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Age-related differences in the time course of capsaicin-induced hyperalgesia

Zheng, Zhena,b; Gibson, Stephen J.a; Khalil, Zeinaba; Helme, Robert D.a,*; McMeeken, Joan M.b

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doi: 10.1016/S0304-3959(99)00247-X
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Abstract

1. Introduction

The effect of age on pain sensitivity is a subject of considerable debate (Harkins et al., 1994; Gibson and Helme, 1995). Clinical observations generally support the view that pain may be reduced in advanced age, for example, an increased incidence of painless or silent myocardial infarction in patients over 65 years old (MacDonald et al., 1983; Luisiani et al., 1994) and a higher frequency of painless epigastric ulcers have been reported (Clinch et al., 1984; Scapa et al., 1989). However, the lack of complaint of pain in some disease states may be due to age-related changes in the degree of pathology rather than differences in pain perception, per se (Harkins et al., 1990).

One way to overcome clinical variability is to use experimentally controlled noxious stimulation and measure pain sensitivity in healthy subjects. To date, most investigations of age differences have been limited to tests of the pain threshold and results are controversial, with the pain threshold being shown to increase (Sherman and Robillard, 1960; Gibson et al., 1991; Chakour et al., 1996), decrease (Collins and Stone, 1966) or remain unchanged (Harkins and Chapman, 1976, 1977) in older persons.

The mismatch between clinical observation and results from experimental studies is probably due to the almost exclusive use of the pain threshold as a psychophysical measure of pain, because it only reflects one end of the pain sensitivity range. The pain threshold is different from most clinical pain states in three important aspects: intensity, duration and accompanying signs. A clinical pain state is typically suprathreshold, lasts for hours, days, or even longer, and is often accompanied by stimulation-evoked pain, i.e. hyperalgesia. In contrast, pain threshold is defined as the point where a non-painful sensation first becomes painful (Gracely, 1994). The duration is as short as milliseconds or seconds and it is never associated with hyperalgesia. For this reason tests of the pain threshold in healthy subjects may be of limited clinical relevance, and there is a need for experimental models that better mimic clinical pain states in order to investigate age-related differences in the pain experience.

Hyperalgesia, an increased response to painful stimulation (Merskey et al., 1994), is one of the most common signs of tissue injury (Meyer et al., 1985; Treede et al., 1992). It can be induced in humans volunteers by intradermal injection (Simone et al., 1989; LaMotte et al., 1991, 1992; Torebjork et al., 1992; Treede and Cole, 1993; Eisenach et al., 1997; Magerl et al., 1998) or topical application of capsaicin (Koltzenburg et al., 1992; Arendt-Nielsen et al., 1996; Morris et al., 1997), by burn injury (Raja et al., 1984), or by electrical stimulation (Lewis, 1935). Primary hyperalgesia is limited to the site of capsaicin application and is characterized by hypersensitivity to both thermal and mechanical stimulation (Culp et al., 1989; Koltzenburg et al., 1992). Secondary hyperalgesia extends beyond the boundary of primary hyperalgesia and exhibits hypersensitivity to mechanical stimulation only (LaMotte et al., 1991). Thus, capsaicin can provide a temporary injury model (Meyer et al., 1994) that mimics the clinical signs of hyperalgesia. This model is particularly useful because the underlying neurophysiology has been well studied, with primary hyperalgesia resulting from sensitization of peripheral nociceptors, and secondary hyperalgesia being mediated by sensitized dorsal horn neurons (Simone et al., 1991; Dougherty and Willis, 1992; LaMotte, 1992; LaMotte et al., 1992; Torebjork et al., 1992; Treede et al., 1992; Park et al., 1995; Andersen et al., 1996).

The aim of the present study was to examine possible age differences in the development and resolution of capsaicin-induced hyperalgesia. Thermal and punctate mechanical stimulation were used to index the magnitude and spatial spread of primary and secondary hyperalgesia. In addition, the area of neurogenic flare response as well as the latency and intensity of capsaicin-induced spontaneous sensation were monitored in all subjects.

2. Methods

2.1. Subjects

Ten young (26.9±4.6 years, range 23–36 years) and 10 elderly (79.0±5.7 years, range 73–88 years) healthy volunteers participated in the study after giving informed consent to a protocol approved by the Ethics Committee of North West Hospital. Each group consisted of four male and six female subjects. By asking their medical and medication history, all subjects were screened for (1) peripheral neuropathy due to diabetes or alcoholism, (2) central nervous system (CNS) diseases, such as stroke and epilepsy, (3) a history of chronic pain, (4) use of medication that might influence the pain experience or the action of capsaicin, such as analgesics, anti-depressants and anti-anxiety agents and (5) allergies to chilli pepper or adhesive paper. Older volunteers were also screened for cognitive impairment using the Abbreviated Mental Test Score (Hodkinson, 1972). Subjects were naive to the specific aims of the experiment and were fully informed of their right to withdraw from the study at any time. No subject withdrew from the study.

2.2. Induction of hyperalgesia

A 5 mg/ml capsaicin solution was prepared by dissolving capsaicin powder (Sigma) in 50% ethanol 50% distilled water (Culp et al., 1989) and 0.1 ml was absorbed onto a patch of filter paper with a diameter of 2 cm. The patch was applied topically to the middle of the volar aspect of the forearm, then covered by a piece of 2×2 cm Tegaderm transparent dressing to retard evaporation.

2.3. Measurement

2.3.1. Intensity of spontaneous pain

A modified visual analogue scale was used to measure the intensity of pre-existing spontaneous pain as well as sensation or pain evoked by the application of capsaicin. One end of the scale represented no sensation and was coded as 0. The other end represented strong pain and was coded as 100. Just painful was at the midpoint and coded as 50. Between 0 and 50, therefore, non-painful sensation was measured, including the warm, hot, itch or tingling sensations induced by capsaicin.

2.3.2. Areas of heat and punctate hyperalgesia, and flare

A Thermal Threshold Tester (TTT, Medonic, Sweden) was used to deliver a standard 37°C stimulus. All subjects perceived this stimulus as warm before the capsaicin treatment and reported it as a burning sensation afterwards. Such a response indicates the presence of heat hyperalgesia. The area of heat hyperalgesia was determined by stimulating along four radiating lines around the capsaicin site (LaMotte et al., 1991) (Fig. 1). The thermode was applied about 4 cm away from the centre of the capsaicin area, then applied every 0.5 cm towards the centre following the line path.

F1-7
Fig. 1:
A diagram of the capsaicin patch, the flare and the areas of hyperalgesia to heat and punctate stimulation. The dotted lines illustrate the eight lines for measuring punctate and heat hyperalgesia.

Mechanical hypersensitivity was measured with a 4.93 lgmgforce (85.3 mN) von Frey monofilament. It was felt as a non-painful prickling or touch sensation when applied on normal skin and evoked an increased sharp sensation or pain accompanied with a burning sensation in hyperalgesic skin. This reflects a state of punctate hyperalgesia, the area of which was measured along eight radiating lines similar to the procedure used for heat hyperalgesia (LaMotte et al., 1991) (Fig. 1). The filament was applied 8 cm away from the centre of the capsaicin area, then moved towards the centre at 1 cm intervals. A punctate stimulus was applied for 1–2 s with an interstimulus interval of 5 s.

The point where subjects first reported a definite increase in the magnitude of sensation, as well as a change in stimulus quality, was marked on the skin. Four or eight points were then connected to form an enclosed region that represented the area of heat or punctate hyperalgesia, respectively. The area of visible flare was also marked. These three enclosed circles were then traced onto a transparent acetate sheet and the area of each region was subsequently calculated with a digital planimeter (Planix, Japan).

2.3.3. Mechanical pain threshold

The mechanical pain threshold was tested with von Frey monofilaments using a pseudo-double random staircase (Gracely, 1988; Chakour et al., 1996). After mapping the area of hyperalgesia, the pain threshold was measured within the area of heat hyperalgesia and between the boundaries of the flare and punctate hyperalgesia. In the cases where punctate hyperalgesia was smaller than the flare, the pain threshold was tested within the flare. The filament with least force that evoked sharp pricking pain on 50% of occasions was recorded as the mechanical pain threshold.

2.4. Testing procedure

Testing was conducted in a quiet, temperature controlled room and skin temperature was frequently checked with a thermometer and maintained at 32±2°C. Before the application of capsaicin, the intensity of pre-existing spontaneous pain and the mechanical pain threshold were measured. Thermal and punctate stimuli were given to familiarize the subjects with the quality of sensation, and then the capsaicin patch was applied for 1 h. During this time, the latency to the onset of pain and to the maximum pain was recorded and subjects were asked to quantify their maximum pain using a VAS.

After 1 h, the patch was taken off. The intensity of spontaneous pain in response to capsaicin was measured again. The area of flare, heat and punctate hyperalgesia and the mechanical pain threshold were determined. All measures were then repeated hourly for a further 2 h. In total, the experiment lasted for 4 h.

2.5. Statistical methods

A two-way analysis of variance (ANOVA) with one repeated measure was applied to the time course of spontaneous sensation, flare, heat and punctate hyperalgesia to test the main effect of age and of time as well as the interaction of age by time. When required, post-hoc analysis was undertaken with a Bonferroni corrected t-test. Comparisons of the two age groups on the magnitude of maximum pain and the latency to the onset of pain were examined with independent sample t-tests. The effect of age on the mechanical pain threshold measured before the application of capsaicin was analyzed using a Mann–Whitney U-test. The effect of time on the mechanical pain threshold within each age group was analyzed using a repeated measure Friedman non-parametric ANOVA. Post-hoc non-parametric Wilcoxon t-tests were then used to identify those time periods (e.g. hour 1, 2, or 3) which differed from the pre-capsaicin measures.

Skin temperature was included as a covariate in all analyses except for t-tests. All values were expressed as the mean±SEM.

3. Results

3.1. Before the application of capsaicin

Prior to the application of capsaicin, no subject reported any pre-existing spontaneous pain and there was no age effect on the mechanical pain threshold (young 5.96±0.27 lgmgforce versus old 6.12±0.19 lgmgforce, Z=−0.35, P=0.73).

3.2. Age effect on the spontaneous sensation evoked by capsaicin

After topical application of capsaicin, both groups gradually developed ongoing painful sensations. As can be seen in Table 1, it took the older subjects almost twice as long as the young volunteers to report the first presence of pain in response to capsaicin (t=−1.93, P=0.08). Consequently, the older adults had a 12 min delay in reporting maximal pain (t=−1.85, P=0.08). This delay failed to reach statistical significance. There was no age effect on the intensity of maximal pain (t=0.99, P=0.34).

T1-7
Table 1:
The effect of age on pain sensitivity before and following topical application of capsaicin

The time course of capsaicin-induced spontaneous sensation for young and older adults is presented in Fig. 2. Over 3 h, there was no main effect of age on the magnitude of sensation (F(1,17)=1.28, P=0.27). After the capsaicin patch was removed, the magnitude of sensation to capsaicin abated quickly in both groups, although the older adults showed a more rapid resolution when compared to the young (F(2,35)=10.13, P<0.001). A Bonferroni corrected t-test showed that the older adults rated their sensation lower than the young adults at hours 2 and 3 (P<0.05).

F2-7
Fig. 2:
The time course of spontaneous pain in both age groups. No sensation is coded as 0, just painful is coded as 50 and strong pain is coded as 100. As soon as the capsaicin patch was taken off 1 h after the application, the magnitude of sensation to capsaicin declined. This decline occurred more quickly in the older adults (F(2,35)=10.13, P<0.001). *Post-hoc age difference significant at P<0.05.

3.3. Age effects on flare and heat hyperalgesia after capsaicin

No age differences in the size of flare (F(1,17)=1.90, P=0.31) or of heat hyperalgesia (F(1,17)=0.12, P=0.74) were found (Fig. 3) and both gradually decreased over time. There was no age by time interaction (flare: F(2,35)=0.61, P=0.55; heat hyperalgesia: F(2,35)=0.24, P=0.79), suggesting a similar pattern of changes over time in young and old adults.

F3-7
Fig. 3:
The time course of the area of flare (upper) and heat hyperalgesia (lower). Both age groups had a similar resolution in flare and heat hyperalgesia.

Skin temperature was also measured and no main effect was detected (F(1,18)=0.16, P=0.70).

3.4. Age effects on punctate hyperalgesia after capsaicin

Hypersensitivity to mechanical stimulation was examined by the size of punctate hyperalgesia and the mechanical pain threshold measured inside and outside of the area of heat hyperalgesia. Changes in the mechanical pain threshold during the test period are illustrated in Fig. 4. There was a decrease in the mechanical pain threshold in both age groups after the application of capsaicin inside and outside of the area of heat hyperalgesia (young, inside: χ2=17.56, P=0.001; outside: χ2=8.45, P=0.037; old, inside: χ2=8.45, P=0.038; outside: χ2=15.27, P=0.002) indicating the development of mechanical hyperalgesia. Post-hoc analysis revealed that within the region of heat hyperalgesia, the mechanical pain threshold was decreased at all time points in both young (hour 1: Z=−2.84, P=0.005; hour 2: Z=−2.52, P=0.011; hour 3: Z=−2.37, P=0.017) and older adults (hour 1: Z=−2.29, P=0.022; hour 2: Z=−2.18, P=0.03; hour 3: Z=−1.98, P=0.05). Outside of the region of heat hyperalgesia, the mechanical pain threshold was significantly lowered at three time points after capsaicin in older adults (hour 1: Z=−2.59, P=0.009; hour 2: Z=−2.67, P=0.007; hour 3: Z=−2.67, P=0.007), whereas in the young subjects the decrease was observed at hour 1 (Z=−2.54, P=0.01) and hour 2 (Z=−2.02, P=0.043) but not at hour 3 (Z=−1.5, P=0.116). Thus, the older adults showed a prolonged time course of diminished mechanical pain threshold at the site of punctate hyperalgesia only when compared to the young adult group.

F4-7
Fig. 4:
The time course of the mechanical pain threshold measured inside (upper) and outside (lower) of the area of heat hyperalgesia. When compared to pre-capsaicin measures, there was a significant decrease in the mechanical pain threshold at several time points for young adults (*P<0.05) and older adults (# P<0.05).

Age differences in the area of punctate hyperalgesia are shown in Fig. 5. Although there was no age difference in the size of punctate hyperalgesia (F(1,17)=2.17, P=0.16), there was a significant age by time interaction in the time course of punctate hyperalgesia (F(2,35)=8.25, P=0.001). The area of punctate hyperalgesia in the young adults reached a peak within the first hour after application of capsaicin and then declined over the remaining 2 h. In marked contrast, older subjects displayed an increase in the area of punctate hyperalgesia from hour 1 to hour 2 with subsequent stability during the remaining test period. A Bonferroni corrected t-test showed a significantly larger area of punctate hyperalgesia in the old adults at hours 2 and 3 (P<0.05).

F5-7
Fig. 5:
The time course of the area of punctate hyperalgesia. In the 3 h test period, the area of punctate hyperalgesia in the young adults reduced quickly, while that in the older adults showed a progressive enlargement, which was maintained until the end of the testing period (F(2,35)=8.25, P=0.001). *Post-hoc age difference significant at P<0.05.

4. Discussion

The current study provides evidence to support the proposition that age is an important factor in the development and decay of hyperalgesia. Both young and older adults displayed a similar magnitude of pain, hyperalgesia and flare in response to the topical application of a 5 mg/ml dose of capsaicin. Older adults exhibited an increased latency to the onset of capsaicin-induced pain and a longer period before reporting maximum pain sensation, when compared to younger persons, but this was not statistically significant. However, the study also demonstrates that the area of post-capsaicin punctate hyperalgesia, but not heat hyperalgesia or flare, takes substantially longer to resolve in adults of advanced age. To accompany this, there was a significant reduction in mechanical pain thresholds within the region of capsaicin-induced punctate hyperalgesia in both age groups, which was maintained for the entire 3 h test period in older adults, but not in the young adult group. In combination, these findings emphasize a differential age-related change in the time course of punctate hyperalgesia and suggest a slower resolution of mechanical tenderness in the region which surrounds a site of capsaicin-induced inflammation.

Using a similar technique, a recent study (Morris et al., 1997) found that the area of punctate hyperalgesia decreased in older people. In the current study, however, the size of flare, heat and punctate hyperalgesia did not differ as a function of age at the first measurement period after capsaicin. This disparity in findings between the two studies is most likely related to the dosage of capsaicin, as a 0.03 mg/ml concentration was applied in the Morris et al. (1997) study, while the concentration in the current study was 160 times greater. It seems reasonable to assume that with a high concentration of capsaicin, all subjects would exhibit a maximal response, whereas a low concentration may favour those adults with best functioning primary afferent neurons. In support of this argument, no age difference was noted in capsaicin-induced flare size when a concentration of 5 mg/ml was applied, but with a concentration of 0.5 mg/ml the size of a visible flare showed a progressive reduction with increasing age (Helme and McKernan, 1985). The intensity-dependent nature of age-related changes to noxious stimulation has also been seen in other studies (Woodrow et al., 1972; Neri and Agazzani, 1984; Harkins et al., 1986; Walsh et al., 1989). With some exceptions (Hardy et al., 1943; Harkins and Chapman, 1977; Kenshalo, 1986), older adults have been shown to display a higher pain threshold, but a similar or lower pain tolerance, thereby reflecting a steeper slope in the stimulus–response function (for review see Gibson and Helme, 1995).

Apart from the dosage of capsaicin, there were also other important methodological differences in the duration for applying capsaicin and the time for conducting hyperalgesic measurements. In the Morris et al. (1997) study, capsaicin was applied for 30 min and the area of punctate hyperalgesia was measured only once at 30–60 min after the initial application, whereas in the present study capsaicin was applied for 1 h and responses were measured at hourly intervals for 3 h. Given the present findings of a longer latency to onset of capsaicin-induced pain in older adults and an increased time to maximum pain, it seems likely that the time of measurement may be an important factor in identifying age-related differences.

There are a number of possible explanations for the altered time course of capsaicin-induced pain and hyperalgesia seen in older adults. Age differences in skin permeability and diffusion of capsaicin, issues relating to skin temperature, an alteration in the peripheral and/or central nervous system mechanisms which mediate the expression of hyperalgesic states, as well as more general psychological influences, such as stoicism or cautiousness in labelling a stimulus as painful, may all contribute. For instance, capsaicin receptors have been shown to be thermally sensitive (Caterina et al., 1997) and the development of punctate hyperalgesia can be modified by skin temperature (Koltzenburg et al., 1992; Liu et al., 1998). For this reason, skin temperature was maintained at a constant level throughout the experiment and age differences in the magnitude and time course of flare and hyperalgesia were analyzed after controlling for variations in skin temperature.

Older adults are thought to be more cautious when making decisions (Botwinick, 1966; Rees and Botwinick, 1971) and labelling a stimulus as painful (Clark and Mehl, 1971). Using signal detection theory techniques, it has been shown that older adults adopt a more stringent response criterion for the report of pain, particularly at low intensity noxious stimulation (Harkins and Chapman, 1976, 1977). In the present study, the age-associated delay in the onset of capsaicin-induced pain, the increased time to maximal pain report and quicker abatement of spontaneous sensation are consistent with a more cautious approach or a more stringent response criterion. On the other hand, these psychological influences are usually more evident at a threshold intensity stimulation of short duration (Clark and Mehl, 1971; Harkins and Chapman, 1976, 1977), whereas the current study examined a prolonged suprathreshold noxious stimulus. Moreover, the 12 min delay in post-capsaicin pain report in the older adults would seem to be substantially longer than noted in previous studies of response bias. These findings suggest that other factors, such as skin permeability or a decreased function in substance P containing primary afferents (Helme and McKernan, 1985), may be more important in explaining the observed age differences.

Senescent skin undergoes structural and functional changes associated with flattening of the epidermal–dermal interface, loss of basal lamina corrugation (Hull and Walfel, 1983) and decreased microcirculation (Balin, 1992). Human research has demonstrated that people over 65 years of age need twice as long as individuals aged in their 30s to absorb and clear substances applied to the skin (Balin and Lin, 1989). A delayed onset of axon reflexes in response to a topical application of capsaicin has been reported in older persons (Helme and McKernan, 1985) and this delay can be eliminated with electrophoresis of capsaicin (LeVasseur, 1992), which effectively bypasses the skin barrier. In the current study, it took older adults almost twice as long to report the onset of capsaicin-induced pain and this delay is consistent with a slower absorption of capsaicin.

Age-related changes in skin, however, are less likely to account for age differences in the time course of hyperalgesia. Firstly, the 12 min delay in post-capsaicin pain report is considerably shorter than the 2 h shift in the time course of mechanical sensitivity. Secondly, there was a differential age-related change only in the time course of punctate hyperalgesia but not in heat hyperalgesia. If the slower clearance of capsaicin was an important contributing factor to the altered time course, one would have expected an increased duration of heat hyperalgesia, flare and self-rated pain, in addition to the observed increase in the duration of punctate hyperalgesia. Indeed, the dissociation between heat and punctate hyperalgesia strongly suggests some specific age-related change in those mechanisms that mediate the expression of punctate hyperalgesia. The finding that each age group shows a different time course in altered mechanical pain thresholds in regions of punctate hyperalgesia, but not at a site of heat hyperalgesia, further support this view.

Previous research has shown that a sensitization of C polymodal nociceptors and novel classes of C-nociceptors can explain heat (LaMotte et al., 1992; Schmelz et al., 1996) and mechanical sensitivity (Schmidt et al., 1995) at the site of stimulation with capsaicin. The state of mechanical hyperalgesia in the unstimulated skin surrounding the primary zone has been shown to be mediated by sensitized spinothalamic tract neurons, such as wide dynamic range (WDR) and high threshold (HT) neurons (Simone et al., 1991; Lin et al., 1999). Thus, an obvious candidate to explain the current findings would be a selective age-related change in spinal cord sensitization processes. In particular, the slower resolution of punctate hyperalgesia may reflect a reduced capacity of the aged CNS to reverse the sensitization process once it has been initiated. Clearly, this view is somewhat speculative and a more direct evaluation of age differences in CNS plasticity would be required to substantiate this claim. However, Harkins et al. (1996) have already shown a similar age-related decline in the temporal summation of C fibre input from the leg, and attribute this change to altered sensitization of second order neurons in the spinal cord. It should also be noted that the idea of reduced CNS plasticity is not new to the ageing literature (deToledo-Morrell et al., 1988; McWilliams, 1988) and it does appear to offer a parsimonious explanation for a selective change in the time course of punctate hyperalgesia.

Another possible explanation for the altered time course involves the role of endogenous pain inhibitory pathways during the development and maintenance of hyperalgesia. Activation of the endogenous analgesic system has been shown to reduce the extent and duration of hyperalgesia during the acute phase of inflammation (Schaible et al., 1991; Tsuruoka and Willis, 1996) and administration of an opioid antagonist can modulate capsaicin-induced hyperalgesia (Eisenach et al., 1997). Several animal studies have investigated age-related changes in endogenous pain inhibitory systems and most report a marked functional decline with advancing age (Hamm and Knisley, 1985, 1986). One could argue, therefore, that age differences in endogenous analgesic mechanisms may contribute to the observed alteration in the time course of capsaicin-induced hyperalgesia. It is also possible that such alterations could occur in addition to any age-related change in the sensitization process of spinal cord nociceptive and WDR neurons. Unfortunately, to date, there have been no human studies of age differences in endogenous analgesic mechanisms and it is difficult to comment on the likely contribution of various neurophysiologic mechanisms without more direct evidence. At present, it seems reasonable to suggest that the altered time course of punctate hyperalgesia probably reflects some age-related change in CNS function, but further research is required in order to substantiate this view.

In conclusion, the present study demonstrates that age is an important factor in the expression of pain and hyperalgesia following topical capsaicin. The magnitude of response was similar in terms of self-reported pain, flare size and area of heat hyperalgesia. However, older adults exhibited a delay in the report of capsaicin-induced pain and a markedly slower resolution of the area of punctate hyperalgesia. These findings probably indicate a reduced plasticity in the aged CNS response to prolonged noxious input, and if translated into the clinical situation, would suggest a slower recovery and an increased duration of post-injury tenderness in adults of advanced age.

Acknowledgments

This study was supported by OPRS (Overseas Postgraduate Research Scholarship) from the Department of Employment, Education and Training, Australia, MRS (Melbourne Research Scholarship) from the University of Melbourne and the National Health Medical Research Council of Australia. We wish to thank Michael Gorman for his technical assistance.

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Keywords:

Ageing; Capsaicin; Hyperalgesia; Human; Psychophysics; Time course

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