José Biurrun Manresa

Generalized expansion of nociceptive reflex receptive fields in chronic pain patients.

&NA; Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain‐free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25–75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38–0.54) and 0.33 (0.27–0.39), respectively (P = 0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P < 0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research.

Is the conditioned pain modulation paradigm reliable?: A test-retest assessment using the nociceptive withdrawal reflex

The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain. Trial Registration: Clinical Trials.gov NCT01636440

Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain

&NA; Acute and chronic musculoskeletal pain conditions are characterized by enlarged reflex receptive fields, lowered reflex and pain thresholds, and facilitated temporal summation. &NA; Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain‐free volunteers (P < .001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P < .001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research.

Long-term facilitation of nociceptive withdrawal reflexes following low-frequency conditioning electrical stimulation: A new model for central sensitization in humans

Central sensitization is believed to be one of the key mechanisms behind chronic pain conditions, and several models have been developed in order to characterize this phenomenon in humans. One of these models relies on conditioning electrical stimulation to elicit long‐lasting effects on the nociceptive system. The aim of this study was to evaluate these effects using an objective electrophysiological measurement, the nociceptive withdrawal reflex (NWR). Long‐term changes in spinal nociception after high‐ and low‐frequency conditioning electrical stimulation were assessed in 13 healthy volunteers. Perceptual intensity ratings to mechanical stimuli and blood flow variations were assessed in the conditioned area (dorsum of the foot) and surroundings. To evaluate the excitability of the nociceptive system, the NWR was elicited within the same innervation area (superficial peroneal nerve) at graded stimulation intensities and recorded in the hamstrings. Following low‐frequency stimulation, an intensity‐independent long‐lasting facilitation of the NWR was observed, with a significant increase in the reflex size (average of 31 ± 4%, p < 0.001) and in the number of reflexes (average increase of 22 ± 10%, p < 0.01), accompanied by a significant increase in the blood flow (average increase of 40 ± 10%, p < 0.001). These findings suggest that activity‐dependent central sensitization can be elicited using conditioning electrical stimulation with a stimulation frequency that lies within the physiological firing range of primary afferents, and that it can be objectively assessed in humans using the NWR.

Central sensitization in spinal cord injured humans assessed by reflex receptive fields

OBJECTIVE To investigate the effects of central sensitization, elicited by intramuscular injection of capsaicin, by comparing the reflex receptive fields (RRF) of spinally-intact volunteers and spinal cord injured volunteers that present presensitized spinal nociceptive mechanisms. METHODS Fifteen volunteers with complete spinal cord injury (SCI) and fourteen non-injured (NI) volunteers participated in the experiment. Repeated electrical stimulation was applied on eight sites on the foot sole to elicit the nociceptive withdrawal reflex (NWR). RRF were assessed before, 1min after and 60min after an intramuscular injection of capsaicin in the foot sole in order to induce central sensitization. RESULTS Both groups presented RRF expansion and lowered NWR thresholds immediately after capsaicin injection, reflected by the enlargement of RRF sensitivity areas and RRF probability areas. Moreover, the topography of the RRF sensitivity and probability areas were significantly different in SCI volunteers compared to NI volunteers in terms of size and shape. CONCLUSIONS SCI volunteers can develop central sensitization, despite adaptive/maladaptive changes in synaptic plasticity and lack of supraspinal control. SIGNIFICANCE Protective plastic mechanisms may still be functional in SCI volunteers.

Reliability of quantitative sensory tests in a low back pain population

Background and Objectives Reliability is an essential condition for using quantitative sensory tests (QSTs) in research and clinical practice, but information on reliability in patients with chronic pain is sparse. The aim of this study was to evaluate the reliability of different QST in patients with chronic low back pain. Methods Eighty-nine patients with chronic low back pain participated in 2 identical experimental sessions, separated by at least 7 days. The following parameters were recorded: pressure pain detection and tolerance thresholds at the toe, electrical pain thresholds to single and repeated stimulation, heat pain detection and tolerance thresholds at the arm and leg, cold pain detection threshold at the arm and leg, and conditioned pain modulation using the cold pressor test. Reliability was analyzed using the coefficient of variation, the coefficient of repeatability, and the intraclass correlation coefficient. It was judged as acceptable or not based primarily on the analysis of the coefficient of repeatability. Results The reliability of most tests was acceptable. Exceptions were cold pain detection thresholds at the leg and arm. Conclusions Most QST measurements have acceptable reliability in patients with chronic low back pain.

Introducing the reflex probability maps in the quantification of nociceptive withdrawal reflex receptive fields in humans

The aim of the present study was to improve the assessment of reflex receptive fields (RRF) in humans, using reflex sensitivity and reflex probability maps. Repeated electrical stimulation was applied to elicit the nociceptive withdrawal reflex (NWR) in fifteen healthy volunteers using two stimulation paradigms: fixed (FSI) and adjusted (ASI) stimulation intensities. Stimulation was applied on sixteen sites in the foot sole, and pain intensity ratings and EMG responses were recorded. RRF sensitivity and probability maps were derived, and RRF areas were calculated. During FSI, the stimulation intensities were constant and the pain ratings dropped significantly (p<0.01). In contrast, during ASI the pain ratings were stable, but there was a significant increase in the stimulation intensities (p<0.01). None of the paradigms altered significantly the RRF areas, but the FSI paradigm had lower estimation error (p<0.01). In all cases, the estimation error remained under 10% and 5% after five and ten repetitions, respectively. The 2nd stimulus in the train consistently rendered larger and more reliable RRF areas than the 1st stimulus. The present analysis can be useful in order to identify the most adequate stimulation parameters and quantification variables for RRF assessment in experimental and clinical pain research.

Probabilistic model for individual assessment of central hyperexcitability using the nociceptive withdrawal reflex: a biomarker for chronic low back and neck pain.

BackgroundThe nociceptive withdrawal reflex (NWR) has been proven to be a valuable tool in the objective assessment of central hyperexcitability in the nociceptive system at spinal level that is present in some chronic pain disorders, particularly chronic low back and neck pain. However, most of the studies on objective assessment of central hyperexcitability focus on population differences between patients and healthy individuals and do not provide tools for individual assessment. In this study, a prediction model was developed to objectively assess central hyperexcitability in individuals. The method is based on statistical properties of the EMG signals associated with the nociceptive withdrawal reflex. The model also supports individualized assessment of patients, including an estimation of the confidence of the predicted result.Resultsup to 80% classification rates were achieved when differentiating between healthy volunteers and chronic low back and neck pain patients. EMG signals recorded after stimulation of the anterolateral and heel regions and of the sole of the foot presented the best prediction rates.ConclusionsA prediction model was proposed and successfully tested as a new approach for objective assessment of central hyperexcitability in the nociceptive system, based on statistical properties of EMG signals recorded after eliciting the NWR. Therefore, the present statistical prediction model constitutes a first step towards potential applications in clinical practice.

Observer agreement and accuracy in the evaluation of bone scans in newly diagnosed prostate cancer

ObjectiveThe aim of the study was to assess the agreement in the interpretation of bone scintigraphy (BS) in a newly diagnosed prostate cancer. Materials and methodsA total of 635 consecutive patients had their planar whole-body BS independently reviewed by three nuclear medicine physicians and classified by two grading systems: (a) a four-category scale (1: benign; 2: equivocal; 3: most likely malignant; and 4: multiple metastases) and (b) a dichotomous scale (bone metastasis present or absent). ResultsAgreement in the same category, or with one or two categories of differences, was found in 66, 34, and 1.3% of the readings, respectively. Average &kgr;-values were 0.59, 0.72, and 0.83 for unweighted, linear, and quadratic weighted variants, respectively. Very high agreement was observed (96% of the readings) with the dichotomous scale (average &kgr;=0.87); a comparison with a final imaging diagnosis with additional CT or MRI showed a sensitivity of 83% and a specificity of 98%. BS categories 1, 3, and 4 were consistent with the final imaging diagnosis in 96–99% of cases. The prevalence of metastasis was 10% in category 2. To optimize the diagnostic characteristics, category 2 should be regarded as a separate option. ConclusionClose agreement was found among trained observers for the evaluation of BS in prostate cancer. The high level of agreement with a dichotomous scale was hampered by diagnostic misclassification. A scale with equivocal findings on planar BS is considered important to allow for additional imaging and correct staging at the bone level of BS in a population with newly diagnosed prostate cancer.

Reliability of mercury-in-silastic strain gauge plethysmography curve reading: influence of clinical clues and observer variation.

Abstract Aim. Mercury-in-silastic strain gauge pletysmography (SGP) is a well-established technique for blood flow and blood pressure measurements. The aim of this study was to examine (i) the possible influence of clinical clues, e.g. the presence of wounds and color changes during blood pressure measurements, and (ii) intra- and inter-observer variation of curve interpretation for segmental blood pressure measurements. Methods. A total of 204 patients with known or suspected peripheral arterial disease (PAD) were included in a diagnostic accuracy trial. Toe and ankle pressures were measured in both limbs, and primary observers analyzed a total of 804 pressure curve sets. The SGP curves were later reanalyzed separately by two observers blinded to clinical clues. Intra- and inter-observer agreement was quantified using Cohens kappa and reliability was quantified using intra-class correlation coefficients, coefficients of variance, and Bland-Altman analysis. Results. There was an overall agreement regarding patient diagnostic classification (PAD/not PAD) in 202/204 (99.0%) for intra-observer (κ = 0.969, p < 0.001), and 201/204 (98.5%) for inter-observer readings (κ = 0.953, p < 0.001). Reliability analysis showed excellent correlation between blinded versus non-blinded and inter-observer readings for determination of absolute segmental pressures (all intraclass correlation coefficients ≥ 0.984). The coefficient of variance for determination of absolute segmental blood pressure ranged from 2.9–3.4% for blinded/non-blinded data and from 3.8–5.0% for inter-observer data. Conclusion. This study shows a low inter-observer variation among experienced laboratory technicians for reading strain gauge curves. The low variation between blinded/non-blinded readings indicates that SGP measurements are minimally biased by clinical clues.