the involvement of the immune system and vasomotor disturbances, and requires further research on these mechanisms of action., (© 2017 International Neuromodulation Society.)

Dexmedetomidine is an upcoming agent with sedative, anxiolytic, and analgesic properties. This review summarizes empirical evidence for the efficacy of dexmedetomidine as a sole sedative agent, and its effectiveness for small diagnostic and therapeutic procedure, in comparison with other frequently used sedatives. All randomized controlled trials on the effect of dexmedetomidine were reviewed. Pain level, patient satisfaction, operator satisfaction, procedure duration, recovery time, and hemodynamic and respiratory characteristics were examined. A total of 1993 patients (1,621 adults; 372 children) from 35 studies were included. In the adult studies, dexmedetomidine yielded significantly lower pain levels compared to the other sedatives (in 31.25% of the included studies) and significantly more patient satisfaction (68.2%). In studies on children, more favorable results concerning respiratory safety and the level of adequate sedation were found compared to the control sedatives. Implications for future studies are discussed., (© 2016 World Institute of Pain.)

Objective: Non-adherence to pain medication is common in chronic pain patients and may result in unfavorable treatment outcomes. Interventions to improve adherence behavior often fail to significantly change medication use. In this report, we describe the application of a theoretical psychological model of behavior change in order to design an intervention to improve medication adherence in chronic pain patients., Methods: This study applies the Behavior Change Wheel framework and the Behavior Change Techniques Taxonomy to design a theory-based intervention to improve pain medication use. Available literature was used to extract determinants of adherence in chronic pain patients., Results: Selected target behaviors to improve medication adherence are: share agreement on follow up policy, monitor medication adherence, provide patient education routinely, discuss attitudes and concerns towards pain medication, develop medication taking habits and use medication reminders. The intervention consists of three components in which relevant behavior change techniques are applied: (1) changes in the electronic patient data management systems to enable medical staff to apply target behaviors; (2) bi-annual education of medical staff to commit the team to the proposed intervention and provide feedback; (3) routine and mandatory education of chronic pain patients following prescription of pain medication., Conclusions: To improve medication adherence in chronic pain patients, most interventions should be focused on providers of pain therapy. Prescribing chronic pain medication should be seen as part of a larger treatment regimen including adequate follow-up, adherence monitoring and patient education during the course of treatment.

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., (© 2016 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

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., (© 2016 European Pain Federation - EFIC®.)

Objective: During implantation of a neuromodulative system, high patient satisfaction is closely associated with the equilibrium between an effective analgesia and sedation regimen, and the possibility for the patient to be awake and cooperative during procedure. This study assessed the efficacy of the sedative dexmedetomidine to achieve this balance, with patient satisfaction as the primary outcome., Methods: Ten patients undergoing implantation of a dorsal column and dorsal root ganglion stimulator received dexmedetomidine (1 mcg/kg over 10 minutes, followed by 0.6 mcg/kg/hour) in combination with remifentanil at a set dose (3 mcg/kg/hour). Sedation was titrated to a Ramsay Sedation Score of 3. Recorded were as follows: patient satisfaction score, patient comfort score, operator comfort score, pain score, rescue medication and number of adjustments of dexmedetomidine intra-operatively, as well as sedation level, hemodynamic (blood pressure and heart rate), and respiratory characteristics (SpO 2 )., Results: Scores were high on patient satisfaction (median 8.5; IQR 2.0), patient comfort (3.0; IQR 1.25), and operator comfort (4.0; IQR 1.0). In all patients, intra-operative heart rate and mean arterial pressure were lower compared with baseline values. No respiratory depression or other complications related to anesthesia were reported. Moments of incident pain were effectively treated in 6 patients requiring an extra bolus of remifentanil., Conclusion: In this study group, dexmedetomidine combined with remifentanil provided a high level of patient satisfaction and comfort, as well as operator comfort, without any clinically relevant adverse events. All patients were highly cooperative and instructable; incident pain needs to be closely monitored., (© 2016 World Institute of Pain.)

Background/objective: Several diagnostic criteria sets are described in the literature to identify low back pain subtypes, but very little is known about the inter-rater reliability of these criteria. We conducted a study to determine the reliability of diagnostic tests that point towards SI joint-, disc- or facet joint pain., Methods: Inter-rater reliability study alongside three randomized clinical trials. Multidisciplinary pain center of general hospital. Patients aged 18 or more with medical history and physical examination suggestive of sacroiliac joint-, disc- and facet joint pain on lumbar level. Making use of nowadays most common used diagnostic criteria, a physical examination is taken independently by three physicians (two pain physicians and one orthopedic surgeon). Inter-rater reliability (Kappa (κ) measure of agreement) and significance (p) between raters are presented. Strengths of agreement, indicated with κ values above 0,20, are presented in order of agreement., Results: One hundred patients were included. None of the parameters from the physical investigation had κ values of more than 0.21 (fair) in all pairs of raters. Between two raters (C and D), there was an almost perfect agreement on three parameters, more specifically ``Abnormal sensory and motor examination, hyperactive or diminished reflexes'', ``Sitting exam shows no reflex, motor or sensory signs in the legs'' and ``Straight leg raising (Laségue) negative between 30 and 70 degrees of flexion''. The ``Drop test positive'' parameters had moderate strength of agreement between raters A and D and fair strength between raters A and B. The ``Digital interspinous pressure test positive'' had moderate strength of agreement between raters C and D and fair strength of agreement between raters A and B as well as raters B and C. Three other parameters had a fair strength of agreement between two raters, all other parameters had a slight or poor strength of agreement. Inter-rater reliability, confidence intervals and significance of pooled items for SI joint-, disc- and facet joint pain are represented; κ values for the pooled parameters of the physical examination suggestive of SI joint pain stayed below 0.20 between all raters. The same applies for the pooled parameters of the physical examination suggestive of facet joint or disc pain., Conclusions: The poor reliability of the diagnostic parameters seriously limits their predictive validity, and as such their use in patients with low back pain for more than 3 months.

The immune system has long been thought to be involved in the pathophysiology of complex regional pain syndrome (CRPS). However, not much is known about the role of the immune system and specifically T-cells in the onset and maintenance of this disease. In this study, we aimed to evaluate T-cell activity in CRPS by comparing blood soluble interleukin-2 receptor (sIL-2R) levels between CRPS patients and healthy controls. CRPS patients had statistically significant elevated levels of sIL-2R as compared to healthy controls (median sIL-2R levels: 4151 pg/ml (Q3 - Q1 = 5731 pg/ml - 3546 pg/ml) versus 1907 pg/ml (Q3 - Q1: 2206 pg/ml - 1374 pg/ml), p < 0.001, resp.). Furthermore, sIL-2R level seems to be a good discriminator between CRPS patients and healthy controls with a high sensitivity (90%) and specificity (89.5%). Our finding indicates increased T-cell activity in patients with CRPS. This finding is of considerable relevance as it could point towards a T-cell-mediated inflammatory process in this disease. This could pave the way for new anti-inflammatory therapies in the treatment of CRPS. Furthermore, sIL-2R could be a promising new marker for determining inflammatory disease activity in CRPS.

Objective: To compare the phenotypes of patients with complex regional pain syndrome (CRPS) of the knee to those with CRPS of the ankle/foot., Setting: A retrospective study., Subjects: Patients with CRPS of the knee and patients with CRPS of the ankle/foot., Methods: We used electronic patient databases to identify patients with CRPS of the knee and patients with CRPS of the ankle/foot. The following variables were recorded: age, gender, duration of complaints, initial injury, and symptoms and signs. Frequency distributions and statistical significant differences between the groups were determined., Results: Included were 50 patients with CRPS of the knee and 64 patients with CRPS of the ankle/foot. These patients were all diagnosed with CRPS according to the criteria used at the time of diagnosis. No significant differences were found in demographic characteristics. A few symptoms and signs appeared to be proportionally more prevalent in patients with CRPS of the ankle/foot. However, patients with CRPS of the knee suffered significantly longer from the disease than patients with CRPS of the ankle/foot., Conclusions: Some signs and symptoms appeared to be statistically significantly more prevalent in CRPS of the ankle/foot than in CRPS confined to the knee. We conclude that the phenotypes of CRPS confined to the knee and CRPS of the ankle/foot are comparable, but not identical. This can be a reason why CRPS in patients with pain of the knee, that is disproportionate to the initial trauma, is sometimes not recognized., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 (80 o C 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., (©2016 The British Editorial Society of Bone & Joint Surgery.)

Objectives: To investigate the effect of a percutaneous radiofrequency (RF) heat lesion compared with a sham procedure, applied to the lateral branches of L5, S1, S2, S3, and S4 nerve roots., Materials and Methods: Sixty patients aged 18 years and above with a medical history and physical examination suggestive for sacroiliac joint pain and a reduction of 2 or more on a numerical rating scale (NRS, 0 to 10) after a sacroiliac joint test block were included in this study. Treatment group: percutaneous RF heat lesion at the lateral branches of S1, S2, S3, and S4 nerve roots and the posterior ramus dorsalis of L5; sham group: same procedure as the treatment group except for the RF heat lesion., Primary Outcome Measure: pain reduction (NRS). Secondary outcome measure: Global Perceived Effect., Results: No statistically significant differences in pain level over time between the groups (Group×Period) (F1,58=0.353; P=0.56) nor within the treatment Group (F1,58=0.212; P=0.65) were found. The Period factor, however, yielded a significant difference (F1,58=61.67; P<0.001), that is, when pooled together the mean pain level of the patients was significantly reduced at T1 compared with T0. In the crossover group, 42.1% experienced a reduction in NRS of 2 or more at 1 month (P=0.65). No statistically significant difference in satisfaction over time between the groups was found (F1,50=2.1; P=0.15). The independent factors Group (F1,50=2.02; P=0.16) and Period (F1,50=0.95; P=0.33) also showed no statistically significant difference. The same applies to recovery: no statistically significant Group×Period effect (F1,51=0.09; P=0.77) was found, neither an effect of Group (F1,51=0.004; P=0.95) nor of Period (F1,51=0.27; P=0.60)., Discussion: The hypothesis of no difference in pain reduction or in Global Perceived Effect between the treatment and sham group cannot be rejected., Level of Evidence: Level 1A.

Objective: Non-adherence to pain medication is common and may jeopardize the effect of prescribed therapy in chronic pain patients. We investigated the effect of medication-specific education on pain medication adherence., Methods: One hundred eligible chronic pain patients were randomized into a control or intervention group. They were assessed during an intake (T0) and two follow-up visits after 4 (T1) and 10 weeks (T2). Immediately after T1, patients in the intervention group additionally watched a video and received written information about the medication prescribed. At T1 and T2, medication adherence according to self-reporting including the Morisky Medication Adherence Scale, prescription knowledge, pain intensity numeric rating scale (NRS), concerns about medication, and patient satisfaction were recorded., Results: Experimental group (control versus intervention) did not significantly contribute to the prediction of medication adherence at T2 (P = 0.38). The non-adherence rates were 31% and 43% at T1 and 53% and 49% at T2 in the control and intervention group, respectively. Changes in patients' knowledge of the prescription were attributable to the intervention (P < 0.01). No other significant differences were identified., Conclusions: Medication-specific education did increase knowledge of the prescribed therapy but did not improve adherence or treatment outcome parameters. There was no association between medication adherence and pain treatment outcome., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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., (© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objectives: To report on the efficacy of dorsal root ganglion stimulation in a patient with complex regional pain syndrome (CRPS) type I of the knee., Materials and Methods: A 48-year-old woman with CRPS type I of the right knee, diagnosed according to the Budapest criteria set, received DRG stimulation for intractable CRPS type I of the knee., Results: After a successful trial period with three DRG stimulation leads on spinal levels L2, L3, and L4 (covering 90% of the painful area of her knee), a definitive pulse generator was implanted. Three months after implantation, the entire painful area was covered, and the patient reported a numeric rating scale score of 1-2., Conclusion: Placement of three DRG stimulation leads at levels L2, L3, and L4 in a patient with intractable CRPS type I of the knee resulted in major pain relief. We recommend further investigation of the effect of DRG stimulation on pain due to CRPS of the knee., (© 2014 International Neuromodulation Society.)

Autoimmunity has been suggested as one of the pathophysiologic mechanisms that may underlie complex regional pain syndrome (CRPS). Screening for antinuclear antibodies (ANA) is one of the diagnostic tests, which is usually performed if a person is suspected to have a systemic autoimmune disease. Antineuronal antibodies are autoantibodies directed against antigens in the central and/or peripheral nervous system. The aim of this study was to compare the prevalence of these antibodies in CRPS patients with the normal values of those antibodies in the healthy population. Twenty seven (33%) of the 82 CRPS patients of whom serum was available showed a positive ANA test. This prevalence is significantly higher than in the general population. Six patients (7.3%) showed a positive result for typical antineuronal antibodies. This proportion, however, does not deviate from that in the general population. Our findings suggest that autoantibodies may be associated with the pathophysiology of CRPS, at least in a subset of patients. Further research is needed into defining this subset and into the role of autoantibodies in the pathogenesis of CRPS.

Background: Surgery has wide ranging immunomodulatory properties of which the mechanism is poorly understood. In order to investigate how different types of surgery influence inflammation, we designed a longitudinal observational study investigating two inflammatory profiles of two separate patient groups undergoing gynaecological operations of differing severity. In addition to measuring the well known inflammatory markers neopterin and IL-6, we also determined the kynurenine/tryptophan ratio. This study was a prospective, single center, two-armed observational study involving 28 female patients. Plasma levels of tryptophan, kynurenine, neopterin and IL-6 were determined from samples taken at: 24 hrs pre-operative, prior to induction, ten minutes before the operation was expected to end, and at 24 and 96 hours post operative in patients undergoing abdominal hysterectomy and vulvectomy., Results: There were 15 and 13 patients included in the vulvectomy and abdominal hysterectomy groups, respectively. In this study we show that anesthesia and surgery significantly increases the enzyme activity of indoleamine 2, 3 dioxygenase (IDO) as measured by the kynurenine/tryptophan ratio (P=0.003), while maintaining stable neopterin levels. However, abdominal hysterectomy causes a considerable IL-6 increase (P<0.001)., Conclusion: Surgery and associated anesthesia cause a significant tryptophan level decrease while significantly increasing IDO activity. Both types of surgery produce nearly identical neopterin time curve relationships, with no significant change occurring in either group. However, even though neopterin is unaffected by the severity of surgery, IL-6 responded to surgical invasiveness by revealing a significant increase during abdominal hysterectomy.

Background: Nonadherence to pharmacological therapy is a common and underexposed problem in patients with chronic nonmalignant pain. It may lead to treatment failure and increased healthcare costs., Methods: In this prospective observational study we analyzed the association between knowledge and adherence in the chronic nonmalignant pain population. We included 96 patients treated with a new pharmacological prescription. During the initial visit (T0), demographic variables, pain intensity, knowledge of the prescription (name, dose, and frequency), self-reported adherence to the prescription, and general knowledge of pharmacological pain therapy (according to the Pain Knowledge Questionnaire, Dutch Language Version (PKQ-DLV) were recorded. During two follow-up visits (T1, T2), apart from demographics, these parameters were measured again., Results: Adherence rates were 42%, 42%, and 46% at T0, T1 and T2, respectively. 53%, 59%, and 48% of patients had knowledge of their current prescription, and mean scores on the PKQ-DLV were 56, 55, and 52 percent of the maximum scores, respectively, at T0, T1 and T2. A multivariate binary logistic regression analysis resulted in a significant contribution of knowledge of the prescription and of age to the prediction of adherence., Conclusions: Knowledge of the analgesic prescription is associated with adherence and significantly contributes to the prediction of adherence to analgesic therapy. An interventional study is needed to determine whether increasing knowledge will improve medication adherence and therapy outcome in patients with chronic nonmalignant pain., (© 2013 World Institute of Pain.)