Michele Curatolo

Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia

&NA; Patients with chronic pain after whiplash injury and fibromyalgia patients display exaggerated pain after sensory stimulation. Because evident tissue damage is usually lacking, this exaggerated pain perception could be explained by hyperexcitability of the central nervous system. The nociceptive withdrawal reflex (a spinal reflex) may be used to study the excitability state of spinal cord neurons. We tested the hypothesis that patients with chronic whiplash pain and fibromyalgia display facilitated withdrawal reflex and therefore spinal cord hypersensitivity. Three groups were studied: whiplash (n=27), fibromyalgia (n=22) and healthy controls (n=29). Two types of transcutaneous electrical stimulation of the sural nerve were applied: single stimulus and five repeated stimuli at 2 Hz. Electromyography was recorded from the biceps femoris muscle. The main outcome measurement was the minimum current intensity eliciting a spinal reflex (reflex threshold). Reflex thresholds were significantly lower in the whiplash compared with the control group, after both single (P=0.024) and repeated (P=0.035) stimulation. The same was observed for the fibromyalgia group, after both stimulation modalities (P=0.001 and 0.046, respectively). We provide evidence for spinal cord hyperexcitability in patients with chronic pain after whiplash injury and in fibromyalgia patients. This can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain, at least in part, pain in the absence of detectable tissue damage.

The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions

From folk medicine and anecdotal reports it is known that Cannabis may reduce pain. In animal studies it has been shown that delta‐9‐tetrahydrocannabinol (THC) has antinociceptive effects or potentiates the antinociceptive effect of morphine. The aim of this study was to measure the analgesic effect of THC, morphine, and a THC‐morphine combination (THC‐morphine) in humans using experimental pain models. THC (20 mg), morphine (30 mg), THC‐morphine (20 mg THC+30 mg morphine), or placebo were given orally and as single doses. Twelve healthy volunteers were included in the randomized, placebo‐controlled, double‐blinded, crossover study. The experimental pain tests (order randomized) were heat, cold, pressure, single and repeated transcutaneous electrical stimulation. Additionally, reaction time, side‐effects (visual analog scales), and vital functions were monitored. For the pharmacokinetic profiling, blood samples were collected. THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC‐morphine. A slight additive analgesic effect could be observed for THC‐morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC‐morphine. Psychotropic and somatic side‐effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.

Reference Values of Mechanical and Thermal Pain Tests in a Pain-Free Population

Quantitative sensory tests are widely used in human research to evaluate the effect of analgesics and explore altered pain mechanisms, such as central sensitization. In order to apply these tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 pain‐free subjects. Pain detection and pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body‐mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short‐Form 36 (SF‐36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the pain measures. Women were more pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the tests for detecting abnormal pain reactions in individual patients.Quantitative sensory tests are widely used in human research to evaluate the effect of analgesics and explore altered pain mechanisms, such as central sensitization. In order to apply these tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 pain-free subjects. Pain detection and pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the pain measures. Women were more pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the tests for detecting abnormal pain reactions in individual patients.

Sonographic visualization and ultrasound-guided blockade of the greater occipital nerve: a comparison of two selective techniques confirmed by anatomical dissection.

BACKGROUNDnLocal anaesthetic blocks of the greater occipital nerve (GON) are frequently performed in different types of headache, but no selective approaches exist. Our cadaver study compares the sonographic visibility of the nerve and the accuracy and specificity of ultrasound-guided injections at two different sites.nnnMETHODSnAfter sonographic measurements in 10 embalmed cadavers, 20 ultrasound-guided injections of the GON were performed with 0.1 ml of dye at the classical site (superior nuchal line) followed by 20 at a newly described site more proximal (C2, superficial to the obliquus capitis inferior muscle). The spread of dye and coloration of nerve were evaluated by dissection.nnnRESULTSnThe median sonographic diameter of the GON was 4.2 x 1.4 mm at the classical and 4.0 x 1.8 mm at the new site. The nerves were found at a median depth of 8 and 17.5 mm, respectively. In 16 of 20 in the classical approach and 20 of 20 in the new approach, the nerve was successfully coloured with the dye. This corresponds to a block success rate of 80% (95% confidence interval: 58-93%) vs 100% (95% confidence interval: 86-100%), which is statistically significant (McNemars test, P=0.002).nnnCONCLUSIONSnOur findings confirm that the GON can be visualized using ultrasound both at the level of the superior nuchal line and C2. This newly described approach superficial to the obliquus capitis inferior muscle has a higher success rate and should allow a more precise blockade of the nerve.

Seeing and identifying with a virtual body decreases pain perception.

Pain and the conscious mind (or the self) are experienced in our body. Both are intimately linked to the subjective quality of conscious experience. Here, we used virtual reality technology and visuo-tactile conflicts in healthy subjects to test whether experimentally induced changes of bodily self-consciousness (self-location; self-identification) lead to changes in pain perception. We found that visuo-tactile stroking of a virtual body but not of a control object led to increased pressure pain thresholds and self-location. This increase was not modulated by the synchrony of stroking as predicted based on earlier work. This differed for self-identification where we found as predicted that synchrony of stroking increased self-identification with the virtual body (but not a control object), and positively correlated with an increase in pain thresholds. We discuss the functional mechanisms of self-identification, self-location, and the visual perception of human bodies with respect to pain perception.Pain and the conscious mind (or the self) are experienced in our body. Both are intimately linked to the subjective quality of conscious experience. Here, we used virtual reality technology and visuo‐tactile conflicts in healthy subjects to test whether experimentally induced changes of bodily self‐consciousness (self‐location; self‐identification) lead to changes in pain perception. We found that visuo‐tactile stroking of a virtual body but not of a control object led to increased pressure pain thresholds and self‐location. This increase was not modulated by the synchrony of stroking as predicted based on earlier work. This differed for self‐identification where we found as predicted that synchrony of stroking increased self‐identification with the virtual body (but not a control object), and positively correlated with an increase in pain thresholds. We discuss the functional mechanisms of self‐identification, self‐location, and the visual perception of human bodies with respect to pain perception.

The nociceptive withdrawal reflex: Normative values of thresholds and reflex receptive fields

Assessments of spinal nociceptive withdrawal reflexes can be used in human research both to evaluate the effect of analgesics and explore pain mechanisms related to sensitization. Before the reflex can be used as a clinical tool, normative values need to be determined in large scale studies. The aim of this study was to determine the reference values of spinal nociceptive reflexes and subjective pain thresholds (to single and repeated stimulation), and of the area of the reflex receptive fields (RRF) in 300 pain‐free volunteers. The influences of gender, age, height, weight, body‐mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short‐Form 36 (SF‐36) were analyzed by multiple regressions. The 95% confidence intervals were determined for all the tests as normative values. Age had a statistically and quantitatively significant impact on the subjective pain threshold to single stimuli. The reflex threshold to single stimulus was lower on the dominant compared to the non‐dominant side. Depression had a negative impact on the subjective pain threshold to single stimuli. All the other analyses either did not reveal statistical significance or displayed quantitatively insignificant correlations. In conclusion, normative values of parameters related to the spinal nociceptive reflex were determined. This allows their clinical application for assessing central hyperexcitability in individual patients. The parameters investigated explore different aspects of sensitization processes that are largely independent of demographic characteristics, cognitive and affective factors.

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.

Test-retest reliability of the nociceptive withdrawal reflex and electrical pain thresholds after single and repeated stimulation in patients with chronic low back pain.

Recent studies have shown that the nociceptive withdrawal reflex threshold (NWR-T) and the electrical pain threshold (EP-T) are reliable measures in pain-free populations. However, it is necessary to investigate the reliability of these measures in patients with chronic pain in order to translate these techniques from laboratory to clinic. The aims of this study were to determine the test–retest reliability of the NWR-T and EP-T after single and repeated (temporal summation) electrical stimulation in a group of patients with chronic low back pain, and to investigate the association between the NWR-T and the EP-T. To this end, 25 patients with chronic pain participated in three identical sessions, separated by 1xa0week in average, in which the NWR-T and the EP-T to single and repeated stimulation were measured. Test–retest reliability was assessed using intra-class correlation coefficient (ICC), coefficient of variation (CV), and Bland–Altman analysis. The association between the thresholds was assessed using the coefficient of determination (r2). The results showed good-to-excellent reliability for both NWR-T and EP-T in all cases, with average ICC values ranging 0.76–0.90 and average CV values ranging 12.0–17.7%. The association between thresholds was better after repeated stimulation than after single stimulation, with average r2 values of 0.83 and 0.56, respectively. In conclusion, the NWR-T and the EP-T are reliable assessment tools for assessing the sensitivity of spinal nociceptive pathways in patients with chronic pain.

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.

Radiological Anatomy of the Obturator Nerve and Its Articular Branches: Basis to Develop a Method of Radiofrequency Denervation for Hip Joint Pain

OBJECTIVEnA previous study of radiofrequency neurotomy of the articular branches of the obturator nerve for hip joint pain produced modest results. Based on an anatomical and radiological study, we sought to define a potentially more effective radiofrequency method.nnnDESIGNnTen cadavers were studied, four of them bilaterally. The obturator nerve and its articular branches were marked by wires. Their radiological relationship to the bone structures on fluoroscopy was imaged and analyzed. A magnetic resonance imaging (MRI) study was undertaken on 20 patients to determine the structures that would be encountered by the radiofrequency electrode during different possible percutaneous approaches.nnnRESULTSnThe articular branches of the obturator nerve vary in location over a wide area. The previously described method of denervating the hip joint did not take this variation into account. Moreover, it approached the nerves perpendicularly. Because optimal coagulation requires electrodes to lie parallel to the nerves, a perpendicular approach probably produced only a minimal lesion. In addition, MRI demonstrated that a perpendicular approach is likely to puncture femoral vessels. Vessel puncture can be avoided if an oblique pass is used. Such an approach minimizes the angle between the target nerves and the electrode, and increases the likelihood of the nerve being captured by the lesion made. Multiple lesions need to be made in order to accommodate the variability in location of the articular nerves.nnnCONCLUSIONSnThe method that we described has the potential to produce complete and reliable nerve coagulation. Moreover, it minimizes the risk of penetrating the great vessels. The efficacy of this approach should be tested in clinical trials.