Challenges of neuropathic pain: focus on diabetic neuropathy.

Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.

Is Preoperative Quantitative Sensory Testing Related to Persistent Postsurgical Pain? A Systematic Literature Review.

Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient's preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.

Avoiding Catch-22: validating the PainDETECT in a in a population of patients with chronic pain.

BACKGROUND: Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system and is a major therapeutic challenge. Several screening tools have been developed to help physicians detect patients with neuropathic pain. These have typically been validated in populations pre-stratified for neuropathic pain, leading to a so called "Catch-22 situation:" "a problematic situation for which the only solution is denied by a circumstance inherent in the problem or by a rule". The validity of screening tools needs to be proven in patients with pain who were not pre-stratified on basis of the target outcome: neuropathic pain or non-neuropathic pain. This study aims to assess the validity of the Dutch PainDETECT (PainDETECT-Dlv) in a large population of patients with chronic pain. METHODS: A cross-sectional multicentre design was used to assess PainDETECT-Dlv validity. Included where patients with low back pain radiating into the leg(s), patients with neck-shoulder-arm pain and patients with pain due to a suspected peripheral nerve damage. Patients' pain was classified as having a neuropathic pain component (yes/no) by two experienced physicians ("gold standard"). Physician opinion based on the Grading System was a secondary comparison. RESULTS: In total, 291 patients were included. Primary analysis was done on patients where both physicians agreed upon the pain classification (n = 228). Compared to the physician's classification, PainDETECT-Dlv had a sensitivity of 80% and specificity of 55%, versus the Grading System it achieved 74 and 46%. CONCLUSION: Despite its internal consistency and test-retest reliability the PainDETECT-Dlv is not an effective screening tool for a neuropathic pain component in a population of patients with chronic pain because of its moderate sensitivity and low specificity. Moreover, the indiscriminate use of the PainDETECT-Dlv as a surrogate for clinical assessment should be avoided in daily clinical practice as well as in (clinical-) research. Catch-22 situations in the validation of screening tools can be prevented by not pre-stratifying the patients on basis of the target outcome before inclusion in a validation study for screening instruments. TRIAL REGISTRATION: The protocol was registered prospectively in the Dutch National Trial Register: NTR 3030 .

Detecting the neuropathic pain component in the clinical setting: a study protocol for validation of screening instruments for the presence of a neuropathic pain component.

BACKGROUND: The presence of nerve damage plays a key role in the development and prognosis of chronic pain states. Assessment of the presence and severity of a neuropathic pain component (NePC) is key in diagnosing chronic pain patients. Low back pain (LBP) and neck and shoulder pain (NSP) are highly prevalent and clinically important medical and societal problems in which a NePC is frequently present. The more severe the NePC, the worse the course of the pain, its prognosis and the results of treatment. Reliable and standardised diagnosis of the NePC remains difficult to achieve. Standardized and validated screening tools may help to reliably identify the NePC in individual chronic pain patients. The aim of this study is to validate the Dutch language versions of the PainDETECT Questionnaire (PDQ-Dlv) and the 'Douleur Neuropathique 4 Questions' (DN4-Dlv) for use in primary and specialist medical care settings to screen for a NePC in patients with chronic pain due to (1) LBP, (2) NSP or (3) known peripheral nerve damage (PND). METHODS/DESIGN: The study design is cross-sectional to assess the validity of the PDQ-Dlv and the DN4-Dlv with 2 weeks follow-up for test-retest reliability and 3 months follow-up for monitoring and prognosis. 438 patients with chronic pain due to (1) LBP, (2) NSP or (3) PND. will be included in this study. Based on the IASP definition of neuropathic pain, two physicians will independently assess whether the patient has a NEPC or not. This result will be compared with the outcome of the PDQ-Dlv & DN4-Dlv, the grading system for neuropathic pain, bed side examination and quantitative sensory testing. This study will further collect data regarding prevalence of NePC, general health status, mental health status, functioning, pain attribution and quality of life. DISCUSSION: The rationale for this study is to provide detailed information on the clinimetric quality of the PDQ-Dlv and DN4-Dlv in Dutch speaking countries. Our innovative multi-factorial approach should help achieve more reliable diagnosis and quantification of a NePC in patients with chronic pain. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR3030).

Establishing central sensitization inventory cut-off values in Dutch-speaking patients with chronic low back pain by unsupervised machine learning.

BACKGROUND: Human Assumed Central Sensitization (HACS) is involved in the development and maintenance of chronic low back pain (CLBP). The Central Sensitization Inventory (CSI) was developed to evaluate the presence of HACS, with a cut-off value of 40/100. However, various factors including pain conditions (e.g., CLBP), contexts, and gender may influence this cut-off value. Unsupervised clustering approaches can address these complexities by considering diverse factors and exploring possible HACS-related subgroups. Therefore, this study aimed to determine the cut-off values for a Dutch-speaking population with CLBP based on unsupervised machine learning. METHODS: Questionnaire data covering pain, physical, and psychological aspects were collected from patients with CLBP and aged-matched healthy controls (HC). Four clustering approaches were applied to identify HACS-related subgroups based on the questionnaire data and gender. The clustering performance was assessed using internal and external indicators. Subsequently, receiver operating characteristic (ROC) analysis was conducted on the best clustering results to determine the optimal cut-off values. RESULTS: The study included 63 HCs and 88 patients with CLBP. Hierarchical clustering yielded the best results, identifying three clusters: healthy group, CLBP with low HACS level, and CLBP with high HACS level groups. The cut-off value for the overall groups were 35 (sensitivity 0.76, specificity 0.76). CONCLUSION: This study found distinct patient subgroups. An overall CSI cut-off value of 35 was suggested. This study may provide new insights into identifying HACS-related patterns and contributes to establishing accurate cut-off values.

Olanzapine as a prophylactic antiemetic for preventing postoperative nausea and vomiting after general anesthesia: A systematic review and meta-analysis.

BACKGROUND: The antiemetic effectiveness of olanzapine, as a prophylactic off-label antiemetic drug, for Postoperative Nausea and Vomiting (PONV) is unknown. In this systematic review and meta-analysis, the authors evaluate the efficacy and side effects of olanzapine as a prophylactic antiemetic in adult patients who undergo general anesthesia and assess adverse effects. METHODS: A systematic search was done on electronic bibliographic databases in July 2023. Randomized controlled trials of olanzapine as a prophylactic antiemetic for PONV in adults who underwent general anesthesia were included. The authors excluded non-RCTs and retracted studies. The authors set no date of publication or language limits. The outcomes were the incidence of PONV within 24 h postoperatively and the safety of olanzapine. The risk of bias was assessed according to the tool suggested by the National Heart, Lung, and Blood Institute. RESULTS: Meta-analysis included 446 adult patients. Olanzapine reduced on average 38 % the incidence of PONV. The estimated risk ratio (95 % CI) of olanzapine versus control was 0.62 (0.42-0.90), p = 0.010, I2 = 67 %. In the subgroup meta-analysis, doses of olanzapine (10 mg) reduced on average 49 % of the incidence of PONV (RR = 0.51 [0.34-0.77], p = 0.001, I2 = 31 %). CONCLUSIONS: This systematic review with meta-analysis indicated that olanzapine as a prophylactic antiemetic alone or combined with other antiemetic agents reduced the incidence of postoperative nausea and vomiting. However, this conclusion must be presented with some degree of uncertainty due to the small number of studies included. There was a lack of any evidence to draw conclusions on side effects.

Temporal relationships between pain, functioning, and human assumed central sensitization in patients with chronic low back pain; a single-case design.

BACKGROUND: Interdisciplinary pain rehabilitation (IPR) aims to improve functioning in people with chronic low back pain (CLBP), and is not primary aimed at pain reduction. Many patients however also report a decrease in pain. An explanation could be that IPR results in a decrease in Central Sensitization (CS). As CS is not directly assessable in humans the term Human Assumed Central Sensitization (HACS) is used in this study. It is unknown whether a decrease in HACS precedes a decrease in pain and improved functioning or vice versa. OBJECTIVES: This study aimed to gain understanding into the temporal relationships between changes in pain, functioning, and HACS in patients with CLBP during IPR. DESIGN: Longitudinal observational small-N-study. METHOD: Twelve patients filled in frequently repeated self-reports 1 week before, during the 12-week IPR program, and 2 weeks after IPR. Pain was assessed by Visual Analogue Scale for pain (daily), functioning by Pain Disability Index (weekly) and Work Ability Score (daily), and HACS by Central Sensitization Inventory part A (bi-weekly). Analyses were performed by visual inspection and time series cross-correlation analyses. RESULTS: Visual inspection showed large fluctuations within and between individual participants in patterns over time. Cross-correlation analyses showed that in most participants, relationships between pain, functioning, and HACS were strongest when analyzed at the same time (55% of comparisons). Strength and direction of (strongest) correlations showed high interindividual variability (neg: 0.33-0.97; pos: 0.22-0.99). CONCLUSION: Overall, relationships between pain, functioning, and HACS did not show consistent temporality in patients with CLBP.

Cross-cultural adaptation to the Dutch language of the PainDETECT-Questionnaire.

BACKGROUND: The PainDETECT-Questionnaire (PDQ) helps to identify neuropathic components in patients suffering from pain. It can be used by clinicians in daily practice and in clinical trials. AIM: The aim of this study is to perform a translation and cross-cultural adaptation of the PDQ for use in the Netherlands and Belgium. METHODS: The first phase was to translate and cross-culturally adapt the PDQ to Dutch. The second phase was to assess the face validity in the Netherlands and Belgium using qualitative and quantitative data collection. RESULTS: The length, the readability, and the clarity of the questionnaire were good for all patients. The questionnaire was judged to have a good layout and to be clearly organized. CONCLUSION: The PDQ Dutch language Version is a well translated and cross-culturally adapted questionnaire, which might be useful for screening for neuropathic components of pain in the Netherlands and Belgium.

Modulation of Pain Sensitivity by a Hyperventilatory Breathing Exercise and Cold Exposure Training.

Background: Evidence indicates that healthy individuals who follow a training program comprised hyperventilatory breathing exercises and cold exposure can voluntarily activate their sympathetic nervous system and attenuate their systemic inflammatory response during experimental endotoxemia (intravenous administration of bacterial endotoxin). Furthermore, trained participants reported less endotoxemia-induced flu-like symptoms. However, it remained to be determined whether the effects on symptoms are due to the mitigated inflammatory response or involve direct analgesic effects of (elements of) the training program. Methods: In the present study, we used Nijmegen-Aalborg Screening Quantitative sensory testing (NASQ) to objectively map pain sensitivity using non-invasive stimuli to address this question. First, NASQ parameters were evaluated in 20 healthy volunteers before, during, and after the conduct of the hyperventilatory breathing exercise. Second, NASQ measurements were performed before and after 48 healthy volunteers followed different modalities of the training program: breathing exercise training, cold exposure training, the combination of both, or no training. Lastly, NASQ measurements were performed in these 48 subjects during experimental endotoxemia. Results: Electrical pain detection thresholds increased during the breathing exercise (p = 0.001) as well as four hours afterwards (p = 0.03). Furthermore, cold exposure training resulted in lower VAS scores during hand immersion in ice water (p < 0.001). Systemic inflammation induced by administration of endotoxin nullified the decreased pain perception during the ice water test in subjects trained in cold exposure. Conclusion: A hyperventilatory breathing exercise decreases pain perception induced by an electrical stimulus. Furthermore, cold exposure training may decrease pain perception induced by hand immersion in ice water.

Validity of the Central Sensitization Inventory to Address Human Assumed Central Sensitization: Newly Proposed Clinically Relevant Values and Associations.

Central sensitization cannot be directly demonstrated in humans and thus a gold standard is missing. Therefore, we used human assumed central sensitization (HACS) when associated with humans. The central sensitization inventory (CSI) is a screening questionnaire for addressing symptoms that are associated with HACS. This cross-sectional study compared patients with chronic pain and at least one central sensitivity syndrome with healthy, pain-free controls via ROC analyses. Analyses were performed for all participants together and for each sex separately. Regression analyses were performed on patients with chronic pain with and without central sensitivity syndromes. Based on 1730 patients and 250 healthy controls, cutoff values for the CSI for the total group were established at 30 points: women: 33 points; men: 25 points. Univariate and multivariate regression analyses were used to identify possible predictors for the CSI score in 2890 patients with chronic pain. The CSI score is associated with all independent factors and has a low association with pain severity in women and a low association with pain severity, age, and body mass index in men. The newly established CSI cutoff values are lower than in previous studies and different per sex, which might be of clinical relevance in daily practice and importance in research.

Role of non-invasive objective markers for the rehabilitative diagnosis of central sensitization in patients with fibromyalgia: A systematic review.

BACKGROUND: Central sensitization cannot be demonstrated directly in humans. Therefore, studies used different proxy markers (signs, symptoms and tools) to identify factors assumed to relate to central sensitization in humans, that is, Human Assumed Central Sensitization (HACS). The aims of this systematic review were to identify non-invasive objective markers of HACS and the instruments to assess these markers in patients with fibromyalgia (FM). METHODS: A systematic review was conducted with the following inclusion criteria: (1) adults, (2) diagnosed with FM, and (3) markers and instruments for HACS had to be non-invasive. Data were subsequently extracted, and studies were assessed for risk of bias using the quality assessment tools developed by the National Institute of Health. RESULTS: 78 studies (n= 5234 participants) were included and the findings were categorized in markers identified to assess peripheral and central manifestations of HACS. The identified markers for peripheral manifestations of HACS, with at least moderate evidence, were pain after-sensation decline rates, mechanical pain thresholds, pressure pain threshold, sound 'pressure' pain threshold, cutaneous silent period, slowly repeated evoked pain sensitization and nociceptive flexion reflex threshold. The identified markers for central manifestations of HACS were efficacy of conditioned pain modulation with pressure pain conditioning and brain perfusion analysis. Instruments to assess these markers are: pin-prick stimulators, cuff-algometry, repetitive pressure stimulation using a pressure algometer, sound, electrodes and neuroimaging techniques. CONCLUSIONS: This review provides an overview of non-invasive markers and instruments for the assessment of HACS in patients with FM. Implementing these findings into clinical settings may help to identify HACS in patients with FM.

The effect of preferred music versus disliked music on pain thresholds in healthy volunteers. An observational study.

Pain is a prevalent and debilitating healthcare problem. Since pharmacological treatments have numerous side-effects, additional treatment could be beneficial. Music has been shown to affect the pain perception and the pain threshold. The objective of this observational study was to evaluate the effect of preferred music as opposed to disliked music on pain (tolerance) thresholds and perceived pain intensity in healthy volunteers. Pain thresholds were measured via quantitative sensory testing. The volunteers were randomly assigned to either handheld pressure algometry to assess the pressure pain threshold to or electrical measurements to assess the electrical pain tolerance threshold while listening to preferred and disliked music. The pain thresholds were administered on the dorsal side of the forearm. The perceived pain intensity was assessed via a numerical rating scale, ranging from 0 (no pain) to 10 (worst pain imaginable). In total 415 volunteers were included in this study. The pressure pain threshold was assessed in 277 volunteers and in the electrical pain tolerance threshold test 138 volunteers were entered. In both groups, preferred music yielded higher pain thresholds than disliked music (P<0.001) and lower perceived pain intensity during the stimulus (P = 0.003). Moreover, the highest pain thresholds of both pressure pain and electrical pain tolerance thresholds were obtained when the preferred music was preceded by disliked music. Listening to preferred music when receiving noxious stimuli leads to higher pain thresholds and lower perceived pain scores in comparison with disliked music. Preferred music could be beneficial for patients with pain or undergoing painful procedures.

Human assumed central sensitisation (HACS) in patients with chronic low back pain radiating to the leg (CLaSSICO study).

INTRODUCTION: Patients with chronic low back pain radiating to the leg (CLBPr) are sometimes referred to a specialised pain clinic for a precise diagnosis based, for example, on a diagnostic selective nerve root block. Possible interventions are therapeutic selective nerve root block or pulsed radiofrequency. Central pain sensitisation is not directly assessable in humans and therefore the term 'human assumed central sensitisation' (HACS) is proposed. The possible existence and degree of sensitisation associated with pain mechanisms assumed present in the human central nervous system, its role in the chronification of pain and its interaction with diagnostic and therapeutic interventions are largely unknown in patients with CLBPr. The aim of quantitative sensory testing (QST) is to estimate quantitatively the presence of HACS and accumulating evidence suggest that a subset of patients with CLBPr have facilitated responses to a range of QST tests.The aims of this study are to identify HACS in patients with CLBPr, to determine associations with the effect of selective nerve root blocks and compare outcomes of HACS in patients to healthy volunteers. METHODS AND ANALYSIS: A prospective observational study including 50 patients with CLBPr. Measurements are performed before diagnostic and therapeutic nerve root block interventions and at 4 weeks follow-up. Data from patients will be compared with those of 50 sex-matched and age-matched healthy volunteers. The primary study parameters are the outcomes of QST and the Central Sensitisation Inventory. Statistical analyses to be performed will be analysis of variance. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee of the University Medical Center Groningen, Groningen, the Netherlands, approved this study (dossier NL60439.042.17). The results will be disseminated via publications in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NTR NL6765.

Changes in quantitative sensory testing and patient perspectives following spinal cord stimulation for persistent spinal pain syndrome: An observational study with long-term follow-up.

BACKGROUND: Spinal cord stimulation (SCS) can impact sensory, pain and tolerance thresholds in various ways, which can be accessed via quantitative sensory testing (QST). The objectives of this study were to (1) assess the subjective sensory responses using QST in patients following SCS therapy for PSPS and (2) to get a clinical impression of the results of SCS during an interview of these patients with PSPS and SCS during long term follow-up. METHODS: Forty patients with PSPS who received SCS treatment underwent QST via electrical and mechanical pressure stimuli. QST was performed at four different moments (1) pre-implantation SCS, (2) two weeks postoperatively, (3) three months after permanent SCS implantation and (4) six months after permanent SCS implantation. Patients' perspectives on pain, use of drugs and quality of life were assessed via semi-structured interviews during a follow-up between 5 and 11 years. RESULTS: We found statistical significant differences in the changes of sensory, pain and tolerance thresholds. A decrease in pain complaints and analgesics use were reported by the patients during follow-up. The quality of life in patients increased from three to eight (NRS 0 [worst QoL imaginable] -10 [best QoL imaginable]) after receiving SCS. CONCLUSIONS: The increased thresholds on areas without pain or being covered by the SCS induced paresthesias may indicate that there are central changes contributing to these deviations in thresholds. The overall QoL in patients improved greatly after receiving SCS. SIGNIFICANCE: This study provides an overview of the effect of SCS on sensory, pain and tolerance thresholds in patients with PSPS throughout the SCS treatment process. In addition, this study presents data from 40 patients with PSPS treated with SCS, analysing several long-term patient-reported outcome measures. The results serve to give more insight into the mechanism of SCS and document SCS as a possible treatment for PSPS.

Reply to Jensen, O.K. On the Use of Quantitative Sensory Testing to Estimate Central Sensitization in Humans. Comment on "Schuttert et al. The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review. J. Clin. Med. 2021, 10, 5931".

We thank Dr. Jensen for his interest [...].

Effects of opioid rotation to buprenorphine/naloxone on pain, pain thresholds, pain tolerance, and quality of life in patients with chronic pain and opioid use disorder.

ABSTRACT: Long-term opioid use in patients with chronic noncancer pain (CNCP) can lead to opioid use disorder (OUD) and has been associated with hyperalgesia and reduced quality of life (QoL). Studies suggest antihyperalgesic properties of buprenorphine, and buprenorphine or naloxone (BuNa) has shown beneficial effects on QoL in patients with OUD without CNCP. This study investigated the added value of BuNa in patients with CNCP with OUD on self-reported pain, pain thresholds, pain tolerance, and QoL. In the current study, 43 outpatients with CNCP and OUD were included for inpatient conversion from full µ-receptor agonist opioids to BuNa. Self-reported pain, pain thresholds, pain tolerance, and QoL were determined at baseline and after 2 months of follow-up, using, respectively, a Visual Analogue Scale (VAS-pain and VAS-QoL), quantitative sensory testing, and EuroQol-5 dimensions. In total, 37 participants completed the protocol, and their data were analyzed. The mean VAS-pain score decreased from 51.3 to 37.2 (27.5%, F = 3.3; P = 0.044), whereas the pressure pain threshold and electric pain threshold or tolerance increased after substitution (F = 7.8; P = 0.005 and F = 44.5; P < 0.001, respectively), as well as QoL (EuroQol-5 dimensions questionnaire: F = 10.4; P = 0.003 and VAS-QoL: F = 4.4; P = 0.043). We found that conversion of full µ-receptor agonists to BuNa, in patients with CNCP with OUD, was accompanied with lower self-reported pain, higher pain thresholds, higher pain tolerance, and improved QoL. Despite several study limitations, these data suggest that BuNa might be of value in patients with CNCP with OUD. Future studies should investigate long-term effects of BuNa in randomized trials.

Buprenorphine/naloxone versus methadone opioid rotation in patients with prescription opioid use disorder and chronic pain: study protocol for a randomized controlled trial.

BACKGROUND: Opioids are effective in pain-management, but long-term opioid users can develop prescription opioid use disorder (OUD). One treatment strategy in patients with OUD is rotating from a short-acting opioid to a long-acting opioid (buprenorphine/naloxone (BuNa) or methadone). Both BuNa and methadone have been shown to be effective strategies in patients with OUD reducing opioid misuse, however data on head-to-head comparison in patients with chronic non-malignant pain and prescription OUD are limited. METHODS: This two-armed open-label, randomized controlled trial aims to compare effectiveness between BuNa and methadone in patients with chronic non-malignant with prescription OUD (n = 100). Participants receive inpatient rotation to either BuNa or methadone with a flexible dosing regimen. The primary outcome is opioid misuse 2 months after rotation. Secondary outcomes include treatment compliance, side effects, analgesia, opioid craving, quality of life, mood symptoms, cognitive and physical functioning over 2- and 6 months follow-up. Linear mixed model analysis will be used to evaluate change in outcome parameters over time between the treatment arms. DISCUSSION: This is one of the first studies comparing buprenorphine/naloxone and methadone for treating prescription OUD in a broad patient group with chronic non-malignant pain. Results may guide future treatment for patients with chronic pain and prescription OUD. Trial registration https://www.trialregister.nl/ , NL9781.

Music and low-frequency vibrations for the treatment of chronic musculoskeletal pain in elderly: A pilot study.

BACKGROUND: Transcutaneous vagal nerve stimulation has analgesic potential and might be elicited by abdominally administered low-frequency vibrations. The objective was to study the safety and effect of a combination of music and abdominally administered low-frequency vibrations on pain intensity in elderly patients with chronic musculoskeletal pain. METHODS: This trial was an international multicenter, randomized controlled pilot study. Patients at age ≥ 65 years with musculoskeletal pain for ≥ 3 months and a daily pain score ≥ 4 out of 10 were recruited at three centers. They were randomized to receive either a combination of music and low-frequency (20-100 Hz) vibrations administered to the abdomen, or a combination with the same music but with higher frequency (200-300 Hz) vibrations administered to the abdomen. Low-frequency vibrations were expected to result in pain reduction measured with a numeric pain rating scale (NRS). Patients in both groups received eight treatments of the music combined with the vibrations in three weeks. Primary outcomes were safety (Serious Adverse Events) and pain intensity measured at baseline, after the last treatment and at six weeks follow-up. Multilevel linear model analyses were performed to study group and time effects. RESULTS: A total of 45 patients were analyzed according to intention-to-treat principle. After 344 treatments, 1 Adverse Event was found related to the intervention, while 13 Adverse Events were possibly related. A multilevel linear model showed that the interaction effect of group by time did not predict pain intensity (F[1, 45.93] = 0.002, p = 0.97) when comparing pain intensity at baseline, after the last treatment and at follow-up. CONCLUSIONS: The combination of music and abdominally administered vibrations was found to be safe and well tolerated by the elderly patients. However, over time, neither the low-frequency treatment group nor the high-frequency treatment group provided clinically meaningful pain relief. There is no evidence that the low-frequency treatment elicited vagal nerve stimulation. TRIAL REGISTRATION: The trial was prospectively registered in the Netherlands Trial Register (NTR: NL7606) on 21-03-2019.

The Definition, Assessment, and Prevalence of (Human Assumed) Central Sensitisation in Patients with Chronic Low Back Pain: A Systematic Review.

Central sensitisation is assumed to be one of the underlying mechanisms for chronic low back pain. Because central sensitisation is not directly assessable in humans, the term 'human assumed central sensitisation' (HACS) is suggested. The objectives were to investigate what definitions for HACS have been used, to evaluate the methods to assess HACS, to assess the validity of those methods, and to estimate the prevalence of HACS. Database search resulted in 34 included studies. Forty different definition references were used to define HACS. This review uncovered twenty quantitative methods to assess HACS, including four questionnaires and sixteen quantitative sensory testing measures. The prevalence of HACS in patients with chronic low back pain was estimated in three studies. The current systematic review highlights that multiple definitions, assessment methods, and prevalence estimates are stated in the literature regarding HACS in patients with chronic low back pain. Most of the assessment methods of HACS are not validated but have been tested for reliability and repeatability. Given the lack of a gold standard to assess HACS, an initial grading system is proposed to standardize clinical and research assessments of HACS in patients with a chronic low back.