Jesper Ellerbæk Nielsen

The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input.

&NA; Hyperactivity of N‐methyl d‐aspartate (NMDA) receptors may be one of the factors in the maintenance of persistent stump and phantom limb pain. Ketamine (bolus at 0.1 mg/kg/5 min followed by an infusion of 7 &mgr;g/kg/min) was administered intravenously to 11 patients with established stump and phantom limb pain in a double‐blind saline‐controlled study. All 11 patients responded with a decrease in the rating of stump and phantom limb pain assessed by visual analogue scale (VAS) and McGill Pain Questionnaire (MPQ). Ketamine increased pressure‐pain thresholds significantly. Wind‐up‐like pain (pain evoked by repeatedly tapping the dysaesthetic skin area) was reduced significantly by ketamine. In contrast, no effect was seen on pain evoked by repeated thermal stimuli. Side effects were observed in nine patients. The results support the notion that stump and phantom pain are generated by activity in afferent fibres activated by mechanical but not by thermal stimuli and that the NMDA receptor is involved in the maintenance of postamputation pain states. NMDA receptor antagonists may have a potential in the treatment of stump and phantom limb pain.

Age effects on pain thresholds, temporal summation and spatial summation of heat and pressure pain.

&NA; Experimental data on age‐related changes in pain perception have so far been contradictory. It has appeared that the type of pain induction method is critical in this context, with sensitivity to heat pain being decreased whereas sensitivity to pressure pain may be even enhanced in the elderly. Furthermore, it has been shown that temporal summation of heat pain is more pronounced in the elderly but it has remained unclear whether age differences in temporal summation are also evident when using other pain induction methods. No studies on age‐related changes in spatial summation of pain have so far been conducted. The aim of the present study was to provide a comprehensive survey on age‐related changes in pain perception, i.e. in somatosensory thresholds (warmth, cold, vibration), pain thresholds (heat, pressure) and spatial and temporal summation of heat and pressure pain. We investigated 20 young (mean age 27.1 years) and 20 elderly (mean age 71.6 years) subjects. Our results confirmed and extended previous findings by showing that somatosensory thresholds for non‐noxious stimuli increase with age whereas pressure pain thresholds decrease and heat pain thresholds show no age‐related changes. Apart from an enhanced temporal summation of heat pain, pain summation was not found to be critically affected by age. The results of the present study provide evidence for stimulus‐specific changes in pain perception in the elderly, with deep tissue (muscle) nociception being affected differently by age than superficial tissue (skin) nociception. Summation mechanisms contribute only moderately to age changes in pain perception.

The relationship between sensory thresholds and mechanical hyperalgesia in nerve injury

&NA; The paradoxical combination of sensory loss within the area where pain is felt together with pain evoked by non‐noxious stimuli (allodynia) is a characteristic feature of neuropathic pain. This study examined the relationship between (mechanical and thermal) pain thresholds and dynamic and static hyperalgesia in 15 patients with traumatic nerve injury and brush‐evoked pain. Sensory tests were carried out both in the allodynic skin area and in the unaffected contralateral mirror image skin. The sensory characteristics included: visual analogue scale (VAS) score of ongoing pain, detection and pain threshold to thermal and mechanical stimuli, and temporal summation to repetitive heat and pinprick stimuli. Temporal summation was evoked by pinprick stimuli at 2.0 Hz but not at 0.2 Hz in allodynic skin. No difference was observed in temporal summation to heat stimuli. There was a significant and inverse relation between heat and cold pain difference and mechanically evoked pain. Patients with heat hyperalgesia had a significantly higher VAS score of mechanical hyperalgesia than patients with heat hypoalgesia. There was no relationship between dynamic and static evoked hyperalgesia. These findings suggest a differential processing of repetitive thermal and mechanical stimuli in the central nervous system. Both dynamic and static mechanical hyperalgesia are maintained by activity in heat‐sensitive nociceptors, but they are probably mediated by distinct mechanisms.

Spatial summation of heat induced pain within and between dermatomes.

The aim was to study spatial summation within and between ipsi- and contralateral dermatomes at different painful temperatures. For heat stimulation we used a computer controlled thermofoil based thermode. The thermode area could be varied in five discrete steps from 3.14 to 15.70 cm2. When we applied the stimuli within a dermatome, the mean heat pain threshold decreased significantly from 45.6 to 43.5 degrees C as the area was increased from minimum (3.14 cm2) to maximum (15.70 cm2). When the areas were increased involving different dermatomes (both ipsi- or contralateral), we found similar decreases in pain threshold. Spatial summation was also found within and between dermatomes at supra-threshold temperatures (46, 48, 50 degrees C). The study shows that spatial summation of pain is most likely a mechanism acting across segments and is existing from pain threshold to tolerance.

The importance of stimulus configuration for temporal summation of first and second pain to repeated heat stimuli

Temporal summation of pain is suggested to be an important factor during various clinical conditions. Controversies exist as to whether temporal summation exists for A8 fibre‐mediated first pain. The aim of the present human experimental study was to investigate the importance of stimulus configuration (intensity, interpulse interval, location) for temporal summation of radiant (laser)‐ and contact‐heat‐induced pain. Consecutive stimuli were applied to the same or to adjacent skin locations. Both stimulation techniques evoked rapid temperature changes, which is an important parameter for recruitment of specific cutaneous nociceptors (Aδ and C fibres). Psychophysical thresholds and intensity ratings were used to assess the pain evoked by repeated stimuli applied to the hairy skin of nine volunteers. Inter‐pulse interval (IPI) and stimulus intensity were important and interrelated parameters for temporal summation of pain. An increase in IPI resulted in a decreased summation, whereas increased stimulus intensity resulted in increased summation. Brief heat pulses evoked both first and second pain, and summation of the different pain qualities was investigated. Taking the latency from stimulation to perception into consideration, we were able to differentiate and find summation of first (A8 fibre‐mediated) and second pain (C fibre‐mediated). Summation of first pain was more pronounced for high (38°C) than for low (30–32°C) baseline temperature.

Cerebral blood-flow changes evoked by two levels of painful heat stimulation: A positron emission tomography study in humans

Positron emission tomography (PET) and accumulation of H2 15O as a marker of neuronal activity were used to create maps of cerebral blood‐flow changes evoked by painful heat stimulation in 10 subjects. Two levels of painful tonic and phasic heat stimuli were applied with use of a newly developed contact heat thermode on the volar surface of the dominant (right) arm. The subjects participated in two separate PET sessions. Maps reflecting low and high levels of painful tonic heat were obtained in the first session, and low and high levels of painful phasic heat in the second session. The subjects scored their peak pain intensity and unpleasantness on 10‐cm visual analogue scales. For each subject, PET images were aligned to nuclear magnetic resonance (NMR) images and remapped into the standardized co‐ordinate system of Talairach. After normalization of the PET volumes, subtraction images were formed voxel‐by‐voxel and converted to a t‐statistic volume. The perceived pain intensity and unpleasantness were identical with painful tonic and phasic heat stimulation. Directed searches revealed significant blood‐flow increases in the contralateral primary sensorimotor cortex (MI/SI), SII, insular cortex and cingulate cortex when the low tonic heat map was subtracted from the high. A similar, but not identical, pain‐processing network was observed for the maps representing the subtraction of low and high phasic heat. In this subtraction, the blood‐flow increases in MSI/SI did not reach statistical significance, and significant blood flow decreases were found in the contralateral middle temporal gyrus. Finally, the location of the activation site in the cingulate cortex was different from that observed during tonic heat pain. This study has provided more evidence for the existence of a common pain‐processing network engaged during the perception of different levels of toxic and phasic heat pain.

Magnetoencephalographic responses to painful impact stimulation

Magnetoencephalographic (MEG) field recordings are unique to detect current dipoles in SI and SII. Few devices are available for painful mechanical stimulation in magnetically shielded MEG rooms. The aim of the present MEG (dual 37-channel biomagnetometer) study was to investigate the location of the cortical generators evoked by painful impact stimuli of different intensities. An airgun was placed outside the shielded MEG room, and small plastic bullets were fired at the arm and trunk of the subjects in the room. The velocity of the bullet was measured and related to the evoked pain intensity. Stimuli were delivered for each of the following three conditions: strong pain intensity elicited from the upper arm and upper trunk; weak pain intensity elicited from the upper trunk. The evoked MEG responses had a major component with the characteristically polarity-reversal deflections indicating a dipole located beneath the coils. The response could be estimated by a single current dipole. When the estimated locations of the dipoles were superimposed on the individual magnetic resonance images (MRIs), consistent bilateral activation of areas corresponding to the secondary sensory cortices (SII) was found.

Spatial summation of heat pain in males and females.

Sex differences in pain sensitivity have been found to vary between considerable and negligible. It has appeared that the pain stimulation method is critical in this context. It was assumed this might be due to the different degrees of spatial summation associated with the different pain stimulus modalities. Hence, sex differences were investigated in spatial summation of heat pain in 20 healthy women and 20 healthy men of similar age. Pain thresholds were assessed by a tracking procedure and responses to supra-threshold pain stimulation by numerical ratings. Heat stimuli were administered by a thermode with contact areas of 1, 3, 6 and 10 cm 2. Pain thresholds were significantly higher with smaller areas stimulated than with larger ones. No significant effect of area was found for the ratings of the supra-threshold stimuli, the intensities of which were tailored to the individual pain threshold. Consequently, spatial summation of heat pain appeared to result mainly in a shift of the pain threshold on the ordinate and not a change of slope of the stimulus-response function in the pain range. In neither of the two pain parameters were there any sex differences. Therefore, the present study demonstrated that sex differences in spatial summation of heat pain are unlikely.Sex differences in pain sensitivity have been found to vary between considerable and negligible. It has appeared that the pain stimulation method is critical in this context. It was assumed this might be due to the different degrees of spatial summation associated with the different pain stimulus modalities. Hence, sex differences were investigated in spatial summation of heat pain in 20 healthy women and 20 healthy men of similar age. Pain thresholds were assessed by a tracking procedure and responses to supra-threshold pain stimulation by numerical ratings. Heat stimuli were administered by a thermode with contact areas of 1, 3, 6 and 10 cm2. Pain thresholds were significantly higher with smaller areas stimulated than with larger ones. No significant effect of area was found for the ratings of the supra-threshold stimuli, the intensities of which were tailored to the individual pain threshold. Consequently, spatial summation of heat pain appeared to result mainly in a shift of the pain threshold on the ordinate and not a change of slope of the stimulus-response function in the pain range. In neither of the two pain parameters were there any sex differences. Therefore, the present study demonstrated that sex differences in spatial summation of heat pain are unlikely.

The influence of rate of temperature change and peak stimulus duration on pain intensity and quality

An important aspect of experimental pain research is that the assessment methods can investigate the different aspects of pain perception. The aim of the present study was to investigate the influence of rate of temperature change and peak stimulus duration on heat evoked pain intensity and quality. All stimuli were applied within the medial aspect of the anterior forearm. The rate of temperature change was varied from 1 to 16 degrees C/s without any effect on the pain threshold. The pain threshold decreased with an increasing peak stimulus duration from 0.1 to 2 s, but not from 2 to 3 s. The pain intensity for suprathreshold stimuli (46 degrees C, 48 degrees C, 50 degrees C) increased for decreasing rates and increasing duration. The pain intensity was highly correlated with the energy of the stimulus. When the rates of temperature change (1-16 degrees C/s) are varied, no differences between pricking and burning pain were present at either low stimulus intensity (46 degrees C) or high stimulus intensity (50 degrees C). At low stimulus intensity (46 degrees C), the pricking pain was not influenced by the duration (0.1-3 s), but the burning pain was intensified when the duration was increased from 1.5 to 3 s. At high intensity stimuli (50 degrees C), the pricking pain intensified with an increased duration, whereas burning pain did not. The heat pain threshold is influenced by the peak stimulus duration, and not by the rate of temperature change. If suprathreshold stimuli are used, both the rate of temperature change and the peak stimulus duration can strongly affect the pain intensity and the pain quality. Therefore, the same stimulus modality can be used to assess the modulation of different pain intensities and of the pricking and burning pain qualities simply by varying the stimulus configuration.

Heat hyperalgesia in humans: assessed by different stimulus temperature profiles

The aim of the present study was to investigate the effect of the rate of temperature increase on the intensity of the evoked pain before and after hyperalgesia induced by topical capsaicin. Further, hyperalgesia to suprathreshold heat stimuli was investigated. Thirteen healthy volunteers were included in the experiment. All stimuli were applied in randomised order within the volar surface of both forearms using a computer‐controlled contact stimulator. In one of the forearms, the effect of the rate of temperature change was investigated for 1.0, 5.0, and 8.0 °C/s reaching a peak temperature of 30.0, 33.0, 36.0, 39.0, and 42.0 °C in the primary hyperalgesic area and reaching a peak temperature of 33.0, 36.0, 39.0, 42.0, 45.0, 47.0, and 49.0 °C in the secondary hyperalgesic area before and after the induction of hyperalgesia. In the other forearm, the same procedure was repeated without capsaicin application as a control measurement. After the induction of hyperalgesia, the pain ratings were significantly higher in the arm treated with capsaicin compared with baseline for 36, 39, and 42 °C heating rates in the primary hyperalgesic area. The pain ratings were significantly higher with 1 °C/s heating rate compared with 5 and 8 °C/s for 36, 39, and 42 °C in the primary hyperalgesic area. Heat hyperalgesia was also observed within the secondary hyperalgesic area to pin‐prick for stimulus temperatures of 45, 47, and 49 °C compared with the baseline measurements. Increased ratings were found for all three heating rates in the secondary hyperalgesic area. There were no heat hyperalgesia in the control arm. In conclusion, hyperalgesia to suprathreshold heat stimuli was observed in the secondary hyperalgesic area and C‐fibres play an important role in the primary hyperalgesia to heat.