Ole Kæseler Andersen

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.

Methods for gait event detection and analysis in ambulatory systems

After stroke, hemiparesis is a common problem resulting in very individual needs for walking assistance. Often patients suffer from foot drop, i.e. inability to lift the foot from the ground during the swing phase of walking. Functional electrical stimulation is commonly used to correct foot drop. For all supporting stimulation devices, it is vital to adequately detect the gait events, which is traditionally obtained by a foot switch placed under the heel. To investigate present methods of gait analysis and detection for use in ambulatory rehabilitation systems, we carried out a meta-analysis on research studies. We found various sensors and sensor combinations capable of analyzing gait in ambulatory settings, ranging form simple force based binary switches to complex setups involving multiple inertial sensors and advanced algorithms. However additional effort is needed to minimize donning/doffing efforts, to overcome cosmetical aspects, and to implement those systems into closed loop ambulatory devices.

Modular organization of human leg withdrawal reflexes elicited by electrical stimulation of the foot sole

Human withdrawal reflex receptive fields were determined for leg muscles by randomized, electrical stimulation at 16 different positions on the foot sole. Tibialis anterior, gastrocnemius medialis, peroneus longus, soleus, rectus femoris, and biceps femoris reflexes, and ankle joint angle changes were recorded from 14 subjects in sitting position. Tibialis anterior reflexes were evoked at the medial, distal foot and correlated well with ankle dorsal flexion. Gastrocnemius medialis reflexes were evoked on the heel and correlated with plantar flexion. Stimulation on the distal, medial sole resulted in inversion (correlated best with tibialis anterior activity), whereas stimulation of the distal, lateral sole evoked eversion. Biceps femoris reflexes were evoked on the entire sole followed by a small reflex in rectus femoris. A detailed withdrawal reflex organization, in which each lower leg muscle has its own receptive field, may explain the ankle joint responses. The thigh activity consisted primarily of flexor activation.

The effect of Ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin — a double-blind, placebo-controlled, human experimental study

&NA; The non‐competitive NMDA‐antagonist, Ketamine, was infused (i.v.) in healthy volunteers to study the effect on central excitability with the presence of cutaneous hyperalgesia. Hyperalgesia was established experimentally on the dorsum of the foot by topical application of capsaicin (1%). Different thermal and mechanical conditioning stimuli were applied to the primary and secondary hyperalgesic areas to modulate the central nociceptive excitability monitored by the nociceptive reflex. When the elicited reflex was combined with an activation of the secondary hyperalgesic area by continuous, non‐painful, electrical stimulation, a facilitation of the reflex was observed. This indicates that summation of activity in non‐nociceptive and nociceptive afferents can occur under mild pathological conditions. Conditioning thermal stimuli of the primary hyperalgesic area were employed to intensify the allodynia prior to testing this interaction between tactile and nociceptive activity. The same reflex facilitation was inhibited by Ketamine. Furthermore, Ketamine decreased the pain intensity associated with the stimuli eliciting the reflex. Psychophysical measures to single and repeated electrical and thermal (laser) stimuli applied within the hyperalgesic areas were also obtained. The intensity of pain sensations produced by single, painful, electrical stimuli applied to the primary hyperalgesic region was reduced after Ketamine infusion. Finally, five repeated, electrical stimuli applied to the secondary hyperalgesic area were used to assess the temporal summation threshold. Ketamine caused an increase in the summation threshold compared to the placebo treatment. In conclusion, these results demonstrate that (1) summation of activity in non‐nociceptive and nociceptive afferents occurs under hyperalgesic conditions and, (2) this summation can be inhibited by NMDA‐antagonists. Therefore, the study shows an apparent involvement of NMDA‐receptors in some of the central mechanisms underlying secondary hyperalgesia.

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.

Facilitation of the withdrawal reflex by repeated transcutaneous electrical stimulation: an experimental study on central integration in humans.

Abstract In the present human study, we aimed to investigate the facilitation of both the subjective pain responses, and the withdrawal reflex to consecutive transcutaneous electrical stimuli as measures of temporal summation. The frequency (0.5–20 Hz) and intensity (0.4–0.8 times the reflex threshold,  ×RT) of the electrical stimuli were systematically varied. When using repeated stimulation, the stimulus intensity that evoked pain was lower than that required by a single stimulus (temporal summation). Temporal summation leading to pain was found to depend significantly upon both frequency and intensity (e.g. stimulation at 1 Hz caused summation at 0.8 × RT, whereas stimulation at 20 Hz caused summation at 0.6 × RT). The strongest reflex facilitation, and hence the strongest pain intensity was obtained for stimulation at 10–20 Hz at an intensity of 0.8 × RT. In conclusion, the results of the present human study demonstrate clearly that a stimulus that is perceived as a localised, repetitive tactile tap can be integrated and cause severe pain. This suggests that pathologically generated sparse nociceptive afferent activity causes strong pain by central integration. This might be one mechanism to explain why clinical conditions can become excruciatingly painful despite the fact that the pathophysiological changes seem to be marginal (e.g. minor nerve trauma).

Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus

Background and aims. Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi‐modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi‐modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia.

A human experimental capsaicin model for trigeminal sensitization. Gender-specific differences.

&NA; Migraine is much more common in women (18%) than in men (6%). Menstrual migraine in female migraineurs also varies from 7 to 19%. The main goals of the present study were (1) to investigate gender specific differences in an experimental capsaicin model of trigeminal sensitization (a proposed mechanism of migraine) and (2) to explore the influence of menstrual cycle phases. Twenty‐eight healthy female and male volunteers were studied. Capsaicin (100 μg/0.1 ml) was injected intradermally to the forehead. Pain intensity and distribution together with the visual flare and allodynic area (central sensitization) were assessed for females (during their menstrual and luteal phases) and for males. Pain area significantly changed across the menstrual cycle with 19.2±2.0 cm×min at menstrual and 16.4±0.9 cm×min at luteal phase (P<0.001). The area was significantly larger in both phases for females compared to males (14.2±1.3 cm×min, P<0.0001). Flare area at menstrual phase (69.2±4.2 cm2) was significantly (P<0.0001) larger than luteal phase (58.6±2.1 cm2). Females, in both phases, showed larger flare area compared to males (44.9±3.6 cm2, P<0.0001). Area of brush‐evoked allodynia was also larger at the menstrual phase compared to the luteal phase (P<0.0001) and males (P<0.0001). A significant difference was found in the capsaicin‐evoked pain distribution with a greater response in menstrual phase compared to the luteal phase (P<0.01) and men (P<0.0001). Capsaicin induced trigeminal sensitization and evoked gender specific sensory and vaso‐motor responses, with menstruating females generally showing the strongest manifestations. The model may be further applied to explore mechanisms of human trigeminal sensitization.

Factor analysis of responses to thermal, electrical, and mechanical painful stimuli supports the importance of multi-modal pain assessment

&NA; During the last decade, a multi‐modal approach has been established in human experimental pain research for assessing pain thresholds and responses to various experimental pain modalities. Studies have concluded that differences in responses to pain stimuli are mainly related to variation between individuals rather than variation in response to different stimulus modalities. In a factor analysis of 272 consecutive volunteers (137 men and 135 women) who underwent tests with different experimental pain modalities, it was determined whether responses to different pain modalities represent distinct individual uncorrelated dimensions of pain perception. Volunteers underwent single painful electrical stimulation, repeated painful electrical stimulation (temporal summation), test for reflex receptive field, pressure pain stimulation, heat pain stimulation, cold pain stimulation, and a cold pressor test (ice water test). Five distinct factors were found representing responses to 5 distinct experimental pain modalities: pressure, heat, cold, electrical stimulation, and reflex‐receptive fields. Each of the factors explained approximately 8% to 35% of the observed variance, and the 5 factors cumulatively explained 94% of the variance. The correlation between the 5 factors was near null (median ρ = 0.00, range −0.03 to 0.05), with 95% confidence intervals for pairwise correlations between 2 factors excluding any relevant correlation. Results were almost similar for analyses stratified according to gender and age. Responses to different experimental pain modalities represent different specific dimensions and should be assessed in combination in future pharmacological and clinical studies to represent the complexity of nociception and pain experience. Responses to different experimental pain modalities represent different specific dimensions, supporting multimodal pain assessment for clinical and research purposes.

The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study

Background and aim The aim of this randomized double blind placebo controlled study was to investigate the effectiveness and the safety of venlafaxine XR 75 and 150 mg on ongoing pain and on quantitative sensory tests in 60 patients with neuropathic pain for 8 weeks.