Nociceptive Flexion Reflex Threshold Research Articles

Nociceptive Flexion Reflex Threshold is No Suitable Marker for Diagnosing Opioid-Induced Hyperalgesia.

Opioid induced hyperalgesia (OIH) describes a state of altered pain sensation due to opioid exposure. It often occurs among persons with opioid use disorder receiving substitution therapy. The purpose of this study was to find out, whether OIH diagnosis could be facilitated by an objective pain indicating marker: the Nociceptive Flexion Reflex (NFR). Forty persons with opioid use disorder, 20 of them maintained on methadone and 20 treated with buprenorphine, as well as a control group of 20 opioid-free subjects, were examined. It was aimed to find out whether and in which way these opioid agonists alter reflex threshold (NFR-T). A cold-pressor test was performed to investigate the prevalence of OIH. Furthermore, electrical stimulation and electromyography analyzation were used for NFR-T measurement. Subjective pain ratings were evaluated with a numeric rating scale. Significantly increased sensitivity to cold pressor pain was found in both maintenance groups when compared to their opioid-free counterparts (p < 0.001). Neither methadone nor buprenorphine showed any effect on NFR-T. This might be explained by the reflex approaching at the wrong location in the central nervous system. Consequently, NFR-T is not a suitable marker for diagnosing OIH. Although methadone and buprenorphine have been proven to cause OIH, no effect on NFR-T was observed. A statistically significant effect could have been observed with a larger number of participants. Further research, with special focus on patients' adjuvant medication, should be conducted in the future, to facilitate diagnosis of OIH and provide appropriate pain management for maintenance patients.

The variability in nociceptive flexion reflex threshold measurement is mostly caused by probabilistic effects of the estimation algorithms: a simulation study

Objectives The nociceptive flexion reflex (NFR) and its threshold are frequently used to investigate spinal nociception in humans. Since this threshold (NFRT) is a probabilistic measure, specific algorithms are used for NFRT estimation based on the stochastic occurrence of reflexes at different stimulus intensities. We used a validated simulation model of the NFR to investigate the amount of NFRT measurement variability induced by different estimation algorithms in a steady setting of reduced external influences. Methods We simulated the behavior of different estimation algorithms in subjects with an artificially steady baseline NFRT variability (standard deviation: 0 mA) or low baseline NFRT variability (standard deviation: 0.156 mA), equaling a quiet experimental setting. The obtained data were analyzed for NFRT measurement variability caused by the algorithms compared to the baseline variability reflecting other physiological influences. Results The standard deviation of the NFRT estimated by the different algorithms ranged between 0.381 and 3.464 mA with 96.8% to 99.6% of the measurement variability attributed to the algorithm used. Out of the investigated algorithms the dynamic staircase algorithm was most precise. Conclusion The NFRT measurement variability observed during quiet and steady experimental sessions is mostly caused by the properties of the estimation algorithms, due to the probabilistic nature of the reflex occurrence. Our results give reference for choosing the optimal estimation algorithm to improve measurement precision.

Short‑term effects of pregabalin plus exercise therapy on pain, emotional status, physical function and nociceptive responses in patients with fibromyalgia.

The aim of the present study was to investigate the effects of pregabalin plus exercise vs. pregabalin treatment alone on the electromyographic nociceptive flexion reflex (NFR) threshold in patients with fibromyalgia (FM). For this purpose, the present study included a total of 40 patients diagnosed with FM according to the American College of Rheumatology 2010 criteria. The patients were divided into two groups as follows: Group 1 received pregabalin treatment only and group 2 received exercise therapy in addition to pregabalin treatment. Assessments were made at baseline and at the 1st month using a visual analog scale (VAS) to measure pain, the Fibromyalgia Impact Questionnaire (FIQ) to measure the severity of FM, Beck's Depression Inventory (BDI) to measure depression and the NFR to measure the compressive forces on peripheral nerves. In both groups, the NFR threshold following treatment was significantly higher than that at the baseline results (P#x003C;0.001). There was no significant difference between the groups as regards the difference from pre- to post-treatment NFR threshold values (P=0.610 and P=0.555, respectively). There was a strong, negative correlation between the pre-treatment NFR threshold and VAS resting, VAS motion and FIQ scores (Rho=-0.62, Rho=-0.69 and Rho=-0.60, respectively). There was a moderate negative correlation between the pre-treatment NFR threshold and BDI scores (Rho=-0.35). On the whole, the present study demonstrates that in the treatment of FM, pregabalin improves the clinical scores and leads to an increase in the NFR threshold. Herewith, it should be noted that short-term exercise therapy does not appear to provide additional benefits.

High intensity-transcutaneous electrical nerve stimulation does not inhibit temporal summation of the nociceptive flexion reflex

Pain facilitation contributes to chronic pain conditions. Transcutaneous electrical nerve stimulation (TENS) is used to alleviate pain. The effects of conventional TENS on chronic pain have been limited, and its effects on pain facilitation are controversial. Because the analgesic effects of TENS depend on the setting parameters (e.g., pulse intensities or treatment time), the optimal TENS settings to maximize analgesic effects under various pain conditions have been investigated. High-intensity TENS (HI-TENS), which involves tolerable-level pulse intensities for a short duration, is another conventional TENS method that used to alleviate pain. However, the effects of HI-TENS on pain facilitation remain unclear. The temporal summation of pain is widely used to evaluate pain facilitation, and the temporal summation-nociceptive flexion reflex (TS-NFR) is a neuropsychological parameter that can be used to evaluate pain facilitation. We aimed to investigate the effects of HI-TENS on the TS-NFR in healthy participants. Participants were randomly allocated into HI-TENS (n = 15) and control groups (n = 16). HI-TENS was administered at the left lateral lower leg for 1 min. The TS-NFR elicited by three noxious stimuluses at the left sural nerve was obtained from electromyography of the left biceps femoris. The nociceptive flexion reflex (NFR) was obtained by a single noxious stimulus. We measured the thresholds of the NFR and the TS-NFR at baseline and post-intervention. The application of HI-TENS significantly increased the NFR threshold (p = 0.013) but not the TS-NFR threshold (p > 0.05). These results suggest that HI-TENS does not inhibit pain facilitation.

Changes of the nociceptive flexion reflex threshold in patients undergoing cardiac surgery-a prospective clinical pilot study.

Opioid dosage for general anaesthesia and sedation relies on surrogate parameters such as heartrate and blood pressure. This implies the risk of both under- and overdosing. A promising tool to provide target-oriented opioid dosing is measuring the nociceptive flexion reflex threshold (NFRT). The aim of this study was to investigate the individual trajectories and to determine this methods' clinical practicability in the perioperative setting of cardiac surgery. NFRT was measured preoperatively (twice as baseline), immediately after surgery and later in the general ward (primary outcomes). No intraoperative measurements were performed since neuromuscular blockade hinders NFRT assessment. Administered analgesics and pain scores were also recorded (secondary outcomes). Data were collected from August 2019 to March 2020. 264 patients scheduled for cardiac surgery were screened for eligibility. 55 patients were included, 30 rendered datasets for analysis. Thresholds after conclusion of surgery [TICU: median (IQR), 31.1mA (21.5-50.0mA)] were significantly higher than preoperatively [Tpre: 9.2mA (5.4-13.4mA); P < 0.001]. In 11 patients (36.7%), no immediate postoperative reflex response was elicited. Later, all reflexes returned, but thresholds remained significantly higher than preoperatively [Tpost: 11.9mA (9.2-16.6mA); P = 0.043]. NFRT values after surgery were higher compared to baseline measurements. Subsequently they decreased but did not reach their baseline levels. There was no corresponding dose-dependency, suggesting multimodal effects on the nociceptive system. Unless measurements are not prevented by technical issues NFRT-assessment appears to be a future tool to target analgesics in patients not able to self-report pain. Trial registration Study registration: DRKS00021617. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021617 (registered retrospectively).

Objective evidence for chronic back pain relief by Medical Yoga therapy.

Chronic low back pain (CLBP) is a musculoskeletal ailment that affects millions globally. The pain is disturbing associated with impaired motor activity, reduced flexibility, decreased productivity and strained interpersonal relationships leading to poor quality of life. Inflammatory mediators in vicinity of nociceptors and amplification of neural signals cause peripheral and central sensitization presented as hyperalgesia and/or allodynia. It could be attributed to either diminished descending pain inhibition or exaggerated ascending pain facilitation. Objective measurement of pain is crucial for diagnosis and management. Nociceptive flexion reflex is a reliable and objective tool for measurement of a subject's pain experience. Medical Yoga Therapy (MYT) has proven to relieve chronic pain, but objective evidence-based assessment of its effects is still lacking. We objectively assessed effect of MYT on pain and quality of life in CLBP patients. We recorded VAS (Visual analogue scale), McGill Pain questionnaire and WHOQOL BREF questionnaire scores, NFR response and Diffuse noxious inhibitory control tests. Medical yoga therapy consisted of an 8-week program (4 weeks supervised and 4 weeks at home practice). CLBP patients (42.5 ± 12.6 years) were randomly allocated to MYT (n = 58) and SCT groups (n = 50), and comparisons between the groups and within the groups were done at baseline and at end of 4 and 8 weeks of both interventions. (VAS) scores for patients in both the groups were comparable at baseline, subjective pain rating decreased significantly more after MYT compared to SCT (p = < 0.0001*, p = 0.005*). McGill Pain questionnaire scores revealed significant reduction in pain experience in MYT group compared to SCT. Nociceptive Flexion Reflex threshold increased significantly in MYT group at end of 4 weeks and 8 weeks, p < 0.0001#, p = < 0.0001∞ respectively) whereas for SCT we did not find any significant change in NFR thresholds. DNIC assessed by CPT also showed significant improvement in descending pain modulation after MYT compared to SCT both at end of 4 and 8 weeks. Quality of life also improved significantly more after MYT. Thus, we conclude with objective evidence that Medical Yoga Therapy relieves chronic low back pain, stress and improves quality of life better than standard care.

Uncovering a Genetic Polymorphism Located in Huntingtin Associated Protein 1 in Modulation of Central Pain Sensitization Signaling Pathways.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to nociceptive stimulus or tenderness. While familial aggregation could suggest a potential hereditary component in FMS development, isolation of genetic determinants has proven difficult due to the multi-factorial nature and complexity of the syndrome. Central sensitization is thought to be one of the key mechanisms leading to FMS in a subset of patients. Enhanced central pain signaling can be measured using the Nociceptive Flexion Reflex (NFR) or RIII threshold. We performed a genome-wide association study (GWAS) using an array to genotype 258,756 human genetic polymorphisms in 225 FMS patients and 77 healthy volunteers and searched for genetic variants associated with a lowered NFR threshold. We have identified a potential association between a single nucleotide polymorphism resulting in a common non-synonymous coding mutation in the Huntingtin associated protein 1 (HAP1) gene (rs4796604, MAF = 0.5) and the NFR threshold (p = 4.78E−06). The Hap1 protein is involved in trafficking and is particularly enriched in neurons. Our results suggest a possible involvement of the neuronal trafficking protein HAP1 in modulating pain signaling pathways and thus participate in the establishment of the NFR threshold.

Measurement of the nociceptive flexion reflex threshold in critically ill patients \u2013 a randomized observational pilot study

BackgroundPain detection and treatment is a major challenge in the care of critically ill patients, rendered more complex by the need to take into consideration the risk of insufficient or excessive analgesia. The nociceptive flexion reflex threshold (NFRT) has become the established basis for measuring the level of analgesia in the perioperative context. However, it remains unclear whether NFRT measurement can be usefully applied to mechanically ventilated, analgosedated critically ill patients who are unable to communicate. Therefore, the aim of the present study was to investigate whether there is an association between the NFRT measurement and the Behavioral Pain Scale (BPS) in critically ill, analgosedated, and mechanically ventilated patients and whether the NFRT measurement can also detect potential excessive analgesia.MethodsThis prospective, observational, randomized single-center pilot study included patients admitted to the surgical Intensive Care Unit of University Hospital Ulm, Germany, all of whom were analgosedated and intubated. Major exclusion criteria were defined as the need for the administration of neuromuscular blocking agents or neurological diseases associated with peripheral nerve conduction restriction. Initial NFRT and BPS measurements were conducted within 12 h after admission. A structured pain assessment was performed at least twice daily until extubation throughout the observation period thereafter (Group A: BPS + NFRT, Group B: BPS).Results114 patients were included in the study. NFRT is associated negatively with BPS. NFRT was almost twice as high in patients with a Richmond Agitation Sedation Scale (RASS) score of -5 than in patients with a RASS score ≥ -4 (RASS -5 – NFRT: 59.40 vs. RASS -4 – NFRT: 29.00, p < 0.001).ConclusionsNFRT measurement is associated negatively with the BPS in critically ill patients. NFRT measurement provides guidance for the evaluation of nociceptive processes in patients with RASS scores ≤ −4, in whom analgesia level is often difficult to assess. However, in order to identify excessive analgesia and derive therapeutic consequences, it is necessary to gradually decrease analgesics and sedatives until a stimulus threshold is reached at which the patient does not feel pain.Trial RegistrationRetrospectively registered in the German Clinical Trials Register, registration number DRKS00021149, date of registration: March 26, 2020. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021149.

Fibromyalgia and Nociceptive Flexion Reflex (NFR) Threshold: A Systematic Review, Meta-Analysis, and Identification of a Possible Source of Heterogeneity.

BackgroundThe nociceptive flexion reflex is a physiological, polysynaptic reflex and refers to the level that an appropriate withdrawal response activates when a painful stimulus is detected. The nociceptive flexion reflex threshold (NFRthr) is defined as the lowest noxious stimulation intensity required to trigger a reflex motor response. Despite wide utilization and reports of the NFRthr, there has been no consensus on a standard and/or best method in assessment of the NFRthr.ObjectiveTo systematically review the literature that compared the NFRthr between individuals with fibromyalgia (FM) and healthy controls; and to identify a source of heterogeneity in these trials.MethodsEmploying the Cochrane methodology, we systematically searched Ovid MEDLINE, Embase, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and PsycINFO for clinical case-controlled trials assessing the NFRthr in individuals with and without fibromyalgia from inception to July 2019. Selected articles were passed for data extraction and meta-analyses. We utilized the random-effects model for meta-analysis assuming the true effect size may vary between studies. The sample sizes as a possible source of heterogeneity in multiple meta-regressions were investigated. This systematic review and meta-analysis were registered in PROSPERO before data extraction.ResultsNine studies met our criteria and were included in the meta-analysis. Methodologies and settings varied between studies, eg, stimulation intensity, duration, and the current increments. Only two articles comprehensively described and reported details about electromyogram amplification, latency, and sampling rate. Evidence from 423 patients with fibromyalgia and 326 healthy individuals suggested that there may not be a meaningful decreased NFRthr in patients (overall mean difference = –3.16; 95% CI:–6.82 to 0.50; Z = 1.69; P=0.09). Published effect sizes were not homogenous (I2 = 0.91, τ2 = 25.04, χ2 = 91.22, df = 8, P < 0.00001). The multiple meta-regression analyses indicated that total and female sample sizes might be the main sources of heterogeneity for the effect sizes SStotal = –0.0570, P = 0.040; SSfemale = –0.0569; P = 0.047.ConclusionEvidence suggests that the nociceptive flexion reflex threshold may not be different between patients with fibromyalgia and healthy controls. A unified and rigorous methodology and sample size calculation (probably sex specific investigation) is required for the assessment of nociceptive flexion reflex threshold in patients with fibromyalgia.

Prediction of Nociception in Children Using the Nociceptive Flexion Reflex Threshold and the Bispectral Index-A Prospective Exploratory Observational Study.

The prediction of patient responses to potentially painful stimuli remains a challenge in PICUs. We investigated the ability of the paintracker analgesia monitor (Dolosys GmbH, Berlin, Germany) measuring the nociceptive flexion reflex threshold, the cerebral sedation monitor bispectral index (Medtronic, Dublin, Ireland), the COMFORT Behavior, and the modified Face, Legs, Activity, Cry, Consolability Scale scores to predict patient responses following a noxious stimulus. Single-center prospective exploratory observational study. Fourteen-bed multidisciplinary PICU at the University Children's Hospital, University Medical Center Hamburg Eppendorf, Germany. Children on mechanical ventilation receiving analgesic and sedative medications. Noxious stimulation by way of endotracheal suctioning. Two independent observers assessed modified Face, Legs, Activity, Cry, Consolability and COMFORT Behavior Scales scores during noxious stimulation (n = 59) in 26 patients. Vital signs were recorded immediately before and during noxious stimulation; bispectral index and nociceptive flexion reflex threshold were recorded continuously. Mean prestimulation bispectral index (55.5; CI, 44.2-66.9 vs 39.9; CI, 33.1-46.8; p = 0.007), and COMFORT Behavior values (9.5; CI, 9.2-13.2 vs 7.5; CI, 6.7-8.5; p = 0.023) were significantly higher in observations with a response than in those without a response. Prediction probability (Pk) values for patient responses were high when the bispectral index was used (Pk = 0.85) but only fair when the nociceptive flexion reflex threshold (Pk = 0.69) or COMFORT Behavior Scale score (Pk = 0.73) was used. A logistic mixed-effects model confirmed the bispectral index as a significant potential predictor of patient response (p = 0.007). In our sample of ventilated children in the PICU, bispectral index and nociceptive flexion reflex threshold provided good and fair prediction accuracy for patient responses to endotracheal suctioning.

The influence of physical activity on the nociceptive flexion reflex in healthy people.

The nociceptive flexion reflex (NFR) is a spinal reflex induced by painful stimuli resulting in an appropriate withdrawal response. The NFR is considered to be an objective physiological correlate of spinal nociception. Previous research has already demonstrated that physical activity (PA) can influence pain assessments. To date, no studies have directly examined the relationship between PA and spinal nociception. Hence, this study aimed to investigate whether the NFR threshold can be predicted by report-based and monitor-based measures of PA in healthy adults. PA and the NFR threshold of 58 healthy adults were assessed. PA was evaluated by self-report using the International Physical Activity Questionnaire and by monitor-based accelerometry data. The NFR threshold was elicited through transcutaneous electrical stimulation of the sural nerve and quantified by the biceps femoris muscle electromyogram. Hierarchical linear regression analyses were performed to determine the relationship between PA and the NFR, while controlling for confounders. Monitor-based measured step count and activities of moderate- to vigorous-intensity predicted the NFR threshold accounting for 23.0% (p=.047) to 37.1% (p=.002) of the variance. Larger amounts of step counts and higher participation in moderate- to vigorous-intensity activities predicted higher NFR thresholds. Monitor-based activities of sedentary intensity predicted the NFR threshold accounting for 35.8% (p=.014) to 35.9% (p=.014) of the variance. Spending more time per day on activities of sedentary intensity predicted lower NFR thresholds. The study provides preliminary evidence indicating that a physically active lifestyle may reduce spinal nociception in healthy adults, while a sedentary lifestyle enhances spinal nociception. The present study provides preliminary evidence that the influencing effects of physical activity on pain are the result of a strong descending control and do not purely rely on supraspinal mechanisms. These study results highlight the importance of considering physical activity levels when evaluating nociceptive processing, given the prognostic value of physical activity in spinal nociception. Furthermore, this study encourages future research to examine the effects of moderate- to vigorous-intensity exercise programmes on spinal nociception in chronic pain populations.

Nociceptive Flexion Reflex Threshold in Chronic Pain Patients: A Needed Update for the Current Evidence.

The nociceptive flexion reflex is a physiological, polysynaptic reflex triggered by a nociceptive stimulus activating a withdrawal response. In chronic musculoskeletal-related pain conditions, a decreased nociceptive flexion reflex threshold has been suggested as a possible recognition evidence for central sensitization that may cause alteration of central nervous system processing. The aim of the study was to systematically review reported comparisons of the nociceptive flexion reflex threshold in chronic pain patients and healthy individuals. Electronic databases covering studies published between January 1990 and December 2019 were systematically searched. After application of exclusion criteria, 20 studies including 28 trials were included in this review. For meta-analysis, we used a random-effects model and funnel plot for publication bias. This research was registered at PROSPERO (CRD42019140354). Compared with healthy controls, standardized mean differences in nociceptive flexion reflex threshold were significantly lower in the total sample of chronic pain patients. Subgroup analysis indicated a homogenous decreased nociceptive flexion reflex threshold in studies reporting fibromyalgia, chronic pain, and joint pain while heterogeneity existed in other included pain conditions. A lower nociceptive flexion reflex threshold in patients experiencing chronic pain conditions may imply hyperexcitability in central nervous system processing. As a preliminary study, the findings would act as a basis for developing a methodology assisting current clinical practices.

The nociceptive flexion reflex: a scoping review and proposed standardized methodology for acquisition in those affected by chronic pain.

The nociceptive flexion reflex (NFR) is used in neurophysiological research as an objective measure of nociception. NFR thresholds are reduced in numerous chronic pain pathologies, which are indicative of common central hyperexcitability within conditions. However, variation exists in both the NFR assessment and determinants of NFR threshold among research groups. Our purpose was to provide a review of the recent literature to (a) confirm the NFR threshold's efficacy in identifying those with chronic pain compared to controls and (b) provide a narrative synthesis on the current methodology used to assess the NFR in clinical populations. We conducted a review of multiple databases (MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar and Cochrane Library), including articles that reported controlled clinical studies of humans, in English, comparing NFR thresholds within chronic pain conditions to matched control subjects, published since the last NFR review in 2010. Our search resulted in nine studies included in our narrative synthesis and eight studies included in a meta-analysis. There was a significant pooled standardized mean difference in NFR threshold between chronic pain conditions and controls (-0.94, 95% confidence interval (CI) -1.33 to -0.55, p < 0.0001), with substantial heterogeneity of pooled estimates (I 2 = 87%, τ 2 = 0.41, Q = 76.13, the degrees of freedom (df) = 11, p < 0.0001). Significant variations in participant positioning, stimulation parameters and determinants of the NFR threshold were evident among included studies. We provided a narrative synthesis on the methodologies of included studies, as a recommendation for future studies in the assessment of the NFR in chronic pain.

A Possible Source of Heterogeneity in Nociceptive Flexion Reflex (NFR) Threshold Among Patients with Fibromyalgia: Systematic Review and Meta-Analysis

Objectives: We aimed to investigate the possibility of sample size as a possible source of heterogeneity in trials comparing the nociceptive flexion reflex threshold (NFRthr) in fibromyalgia (FM) patients and healthy controls. Methods: A systematic search strategy was designed and conducted in electronic databases such as Ovid MEDLINE, Cochrane Libraries, Embase, and PsycINFO. In total, nine scholarly records were filtered by the inclusion and exclusion criteria, passed for data extraction (e.g. study designs and settings; methodology; total, male, and female sample sizes in FM and healthy control groups, and effect sizes), and statistical analyses (e.g. metaanalysis and meta-regression). Using random-effects model, the effect size (i.e. mean difference between the NFRthr in FM patients and healthy controls) was meta-analyzed. Investigating the sample size as a possible source of heterogeneity and utilizing a restricted maximum likelihood (REML) technique, the trials’ effect sizes were meta-regressed in multiple meta-regression against the total, male, and female sample sizes. Prior to any investigations, the aims of this research were registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019140354). Results: Results indicated the deficit in NFRthr (overall mean difference = −3.16; 95% 𝐶𝐼: −6.82 𝑡𝑜 0.50) was heterogenous (𝐼 2 = 0.91, 𝜏 2 = 25.04, 𝜒2= 91.22, df & < 0.00001) and the overall effect was not statistically significant (Z = 1.69; 𝑃 = 0.09). The multiple meta-regression analyses indicated that one of the main sources of bias to the effect size in the trials was found to be the total (𝑆𝑆𝑡𝑜𝑡𝑎𝑙 = −0.0570; 𝑃 = 0.040) and female (𝑆𝑆𝑓𝑒𝑚𝑎𝑙𝑒 = −0.0569; 𝑃 = 0.047) sample sizes that participated in the studies. Conclusion: The findings suggest that the total and female sample sizes might be possible sources of bias to effect sizes determined in NFRthr in FM patient and healthy controls. A possible solution might be to conduct sex-specific trials to determine the NFRthr among FM patients in future research. Funding Statement: Authors received no source of funding for this research. Declaration of Interests: Authors declare no conflict of interest. Ethics Approval Statement: PROSPERO; registration number: CRD42019140354

Modified Biofeedback (Conditioned Biofeedback) Promotes Antinociception by Increasing the Nociceptive Flexion Reflex Threshold and Reducing Temporal Summation of Pain: A Controlled Trial

This study examined whether a modified version of biofeedback (ie, Conditioned Biofeedback) that incorporated placebo analgesia-like manipulations could promote antinociception in healthy, pain-free participants. During Conditioned Biofeedback (n = 28), sympathetic arousal level was displayed visually and participants were asked to reduce it while they received painful electric stimulations that were surreptitiously controlled by their arousal level. Thus, electric pain decreased as arousal decreased to associate successful arousal-reduction/relaxation with pain relief, and to promote expectations for future pain relief. A Biofeedback Only group (n = 24) controlled for the general effects of biofeedback/relaxation. A Biofeedback+Shock group (n = 21) controlled for the effects of practicing biofeedback during painful shocks. Nociceptive flexion reflex (NFR) threshold and temporal summation of pain (TS-pain) were used to assess changes in spinal nociception and pain facilitation, respectively. Results indicated all groups showed pre- to postbiofeedback increases in NFR threshold, but only the Conditioned Biofeedback group showed pre- to postbiofeedback reductions in TS-pain. Moreover, Conditioned Biofeedback resulted in a persistent (prebiofeedback) increase in NFR threshold across sessions, whereas Biofeedback Only resulted in a persistent (prebiofeedback) decrease in TS-pain. In sum, Conditioned Biofeedback may promote antinociception in healthy participants thus reducing risk for chronic pain. The study was registered prospectively on ClinicalTrials.gov (TU1560). PerspectiveA modified version of biofeedback that employs placebo analgesia manipulations was successful in increasing descending inhibition and reducing pain facilitation in healthy volunteers. As a result, it may be an effective means of reducing risk of future chronic pain onset by promoting an antinociceptive pain profile.

Can aberrant spinal nociception be a marker of chronicity of pain in fibromyalgia syndrome?

Pain sensitivity is a recognized feature of fibromyalgia syndrome (FMS) but the contribution of spinal nociceptive circuitry to this phenomenon is unknown. Therefore, the objectives were to study the changes in spinal nociception i.e. nociceptive flexion reflex (NFR) in patients with FMS and to investigate correlation if any, between NFR threshold, pain duration and tender points in FMS. One hundred and three patients with FMS and 74 healthy volunteers participated in the study. To record NFR, sural nerve was stimulated in the retro malleolar region and the reflex response was recorded from the short head of biceps femoris muscle. NFR was elicited at significantly lower [21.0(18.0–25.0)V] thresholds in FMS group when compared to healthy subjects [30.0(24.75–35.0)V; p = 0.001] indicating hyperalgesic response to electrocutaneous stimulation in FMS patients. The latency and other parameters of NFR were comparable in both the groups. No significant correlation was found among NFR threshold and pain duration or tender points. On the basis of results of present study, it may be concluded that the functional deficit of the spinal nociceptive system can contribute to hyperalgesia in FMS. This is first study that correlates a marker of central hyper-excitability (NFR threshold) with clinical symptoms (pain duration and tender points) of FMS.

(101) Using Quantitative Sensory Testing to Assess the Pain System in Sexual Assault Survivors

Trauma exposure, especially sexual assault (SA), is highly correlated with pain conditions, in that many chronic pain samples report trauma histories. However, our understanding of the mechanisms behind this relationship is limited. Previous findings from our lab suggest that SA disrupts descending pain modulation. However, to date, no study has used quantitative sensory testing (QST) to comprehensively assess the pain system in SA survivors. 41 healthy, pain-free SA survivors were matched to a group of 41 healthy, pain-free trauma exposed persons without SA (TE). These groups were compared to a group of healthy, pain-free persons with no trauma history (no-TE; N=62). QST included warm, cool, heat, cold, ischemia, and electric thresholds, and heat, cold, ischemia, and electric tolerances. The nociceptive flexion reflex (NFR) threshold was used to assess spinal nociception. Results suggested SA survivors had higher cool thresholds than the TE and no-TE groups. Moreover, SA survivors had lower cold thresholds, cold tolerances, and heat tolerances than no-TE. Surprisingly, SA survivors had higher ischemia tolerances than no-TE and TE groups. The TE group had lower heat and cold tolerances than the no-TE group. None of the other group differences were significant for any pain outcome. These findings suggest that SA is associated with greater sensitivity in A-delta fibers (cool thresholds) and hyperalgesia in response to thermal stimuli (heat, cold). However, hypoalgesia was noted in response to deep tissue pain (ischemia). By contrast, TE is primarily associated with reduced tolerance to heat and cold. These group differences are not likely due to spinal sensitization due to the lack of group differences in NFR. Future studies are needed to replicate these findings and determine whether QST responses can predict negative sequela of SA and non-SA trauma exposure.

Repetitive transcranial magnetic stimulation in chronic tension-type headache: A pilot study.

Background & objectives:Tension-type headache (TTH) is the most common type of primary headache disorder. Its chronic form is often the most ignored and challenging to treat. Transcranial magnetic stimulation (TMS) is a novel technique in the treatment of chronic pain. The aim of this pilot study was to explore the effect of low-frequency repetitive TMS (rTMS) on pain status in chronic TTH (CTTH) by subjective and objective pain assessment.Methods:Patients (n=30) diagnosed with CTTH were randomized into rTMS (n=15) and placebo (n=15) groups in this study. Pre-intervention detailed history of patients was taken. Numerical Rating Scale (NRS) for Pain and questionnaires [Headache Impact Test-6 (HIT-6), McGill Pain Questionnaire, Pain Beliefs Questionnaire, Coping Strategies Questionnaire, State-Trait Anxiety Inventory Test, Hamilton Rating Scale for Depression and WHO-Quality of Life Questionnaire-Brief version] were filled, and objective assessments such as nociceptive flexion reflex (NFR) and conditioned pain modulation were done. The tests were repeated after 20 sessions (5 days/week). In the rTMS group, 1200 pulses in eight trains of 150 pulses each were given at 1Hz over the right dorsolateral prefrontal cortex (RDLPFC). In the placebo group, the rTMS coil was placed such that magnetic stimulation did not reach the cortex.Results:The NRS score decreased significantly (P<0.001) and NFR thresholds increased significantly (P=0.011) in the rTMS group when compared to placebo group.Interpretation & conclusions:Subjective improvements in the NRS, HIT-6, McGill Present Pain Intensity, trait of anxiety and psychological pain beliefs were observed. The increase in the thresholds of NFR served as an objective marker for improvement in pain status. Further studies need to be done to confirm our preliminary findings.

Intraoperative recording of nociceptive flexion reflex

Hemodynamic responses to noxious stimuli during general anesthesia are regarded as signs of nociception. In this sense, modifications of intraoperative administration of opiates are made on clinical bases. However, recording of nociceptive flexion reflex (NFR), has been proposed as an objective tool in order to assess nociception/antinociception balance. To test the correlation between intraoperative NFR, hemodynamics modifications and range of opiates administration in patients undergoing spinal spinal/spinal cord surgery. The NFR was intraoperatively assessed in 15 patients during TIVA/TCI (10 subjects) or alogenates (5 pts.) anesthesia for spine surgery. In order to elicits NFR, the sural nerve was stimulated at the ankle (train of 5 stimuli, ISI 4 ms, intensity up to 100 mA): responses were recorded from the ipsilateral biceps femoris. In the alogenates group NFR was abolished. NFR threshold correlated with opiates administration changes in 6/10 patients. NFR threshold seems to correlate with nociception/antinociception balance. Further studies are needed in order to test the correlation between intraoperative changes of hemodynamic parameters, the amount of intraoperative opiates administration and postoperative pain.

CHRONIC TENSION-TYPE HEADACHE: MUSCLE OVERACTIVITY VERSUS DEFICIENT PAIN CONTROLS

Objective: The oscillating school of thought between the peripheral and central mechanisms of pain origin hinders the selection of appropriate therapy for chronic tension-type headache (CTTH). The aim of this study was to assess the role of central and peripheral pain mechanisms together in CTTH.Methods: In the present study, we compared surface electromyography (sEMG) amplitudes and nociceptive flexion thresholds in patients diagnosed with CTTH (n=30) with age-matched healthy controls (n=30). For central pain modulation with spinal and supraspinal influences on nociception, we recorded nociceptive flexion reflex (NFR) by stimulating the sural nerve and observing the biceps femoris muscle response. sEMG was done for the temporalis and trapezius muscles at rest, during mental activity and during maximum voluntary contraction to assess contribution from peripheral pain.Results: We observed a decreased NFR threshold in CTTH patients as compared to healthy controls, suggesting a hyperalgesic state due to central factors. Electromyographic activity of trapezius muscle was increased at rest in CTTH while both temporalis and trapezius showed an overactivity in patients during mental task.Conclusion: Central factors are important in the pathogenesis of CTTH while, peripheral factors, such as stress-related muscle spasm may also contribute to pain state.