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Objectives: Quantitative sensory testing (QST) has been used for decades to study sensory abnormalities in multiple conditions in which the somatosensory system is compromised, including pain. It is commonly used in pharmacologic studies on chronic pain but less so in conjunction with neuromodulation. This review aims to assess the utility of QST in spinal cord stimulation (SCS) protocols. Materials and Methods: For this narrative review, we searched PubMed for records of studies in which sensory testing has been performed as part of a clinical study on SCS from 1975 onward until October 2023. We focused on studies in which QST has been used to explore the effect of SCS on neuropathic, neuropathic-like, or mixed pain. Results: Our search identified 22 useful studies, all small and exploratory, using heterogeneous methods. Four studies used the full battery of validated German Research Network on Neuropathic Pain QST. There is emerging evidence that assessment dynamic mechanical allodynia (eight studies), and mechanical/thermal temporal summation of pain (eight studies) may have a role in quantifying the response to various SCS waveforms. There also were sporadic reports of improvement of sensory deficits in a proportion of patients with neuropathic pain that warrant further study. Conclusions: We recommend the adoption of QST into future clinical research protocols, using either the full QST protocol or a less time-demanding short-form QST.

Introduction: Spinal neurostimulation is a therapy for otherwise intractable chronic pain. Spinal neurostimulation includes stimulation of the spinal cord (SCS), dorsal root ganglion (DRGS), and dorsal root entry zone (DREZS). New paresthesia-free neurostimulation paradigms may rely on different mechanisms of action from those of conventional tonic neurostimulation. The aim of this systematic review is to assess the existing knowledge on the effect of spinal neurostimulation on somatosensory processing in patients with chronic pain. We therefore reviewed the existing literature on the effect of various spinal neurostimulation paradigms on the supraspinal somatosensory evoked response (SER). Materials and Methods: Multiple scientific data bases were searched for studies that assessed the effect of spinal neurostimulation on the supraspinal SER, evoked by painful or nonpainful peripheral stimuli in patients with chronic pain. We found 205 studies, of which 24 were included. Demographic data, study design, and study outcome were extracted. Results: Of the 24 included studies, 23 used electroencephalography to assess the SER; one study used magnetoencephalography. Fifteen studies evaluated tonic SCS; six studies (also) evaluated paresthesia-free paradigms; three studies evaluated the effect of tonic DRGS or DREZS. Sixteen studies used nonpainful stimuli to elicit the SER, 14 observed a decreased SER amplitude. Ten studies used painful stimuli to elicit the SER, yielding mixed results. Discussion: The included studies suggest that both paresthesia-based and paresthesia-free spinal neurostimulation paradigms can decrease (part of) the SER elicited by a nonpainful peripheral stimulus. The observed SER amplitude reduction likely is the effect of various spinal and supraspinal mechanisms of spinal neurostimulation that also contribute to pain relief. Conclusions: Spinal neurostimulation modulates

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

Background: Evidence-based guidelines for managing anterior cutaneous nerve entrapment syndrome (ACNES) in children are absent. The primary aim of this review was to scrutinize the evidence supporting currently used treatment interventions. In accordance with the World Health Organization (WHO) guidelines for managing chronic pain in children, these patients and their families and caregivers should be treated within the context of the biopsychosocial model; pain should not be treated purely as a biomedical problem. Therefore, our second aim was to evaluate whether these interventions are applied within the context of the biopsychosocial model, utilizing an inter- or multidisciplinary approach. Materials and Methods: A scoping review of the literature was conducted to explore treatment strategies for ACNES in children. To ensure a comprehensive overview of published literature on this topic, the search was not restricted based on study type. Two reviewers independently assessed titles and abstracts. After excluding records unrelated to children, full texts were screened for inclusion. Any discrepancies in judgement were resolved through discussion with a third reviewer. Results: Out of 35 relevant titles, 22 were included in this review. Only 4 articles provided information on long-term outcomes. The overall quality of the review was deemed low. The majority of reports did not address treatment or education within the psychological and social domains. A structural qualitative analysis was not feasible due to the substantial heterogeneity of the data. Conclusion: The evidence supporting current treatment strategies in children with ACNES is of low quality. More research is needed to establish an evidence-based treatment algorithm for patients with this challenging pain problem. In line with the WHO recommendation, greater emphasis should be placed on a biopsychosocial approach. The ultimat

BACKGROUND: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. METHODS: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. FINDINGS: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We

Objective: A potentially useful biomarker for Complex Regional Pain Syndrome (CRPS) is the serum soluble interleukin-2 receptor (sIL-2R) level, which is a marker for T-cell activation. Elevated serum sIL-2R levels have been described in CRPS patients compared to healthy controls. In T-cell mediated inflammatory diseases such as sarcoidosis and rheumatoid arthritis, the serum sIL-2R levels correlate with disease severity. In this study, we investigate whether an association exists between serum sIL-2R levels in CRPS patients and CRPS severity. Methods: A cross-sectional cohort study was conducted in a tertiary pain referral center in the Netherlands. Adult CRPS patients diagnosed by the IASP criteria were included between October 2018 until October 2022. The main study parameters were serum sIL-2R levels and the CRPS severity score. Results: Fifty-three CRPS patients were included with a mean syndrome duration of 84 months (Q3 – Q1:180 – 48). The majority had persistent CRPS with a syndrome duration >1 year (n ¼ 52, 98%). The median pain Numerical Rating Score (NRS) was 7 (Q3 – Q1: 8 – 5) and the mean CRPS severity score was 11 (SD 6 2.3). The median serum sIL-2R level was 330 U/mL (Q3 – Q1:451 – 256). No statistically significant correlation was observed between serum sIL-2R levels and the CRPS severity score (r s ¼ 0.15, P ¼ .28). Conclusions: Our findings suggest that serum sIL-2R levels cannot be used as a biomarker for syndrome severity in persistent CRPS (syndrome duration >1 year). Serial measurements of serum sIL-2R from early CRPS to persistent CRPS are needed to investigate whether serum sIL-2R levels can be used to monitor T-cell mediated inflammatory syndrome activity.

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 st

Background: Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. Methods: In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patie

Objectives: To develop and validate approaches for mapping Oswestry Disability Index responses to 3-level version of EQ-5D utility values and to evaluate the impact of using mapped utility values on cost-utility results compared with published regression models. Methods: Three response mapping approaches were developed in a random sample of 70% of 18 692 patients with low back pain: nonparametric approach (Non-p), nonparametric approach excluding logical inconsistencies (Non-peLI), and ordinal logistic regression (OLR). Performance was assessed in the remaining 30% using R-square (R2), root mean square error (RMSE), and mean absolute error (MAE). To evaluate whether MAEs and their 95% limits of agreement (LA) were clinically relevant, a minimally clinically important difference of 0.074 was used. Probabilities of cost-effectiveness estimated using observed and mapped utility values were compared in 2 economic evaluations. Results: The Non-p performed the best (R2 = 0.43; RMSE = 0.22; MAE = 0.03; 95% LA = −0.40 to 0.47) compared with the Non-peLI (R2 = 0.07; RMSE = 0.29; MAE = −0.15; 95% LA = −0.63 to 0.34) and OLR (R2 = 0.22; RMSE = 0.26; MAE = 0.02; 95% LA = −0.49 to 0.53). MAEs were lower than the minimally clinically important difference for the Non-p and OLR but not for the Non-peLI. Differences in probabilities of cost-effectiveness ranged from 1% to 4% (Non-p), 0.1% to 9% (Non-peLI), and 0.1% to 20% (OLR). Conclusions: Results suggest that the developed response mapping approaches are not valid for estimating individual patients’ 3-level version of EQ-5D utility values, and—depending on the approach—may considerably affect cost-utility results. The developed approaches did not perform better than previously published regression-based models and are therefore not recommended for use in economic evaluations.

Background: The lack of knowledge about the intra- and interindividual attack frequency variability in chronic cluster headache complicates power and sample size calculations for baseline periods of trials, and consensus on their most optimal duration. Methods: We analyzed the 12-week baseline of the ICON trial (occipital nerve stimulation in medically intractable chronic cluster headache) for: (i) weekly vs. instantaneous recording of attack frequency; (ii) intra-individual and seasonal variability of attack frequency; and (iii) the smallest number of weeks to obtain a reliable estimate of baseline attack frequency. Results: Weekly median (14.4 [8.2–24.0]) and instantaneous (14.2 [8.0–24.5]) attack frequency recordings were similar (p = 0.20; Bland-Altman plot). Median weekly attack frequency was 15.3 (range 4.2–140) and highest during spring (p = 0.001) compared to the other seasons. Relative attack frequency variability decreased with increasing attack frequency (p = 0.010). We tabulated the weekly attack frequency estimation accuracies compared to, and the associated deviations from, the 12-week gold standard for different lengths of the observation period. Conclusion: Weekly retrospective attack frequency recording is as good as instantaneous recording and more convenient. Attack frequency is highest in spring. Participants with ≥3 daily attacks show less attack frequency variability than those with <3 daily attacks. An optimal balance between 90% accuracy and feasibility is achieved at a baseline period of seven weeks. The ICON trial is registered in ClinicalTrials.gov under number NCT01151631.

Complex regional pain syndrome (CRPS) is a debilitating painful state of an extremity that can develop after trauma. CRPS is diagnosed by the new International Association for the Study of Pain (IASP) diagnostic criteria for CRPS. The syndrome is characterized by continuing regional pain with abnormal sensory, motor, sudomotor, vasomotor, edema, and/or trophic signs. The clinical presentation of CRPS can be very heterogeneous because CRPS is a multi-mechanism syndrome. Therefore, mechanism-based subgroups have been suggested to personalize treatment for CRPS. Additionally, the presentation of symptom pain may also be able to identify different subgroups of CRPS. In this review, the types of pain recognized by the IASP―nociceptive, neuropathic, and nociplastic pain―will be discussed as possible subgroups for CRPS. Each pain type should be identified in CRPS patients, with a thorough history taking, physical examination, and diagnostic tests or (novel) biomarkers to optimize treatment effectiveness. Over the course of the syndrome, patients with CRPS probably experience more than one distinct pain type. Therefore, pain specialists should be alert to not only adjust their treatment if underlying pathophysiologic mechanisms tend to change but also to personalize the treatment of the associated type of pain in the CRPS patient.

Background: Early identification of patients at risk of developing chronic postsurgical pain (CPSP) is an essential step in reducing pain chronification in postsurgical patients. We aimed to develop and validate a prognostic model for the early prediction of CPSP including pain characteristics indicating altered pain processing within 2 weeks after surgery. Methods: A prospective cohort study was conducted in adult patients undergoing orthopaedic, vascular, trauma, or general surgery between 2018 and 2019. Multivariable logistic regression models for CPSP were developed using data from the University Medical Centre (UMC) Utrecht and validated in data from the Erasmus UMC Rotterdam, The Netherlands. Results: In the development (n=344) and the validation (n=150) cohorts, 28.8% and 21.3% of patients reported CPSP. The best performing model (area under the curve=0.82; 95% confidence interval [CI], 0.76–0.87) included preoperative treatment with opioids (odds ratio [OR]=4.04; 95% CI, 2.13–7.70), bone surgery (OR=2.01; 95% CI, 1.10–3.67), numerical rating scale pain score on postoperative day 14 (OR=1.57; 95% CI, 1.34–1.83), and the presence of painful cold within the painful area 2 weeks after surgery (OR=4.85; 95% CI, 1.85–12.68). Predictive performance was confirmed by external validation. Conclusions: As only four easily obtainable predictors are necessary for reliable CPSP prediction, the models are useful for the clinician to be alerted to further assess and treat individual patients at risk. Identification of the presence of painful cold within 2 weeks after surgery as a strong predictor supports altered pain processing as an important contributor to CPSP development.

Complex regional pain syndrome (CRPS) is a debilitating painful condition of a distal extremity that can develop after tissue damage. CRPS is thought to be a multimechanism syndrome and ideally the most prominent mechanism(s) should be targeted by drugs in an individually tailored manner. This review gives an overview of the action and evidence of current and future pharmacotherapeutic options for CRPS. The available options are grouped in four categories by their therapeutic actions on the CRPS mechanisms, i.e. inflammation, central sensitisation, vasomotor disturbances and motor disturbances. More knowledge about the underlying mechanisms of CRPS helps to specifically target important CRPS mechanisms. In the future, objective biomarkers could potentially aid in selecting appropriate mechanism-based drugs in order to increase the effectiveness of CRPS treatment. Using this approach, current and future pharmacotherapeutic options for CRPS should be studied in multicentre trials to prove their efficacy. The ultimate goal is to shift the symptom-based selection of therapy into a mechanism-based selection of therapy in CRPS.

Purpose: To assess whether regression modeling can be used to predict EQ-5D-3L utility values from the Oswestry Disability Index (ODI) in low back pain (LBP) patients for use in cost-effectiveness analysis. Methods: EQ-5D-3L utility values of LBP patients were estimated using their ODI scores as independent variables using regression analyses, while adjusting for case-mix variables. Six different models were estimated: (1) Ordinary Least Squares (OLS) regression, with total ODI score, (2) OLS, with ODI item scores as continuous variables, (3) OLS, with ODI item scores as ordinal variables, (4) Tobit model, with total ODI score, (5) Tobit model, with ODI item scores as continuous variables, and (6) Tobit model, with ODI item scores as ordinal variables. The models’ performance was assessed using explained variance (R2) and root mean squared error (RMSE). The potential impact of using predicted instead of observed EQ-5D-3L utility values on cost-effectiveness outcomes was evaluated in two empirical cost-effectiveness analysis. Results: Complete individual patient data of 18,692 low back pain patients were analyzed. All models had a more or less similar R2 (range 45–52%) and RMSE (range 0.21–0.22). The two best performing models produced similar probabilities of cost-effectiveness for a range of willingness-to-pay (WTP) values compared to those based on the observed EQ-5D-3L values. For example, the difference in probabilities ranged from 2 to 5% at a WTP of 50,000 €/QALY gained. Conclusion: Results suggest that the ODI can be validly used to predict low back pain patients’ EQ-5D-3L utility values and QALYs for use in cost-effectiveness analyses.