Cutaneous pain and detection thresholds to short CO2 laser pulses in humans: evidence on afferent mechanisms and the influence of varying stimulus conditions

Pain and detection thresholds to short CO2 laser pulses were studied in healthy human subjects. Pain thresholds were significantly higher than detection thresholds in both hairy and glabrous skin; in the glabrous skin both thresholds were higher in the hairy skin. The range from detection threshold to pain threshold was larger in the glabrous skin. The minimal energy per surface area needed to produce any sensation (detection) or pain sensation decreased with increasing stimulus surface, and this spatial summation effect was to equal magnitude in the hairy and the glabrous skin. With decreasing stimulus pulse duration (from 45 to 15 msec) the detection and pain thresholds were elevated: this effect was stronger on pain thresholds. With increasing adapting skin temperature, less energy was needed to produce any sensation (detection) or pain sensation. The effect of adapting skin temperature was equal on pain and detection thresholds. The conduction velocity of fibers mediating laser evoked first sensations was in the thin fiber range (less than 10 msec), according to a reaction time study. The results suggest that short CO2 laser pulses produce both non-pain and pain sensations, but that both these sensations are based on the activation of the same primary afferent fiber population of slowly conducting nociceptive fibers. Central summation of primary afferent impulses is needed to elicit a liminal non-painful sensation, and an increased number of impulses in the same fibers produces pain.     

Heart rate changes as an autonomic component of the pain response

Autonomic variables have been recommended as measures of the affective-motivational component of the pain response in objective algesimetry. In the present study components of heart rate responses to painful heat stimuli and their relation to stimulus and sensation variables were analyzed. Twelve healthy subjects served. Sixty phasic stimuli of varying temperatures above and below pain threshold were delivered through a Marstock thermode in 1 session. Heart rate, respiration, and subjective stimulus ratings were recorded simultaneously. Phasic heat stimulation above and below pain threshold induced a tonic increase of the heart rate lasting up to more than 20 sec. High intensity stimulation generated steeper rises and greater mean increase than low intensity stimulation. In general, heart rate responses were more closely related to subjective sensation than to stimulus intensity. However, differential temporal analysis demonstrates that, until about 3 sec after stimulation, the autonomic response is determined solely by stimulus temperature, whereas, after approximately 6 sec, it is related only to subjective judgement. Accordingly, the heart rate responses reflect both a brief nocifensive reflex induced by the sensory component and, subsequently, a longer-lasting response which seems to be related to affective and/or cognitive evaluation. This separation of different stages of pain-processing by an autonomic indicator may be useful in clinical algesimetry.     

Psychophysical study of stinging pain evoked by brief freezing of superficial skin and ensuing short-lasting changes in sensations of cool and cold pain

Psychophysical methods were used to investigate pain in human subjects elicited by controlled freezing of the skin using a novel vortex thermode. When cooling stimuli delivered with a small thermode (7 mm diameter) exceeded the normal cold pain threshold into the sub-zero temperature range (−5 to −11°C), all subjects reported an intense, sharp stinging pain sensation which occurred suddenly and was readily differentiated from normal cold pain. The onset of this stinging `freezing' pain was closely correlated with a sudden increase in skin temperature beneath the thermode of 4.77±0.86°C (±SD) associated with the phase transition of supercooled water to ice. The mean intensity of freezing pain was rated as 1.7 times as intense as cold pain at threshold. Subjects' mean reaction-time latency to signal stinging pain following the onset of phase transition on the volar forearm was 687±220 ms, which was slower than that for mechanically evoked impact pain. Freezing pain is suggested to be mediated by A-delta fibers, based on estimates of conduction velocity and on the observation that the freezing pain took on a burning quality of slower onset during an A-fiber pressure block of nerve fibers. We also investigated changes in skin sensation following the freezing stimulus, and found that freezing led to (a) an immediate, significant decrease in the cold pain threshold (to higher temperatures), which recovered to baseline in <16 min, (b) a concomitant change in the quality of cold pain from dull to burning, (c) a significant, parallel increase in the threshold for the perception of cooling (to lower temperatures) which frequently manifested as a complete loss of cold sensation, and (d) a mild heat pain hyperalgesia which was still present 24 h later. The changes in thermal sensitivity were not accompanied by consistent changes in mechanical sensitivity. These results indicate that a characteristic sharp, stinging pain is reliably evoked abruptly at the phase transition of supercooled skin water to ice The ensuing brief decrease in cold pain threshold with burning quality, coupled with decreased sensitivity to cold, are speculated to reflect a central disinhibition of C-fiber nociceptor input due to reduced cold fiber activity. These effects may be relevant to frostbite, and distinguish themselves from the more pronounced thermal and mechanical hyperalgesia seen following intense freeze lesion of the skin.     

Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans.

Cutaneous sensibility and neurogenic vasodilatation (flare) were measured before, during and after long-term topical application of capsaicin in humans. Each subject applied a vehicle cream containing 0.075% capsaicin (Axsain, GalenPharma Inc.) to a 4 cm2 area of skin on one volar forearm and vehicle alone to an identical treatment area on the other forearm, according to a double-blind procedure. Each substance was applied 4 times/day for 6 weeks. Psychophysical measurements of sensory detection thresholds, magnitude of suprathreshold heat pain, magnitude and duration of histamine-induced itch and flare area were obtained before, at 1, 3 and 7 days after the first application, and once a week thereafter for a total of 8 weeks. Capsaicin produced mild burning in all subjects which diminished in magnitude and duration over several weeks. Capsaicin significantly altered detection thresholds for heat pain and the magnitude of pain produced by suprathreshold painful stimuli. Mean detection threshold for heat pain was lowered 1.6 degrees C following 1 day of capsaicin application but subsequently increased to become elevated 3.5 degrees C after 6 weeks of application. In addition, mean magnitude of suprathreshold heat pain diminished progressively after 1 week. Heat pain thresholds returned to or near pretreatment values within 2 weeks after discontinuing application. Detection thresholds for touch, cold sensation and pain induced by low temperature and by mechanical stimulation were not altered by capsaicin. Similarly, capsaicin did not alter the magnitude or duration of itch produced by intradermal injection of 1 microgram histamine. However, the area of flare produced by histamine was significantly reduced in capsaicin-treated skin. These studies demonstrate that prolonged application of capsaicin at low concentration selectively diminishes sensations of heat pain and neurogenic vasodilatation, presumably via desensitization of heat-sensitive nociceptors. It is also shown that the decrease in heat pain is temporary and is maintained with repeated capsaicin application. There appears to be a therapeutic role for capsaicin in cutaneous painful syndromes mediated, at least in part, by activity of heat-sensitive nociceptors.     

Central suppression of cold-induced C fibre pain by myelinated fibre input

Changes in thermal sensibility for warmth, cold, heat pain and cold pain during nerve compression block of impulse conduction in myelinated fibres were studied in 20 healthy subjects. When mainly unmyelinated fibres were conducting, after 30-36 min of nerve compression, the pain threshold, induced by cold stimulation, was shifted towards higher temperatures (from 19.1 degrees C to 22.8 degrees C, mean values). Furthermore, the sensation of cold pain became more unpleasant and had a hot burning rather than a cold quality. These results indicate that a change in central decoding of the afferent input has occurred, possibly due to lack of inhibition normally exerted by concomitant activation of myelinated fibres. Whereas dramatic changes in the sensation of cold pain were observed during the course of nerve compression, no alteration in heat pain threshold was seen. This implies that heat pain threshold in hairy skin is due to activation of C nociceptor fibres without any significant contribution from myelinated nociceptor fibres. Furthermore, no gating from heat-sensitive myelinated fibre input was evident on heat pain threshold.     

带状疱疹与带状疱疹后神经痛患者温度觉阈值变化及其意义

目的:分析躯干部位带状疱疹、带状疱疹后神经痛患者皮肤温度觉阈值的变化与差异,推测其感觉功能改变及疼痛的病理机制.方法:应用NA-Ⅱ温度觉定量分析仪测定躯干部位带状疱疹、带状疱疹后神经痛患者及对照组相应皮肤的温度觉阈值.结果:带状疱疹后神经痛患者较带状疱疹患者皮肤的冷觉、热觉、热痛觉阈值均升高,其中冷觉阈值升高最为明显.带状疱疹患者冷觉与热觉阈值之间相关性无统计学意义,而带状疱疹后神经痛患者冷觉与热觉阈值之间呈负相关.结论:病变发展过程中,Aδ,C类神经纤维损伤程度有所加重,并以传导冷觉的Aδ神经纤维受损更为严重,表现为带状疱疹后神经痛患者对冷觉、热觉和热痛觉耐受性高于带状疱疹患者,而且对温度觉或痛觉的辨别度减低.     

Experimental muscle pain provokes long-lasting alterations of thermal sensitivity in the referred pain area.

This study explores thermal sensitivity and thermal nociception for signs of central sensitization in the area of referred muscle pain. Two groups of 24 healthy subjects (ss) each, and with mean ages of, respectively, 27 and 55 years, were first trained in quantitative sensory testing and pain rating. Then, in a second session, referred pain was evoked by injection of 6% hypertonic saline into the infraspinatus muscle. Cold and warm thresholds, synthetic heat threshold (SHT--evoked by an alternating pattern of adjacent cold and warmth), and thermal pain thresholds were measured within the referred pain area at a rate of 1/20 min for 60-120 min. All ss of both groups experienced referred pain mostly in the upper arm and of medium intensity. Pain lasted for approximately 12min with a shorter duration in the older group (p<0.02). The cold threshold increased significantly (p<0.001), and the warm threshold slightly, after the injection and remained high for the whole observation period (i.e. lower and higher temperatures were necessary to elicit cold and warmth, respectively). Threshold recovery was more delayed in the older age group. Of those 28 ss in whom cold pain threshold could be followed during the whole observation period, 18 ss showed an immediate threshold decrease of average 6 degrees C which outlasted the observation period. Four ss responded with a threshold increase. Heat pain thresholds were not affected in the referred pain area. Average synthetic heat threshold did not change; there were, however, distinct and lasting individual threshold shifts in either direction. Ss with lowered cold pain thresholds or evident threshold shifts for synthetic heat had also higher pain ratings. The results demonstrate that experimental muscle pain can induce long-lasting changes in thermal sensitivity and nociception. The unexpected cold threshold increase may tentatively be explained as an expression of long-term depression. The decrease of cold pain threshold or SHT in subgroups of ss may indicate central sensitization. However, the observed changes in this experiment do not provide an unambiguous indicator for central sensitization which seems to be rather individual and might depend on pain intensity and proneness to express central mechanisms of sensitization. Therefore in clinical pain states the individual pattern of sensory abnormalities has to be analysed and interpreted in addition to the pain parameters to assess central involvement.     

Investigation of the paradoxical painful sensation ('illusion of pain') produced by a thermal grill

A paradoxical painful sensation can be elicited by the simultaneous application of innocuous warm and cold stimuli to the skin. In the present study, we analyzed the conditions of production of this unique experimental illusion of pain in 52 healthy volunteers (27 men, 25 women). The stimuli were produced by a thermode composed of six bars whose temperature was controlled by Peltier elements. The temperature of alternate (even- and odd-numbered) bars could be controlled independently to produce various patterns of the 'thermal grill'. After measuring the cold and heat pain thresholds, a series of combinations of warm and cold stimuli, whose distance to the thermal pain threshold was at least 4 degrees C, were applied on the palmar surface of the right hand during 30s. After each stimulus, the subjects had to describe and rate their sensations on visual analog scales. Paradoxical painful sensations, mostly described as burning, were reported by all the subjects but three. However, the phenomenon was less frequent in approximately one third of ('low responder') volunteers. The frequency and intensity of such painful sensations were directly related to the magnitude (i.e. 5-25 degrees C) of the difference of the temperature between the warm and cold bars of the grill. The combination of increasingly colder temperature to a given warm temperature induces similar effects as combining increasingly warmer temperature to a given cold temperature. These results suggest that pain can be the result of a simple addition of non-noxious warm and cold signals.     

Subjective sensitization to tonic heat as an indicator of thermal pain

In 144 healthy subjects tonic heat stimuli were applied with a contact thermode and systematically varied with respect to 3 parameters: temperature T, rate of temperature change RTC, and duration D. In addition, the stimulus temperature at which the first sensation of pain occurred was produced by some subjects. In both types of experiments, subjects compared heat intensity felt at the beginning and the end of the stimulus and then set stimulus temperature to correspond with their initial sensation. The direction of this temperature change (delta T) indicates whether the subject senses an augmentation or a diminution of heat intensity. There was a parallel occurrence of pain and sensitization to sustained heat. The average skin temperature of the point of transition from adaptation to sensitization was equal to the average pain threshold temperature. The temperature change response maintained individual differences of thermal and pain sensitivity and was highly consistent for each subject. Potential applications of the procedure in clinical and experimental pain research are discussed.     

The assessment of radiating low back pain by thermal sensory testing

Low back pain radiating into the legs is a common pain syndrome. However, neurological examination, imaging and electromyographic studies are of limited value for prognosis or therapy. The origin of the pain remains unknown. The aim was to evaluate the potential of thermal sensory testing to serve as a diagnostic tool in 24 patients who had low back pain radiating down the S1 dermatome, compared with 26 pain-free controls. The method of limits was used to detect the thresholds of warm sensation, cold sensation, warm pain and cold pain at the L4, L5 and S1 dermatomes of the symptomatic and the non-symptomatic legs. Thresholds on the asymptomatic leg were similar to values obtained in controls. We found a significantly higher threshold for cold sensation in the S1 dermatome of the symptomatic leg of the patients compared with the controls (p< 0.005). In addition, patients who had abnormal neurological examination (50%) had higher thresholds for cold sensation or cold pain in the three dermatomes tested at the symptomatic leg compared with the non-symptomatic leg. No differences in the thresholds of warm sensation or warm pain were detected. We propose that these findings indicate selective damage to the Adelta fibres which are involved in transmission of cold sensation and pain, presumably by root compression. We found no evidence of involvement of C fibres, which transmit warm sensation and pain. Thermal testing should be considered among the testing modalities that are capable of demonstrating objective findings in patients with radiating low back pain.     

Quantitative Sensory Testing (QST) Estimation of Regional Cutaneous Thermal Sensitivity During Waking State,Neutral Hypnosis,and Temperature Specific Suggestions

This study aimed to determine the effects of neutral hypnosis and hypnotic temperature suggestions in thermal and pain thresholds compared to resting state. Sixteen healthy medium or high hypnotizable volunteers were enrolled. Hypnotizability was assessed with the Hypnotic Induction Profile (HIP); QST was checked in resting state, in neutral hypnosis, after suggestions of heat and cold, and after deinduction. A significant increase in heat threshold was recorded during hypnosis with both cold and heat suggestions compared to neutral hypnosis. HIP induction score showed a linear correlation with changes of temperature thresholds after heat and cold suggestions. Thermal suggestions may result in a significant increase of heat perception thresholds with respect to neutral hypnosis. HIP score is related to thermal threshold changes. QST is a valuable and manageable tool to measure temperature threshold change during hypnosis.     

Noxious cold evokes multiple sensations with distinct time courses

A noxious cold stimulus can evoke multiple sensations each occurring with a different time course. We have performed psychophysical studies to identify the time course of five sensations evoked by a noxious cold stimulus applied to the hand. Subjects continuously rated either pain, ache, cold, heat or prickle sensations throughout repeated presentations of a noxious cold stimulus (3 degrees C) from a neutral (32 degrees C) baseline. Separate runs were used to assess each of the five types of sensation. Cold was reported throughout the period of cooling. The time course of pain and ache sensations were similar. However, prickle and heat sensations had time courses that could be distinguished from each other, and from ache and pain. Identification of these temporal profiles could provide clues to their underlying mechanisms. The temporal dissociation of these sensations will also enable neuroimaging studies of the cortical mechanisms associated with these sensations. Thus our results constitute a first step toward identifying the distinct modes of neural activity associated with different types of pain sensation.     

Une approche de la douleur exp??rimentale commune ?? l??homme et ?? l??animal

From a psychophysical point of view, the analysis of experimental pain caused by heat is problematic for two main reasons: 1) a heat stimulus is always progressive; 2) a pain stimulus can activate two types of pain receptors, connected to the peripheral A?? and C fibres, which have different conduction velocities. Nevertheless, in many pain receptor behaviour tests in animals it is the reaction time that is measured, i.e. the time elapsed between the start of the application of heat and the evoked response. As it is technically impossible to heat the skin instantaneously by conventional means, the validity of a reaction time obtained under these conditions must be questioned. We have developed a theoretical framework, an experimental paradigm and a model to analyse the psychophysical response in rats produced by the application of varying levels of nociceptive radiant heat. We have extended this approach to humans, based on the joint analysis of stimuli and the response from the subject, in order to measure the heat thresholds and the pain latencies produced by A?? and C fibres.     

Quantitative sensory studies in complex regional pain syndrome type 1/RSD

OBJECTIVE: Patients with complex regional pain syndrome type I (CRPSD1) may have thermal allodynia after application of a non-noxious thermal stimulus to the affected limb. We measured the warm, cold, heat-evoked pain threshold and the cold-evoked pain threshold in the affected area of 16 control patients and patients with complex regional pain syndrome type 1/RSD to test the hypothesis that allodynia results from an abnormality in sensory physiology. SETTING: A contact thermode was used to apply a constant 1 degrees C/second increasing (warm and heat-evoked pain) or decreasing (cold and cold-evoked pain) thermal stimulus until the patient pressed the response button to show that a temperature change was felt by the patient. Student t test was used to compare thresholds in patients and control patients. RESULTS: The cold-evoked pain threshold in patients with CRPSD1/RSD (p <0.001) was significantly decreased when compared with the thresholds in control patients (i.e., a smaller decrease in temperature was necessary to elicit cold-pain in patients with CRPSD1/RSD than in control patients). The heat-evoked pain threshold in patients with CRPS1/RSD was (p <0.05) decreased significantly when compared with thresholds in control patients. The warm- and cold-detection thresholds in patients with CRPS1/RSD were similar to the thresholds in control patients. CONCLUSIONS: This study suggests that thermal allodynia in patients with CRPS1/RSD results from decreased cold-evoked and heat-evoked pain thresholds. The thermal pain thresholds are reset (decreased) so that non-noxious thermal stimuli are perceived to be pain (allodynia).     

Influence of estrogen levels on thermal perception, pain thresholds, and pain tolerance: studies on women undergoing in vitro fertilization

We examined the relationship between estrogen and pain in women undergoing in vitro fertilization (IVF). Quantitative sensory tests (QST) were performed twice during the IVF-regimen: once during hormonal down-regulation and once during hormonal up-regulation. A group of healthy men and a group of women using monophasic contraceptives were also examined, to control for session-to-session effects. Among the women undergoing IVF, serum 17β-estradiol levels differed strongly between treatments as expected, and increased from 65.7 (SD = 26) pmol/L during the down-regulation phase, to 5,188 (SD = 2,524) pmol/L during the up-regulation phase. Significant outcomes in the QST were only seen for temperature perception thresholds (1.7 °C versus 2.2 °C; P = .003) and cold pain threshold (11.5 °C versus 14.5 °C; P = .04). A similar change in cold pain threshold was also seen in the 2 control groups, however, and statistical analysis suggested that this change was due to a session-to-session effect rather than being the result of hormonal modulation. Heat pain thresholds, heat tolerance, pressure pain thresholds, and the cold pressor test showed no significant differences between sessions. These data demonstrate that pain perception and pain thresholds in healthy women show little, if any, changes even with major variations in serum estradiol levels. PERSPECTIVE: This study shows that pain perception and tolerance in women undergoing in vitro fertilization do not vary, despite the dramatic changes in 17β-estradiol levels induced by the treatment regimen. The result thus suggests that in humans, contrary to experimental animals, changes in estrogen levels have little influence on pain sensitivity.     

Neural gliding versus neural tensioning: Effects on heat and cold thresholds,pain thresholds and hand grip strength in asymptomatic individuals

IntroductionNeural mobilization can be performed in a way that facilitates movement through a stretching technique (tensioning) or in a way that maximizes the gliding of peripheral nerves in relation to adjacent structures (gliding). Evidence on how these techniques compare in terms of effects are scarce. The aim of this study is to compare the effects of neural gliding and neural tensioning targeting the median nerve on heat and cold temperature threshold, heat pain threshold, pressure pain thresholds and hand grip strength in asymptomatic participants.MethodsParticipants received 4 series of 10 repetitions of either neural gliding (n = 30) or neural tensioning (n = 30) and were assessed for heat and cold temperature threshold, heat pain threshold, pressure pain threshold, and hand grip strength at baseline, immediately after the intervention, and 30 min post-intervention.ResultsA significant main interaction between time and intervention was found for the PPT at the forearm (F(2,55) = 5.98; p = 0.004), favouring the tensioning neural mobilization. No significant differences were found for the other variables.ConclusionsFour series of 10 repetitions of neural tensioning targeting the median nerve in asymptomatic subjects seem to be enough to induce hypoalgesia and have no negative effects on A-delta and C mediated sensory function and on hand grip strength production.     

The level of small nerve fiber dysfunction does not predict pain in diabetic Neuropathy: a study using quantitative sensory testing

OBJECTIVES: To determine whether small nerve fiber dysfunction predicts pain in diabetic neuropathy using quantitative sensory testing of thermal thresholds. METHODS: Diabetic patients with or without painful neuropathy (n=191) were studied. Small nerve fiber function was assessed by quantitative sensory testing of cold detection and heat pain thresholds. Subjects were also categorized as being hyperalgesic (<10th percentile) or hyposensitive (>90th percentile) by comparing with normative data. Vibration perception threshold, a large nerve fiber function, was measured using a biothesiometer (Bio-medical Instrument, Newbury, OH). RESULTS: In the patients with pain, cold stimulus was detected after a greater reduction in temperature from baseline (-3.7 degrees C vs. -0.6 in the no-pain group, P<0.0001). There were no differences between the pain and painless groups in the heat pain tests, with hyperalgesia noted in about 60% of subjects. Vibration perception threshold and loss of ankle reflexes were significant determinants of pain, but together they accounted for only 6.8% of the variance. If these were removed from the model, cold detection threshold became a significant determinant of pain but accounted for only 3.0% of the variance. CONCLUSIONS: Quantitative sensory testing of small nerve fiber function is a useful test to detect the presence of neuropathy, and overall diabetic patients with neuropathic pain have more sensory loss. However, small nerve fiber abnormalities detected by quantitative sensory testing do not predict the presence of pain in diabetic neuropathy.     

Cognitive modification of pain: information in combination with N2O

The present study sought to discover whether information clarifying how the analgesic/sedative drug nitrous oxide (N2O) works would result in increased analgesic responses to painful stimuli when various concentrations of N2O were administered. Subjects were provided with high and low levels of information regarding the action and use of N2O as an analgesic and sedative. Absolute sensation threshold (AST), pain threshold (PTh), and pain tolerance (PTo) to tooth pulp shock were measured in microamperes during administration of each of 3 concentrations of N2O (15%, 30%, and 45%, with oxygen). Subjects rated stimulus intensity and stimulus aversiveness in response to a fixed painful stimulus, and completed questionnaires regarding the perceived efficacy of N2O and their subjective mood state throughout the session. The marked differences observed in pain reports between the high information group and the control group confirm that providing information to people receiving a drug for pain relief yields higher sensation thresholds, pain thresholds, and tolerance of pain. In addition, we observed that in the presence of N2O an equivalent fixed painful stimulus will be perceived as less painful after appropriate information is provided. These findings suggest that experimentally influencing thought processes, in combination with an analgesic, can have the effect of increasing analgesia.