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New life for an old idea: Assessing tonic heat pain by means of participant controlled temperature
Journal of Neuroscience Methods 321 (2019) 20–27
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Journal of Neuroscience Methods journal homepage: www.elsevier.com/locate/jneumeth
New life for an old idea: Assessing tonic heat pain by means of participant controlled temperature
T
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Catherine R. Jutzelera,b,c,1, , Laura Siruceka, Paulina S. Scheurenb, Tong Bobob, Eitan Anenbergb, Oscar Ortizb, Jan Rosnera, Michèle Hublia, John L.K. Kramerb,c a
Spinal Cord Injury Center, University Hospital Balgrist, University of Zurich, Zurich, Switzerland ICORD, University of British Columbia, Vancouver, British Columbia, Canada c School of Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada b
A R T I C LE I N FO
A B S T R A C T
Keywords: Tonic heat pain Temporal summation of pain Participant-controlled temperature Test-retest reliability Experimental model of pain
Background: Temporal changes of pain perception to prolonged tonic heat pain are conventionally assessed using a computerized visual analog scale. Such a rating-based approach is, however, prone to floor and ceiling effects, which limit the assessment of temporal changes in perception. Thus, alternative methods that overcome these shortcomings are warranted. New method: The aim of this study was to assess the feasibility and reliability of a psychophysical approach, i.e., participant-controlled temperature (PCT), to evaluate ongoing human perception of tonic heat pain. Fifty participants were presented with a 45 °C stimulus on the non-dominant hand, and were instructed to maintain their initial sensation for two minutes via a feedback controller in the dominant hand. A subset of participants (n = 17) performed PCT tonic heat protocols on two different days to determine the test-retest reliability. As participants controlled temperature to maintain a stable pain perception, any adjustments made reflected shifts in their perception of heat. Results: In 33 (71.7%) participants, we observed an initial adaptation (participant increased temperature) followed by temporal summation of pain (participant decreased temperature). Twelve participants (26.1%) showed only adaptation and one (2.2%) only temporal summation. No sex differences were observed, nor did the initial rating of pain have an effect on PCT outcomes. Temporal summation of pain showed moderate to substantial reliability upon retest. Conclusions: PCT represents can be reliably performed using a contact heat stimulator to measure the temporal summation of pain. The standardized setup and overall good reliability of the outcome measures facilitate a sound implementation into the clinical work-up of patients with pain conditions.
1. Introduction Tonic heat stimulation has been proposed as a physiologically relevant alternative to noxious, phasic, stimuli, suitable for the assessment of wind-up in humans – so-called temporal summation of pain (Price et al., 1977; Granot et al., 2006; Suzan et al., 2015). Conventional tonic heat stimulation paradigms apply a fixed heat stimulus over a one to two-minute period and acquire intermittent or continuous ratings of perceived intensity. An individual’s perception is characterized by initial decreases, promptly followed by increased ratings. The latter is thought to represent central wind-up of noxious stimuli, which
is believed to occur at the level of the spinal cord (Price et al., 1977; Staud et al., 2003). Emphasizing a need for a valid and reliable assessment, studies have reported increased temporal summation of pain as a characteristic of chronic pain (Staud et al., 2001, 2014). The earliest studies examining responses to tonic heat reported changes in temporal summation of pain, not based on rating, but rather on changes in temperature. Applying a “thermal radiation” instrument, Greene and Hardy instructed participants to adjust stimulus energy so as to maintain a constant intensity (Greene and Hardy, 1962). The focus of this study was on adaptation and to what extent adaptation occurred during presentation of a noxious stimulus. To our knowledge, no study
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Corresponding author at: 818W 10th Ave, Vancouver, BC, V5Z 1M9, Canada. E-mail addresses: [email protected] (C.R. Jutzeler), [email protected] (L. Sirucek), [email protected] (P.S. Scheuren), [email protected] (T. Bobo), [email protected] (E. Anenberg), [email protected] (O. Ortiz), [email protected] (J. Rosner), [email protected] (M. Hubli), [email protected] (J.L.K. Kramer). 1 URL: www.icord.org. https://doi.org/10.1016/j.jneumeth.2019.04.003 Received 2 November 2018; Received in revised form 20 March 2019; Accepted 5 April 2019 Available online 06 April 2019 0165-0270/ © 2019 Elsevier B.V. All rights reserved.
Journal of Neuroscience Methods 321 (2019) 20–27
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PCT
45
32
0
Dominant Hand
120 Time [sec]
+ +
46.0
45.5
AUC ADT AUC Plateau
slope TSP slope ADT ADT Magnitude
AUC Total
AUC TSP
TSP Magnitude
Fig. 1. Study design details. (A) Tonic heat was applied from a baseline temperature of 32 °C and ramped up to 45 °C using a heating rate of 70 °C/s. Upon reaching 45 °C, thermode temperature control was relinquished to the participant for two minutes. Participants rated their pain perception using a numeric rating scale (NRS, 0–10, 0 - ‘no pain at all’, 10 - ‘worst pain imaginable’) at the beginning and end of this two-minute period. (B) Individuals were instructed to maintain their initial sensation for two minutes via a feedback controller in the dominant hand. Temperature change increments/decrements were nominally set at 0.1 °C per participant response (i.e., one “click”). (C) Model representing the interpretation of tonic heat using the participant-controlled temperature (PCT) approach, where increases in temperature demonstrate an adaptation to the stimulus, and any decreases in temperature represent sensitization (temporal summation of pain). AUC: Area under the curve, ADT: Adaptation, TSP: Temporal summation of pain.
45.0
reliability. Three trained experimenters (2 male and 1 female) performed the assessments.
since has adopted this approach or evaluated such a technique to measure the temporal summation of pain. Here, we reintroduce a psychophysical approach using a common quantitative sensory testing device to assess adaptation and temporal summation of pain based on continuous adjustments in temperature. Similar to the method proposed by Hardy and colleagues, participants were in control of stimulus temperature and instructed to maintain their initially perceived pain evoked by the 45 °C stimulus. Alterations in temperature were then extracted to reflect individual pain modulation in a participants’ perception – termed participant-controlled temperature (PCT). The primary aim of the study was to assess the feasibility and reliability of the PCT approach.
2.3. Data acquisition
A total of 50 (25 male and 25 female) participants were recruited for this study through advertisement at the research and academic institutions. Inclusion criteria included age of 18–40 years and native language being English. Exclusion criteria comprised pregnancy, intake of any medication (except birth control), and any obvious neurological and/or pain conditions.
For all procedures, the Pathway (Medoc Advanced Medical Systems, Ramat Yishai, Israel) ATS thermode (30 x 30 mm) was placed firmly against the posterior radial cutaneous area of the dominant hand (C6 dermatome) allowing for a good contact surface. Tonic heat was applied from a baseline temperature of 32 °C and ramped up to 45 °C using a heating rate of 70 °C/s (Fig. 1A). Upon reaching 45 °C, thermode temperature control was relinquished to the participant for two minutes. Participants rated their pain perception using a numeric rating scale (NRS, 0–10, 0 - ‘no pain at all’, 10 - ‘worst pain imaginable’) at the beginning and end of this two-minute period. It was explained to participants, with standardized instructions, that their goal was to use a controller with their dominant hand to maintain the temperature such that they would maintain the intensity of heat pain as initially reported. No statement was made to suggest that without participant control the thermode temperature remained constant or changed. Temperature change increments were nominally set at 0.1 °C per participant response (i.e., one “click”) (Fig. 1B). Left clicks on the controller resulted in an increase in temperature, while right clicks reduced it. It was made clear to participants that the stimulator had a built-in safety that would not allow temperatures to reach harmful intensities. This technique was conceptualized based on the original publication by Hardy and colleagues (Greene and Hardy, 1962). All signals were recorded using a builtin software at 200 Hz.
2.2. Experimental design
2.4. Data extraction
Tonic heat was always applied to the base of the thumb on the dorsum of the non-dominant hand. Participants were asked to control the temperature with the dominant hand using a commercially available device (Medoc Advanced Medical Systems, Ramat Yishai, Israel). A randomly selected subset of participants (n = 17) performed PCT tonic heat protocols on two different days to determine the test-retest
Based on what is known about behavioral responses to tonic heat (Greene and Hardy, 1962; Severin et al., 1985; Kleinböhl et al., 1999; Granot et al., 2006), PCT curves were divided into an adaptation and temporal summation of pain phase. Adaptation is characterized by a reduction in perception, conveyed as an increase in temperature of ≥ 2 clicks. In contrast, temporal summation is represented as a decrease in
2. Methods The Clinical Research Ethics Board of the University of British Columbia approved all experimental procedures. Furthermore, study procedures were in accordance with the Declaration of Helsinki and all participants provided written informed consent. 2.1. Individuals
21
Age [years]
20 20 29 21 27 22 19 32 21 21 32 20 21 29 24 26 30 30 25 23 24 24 24 32 46 25 26 27 28 28 25 63 23 36 32 36 39 28 41 28 22 23 62 34 27 21 20 20 29 21 27
ID
C01 C02 C03 C04 C05 C06 C07 C08 C09 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 C29 C30 C31 C32 C33 C34 C35 C36 C37 C38 C39 C40 C41 C42 C43 C44 C45 C46 C01 C02 C03 C04 C05
f m f f f f f m f f m f f m m f m f f f m f f m m f m f m f m m m f f m m m m f m m m m f f f m f f f
Sex
Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2
Testing Day
2 2 2 2 2 2 2 7 7 – 7 – – – – – – – – – – – – – – – – – 65 67 25 5 6 59 4 – – – – – – – – – – – 2 2 2 2 2
Days between sessions Normal Normal ADT only Normal ADT only Normal Normal Normal ADT only ADT only Normal Normal Normal Normal Normal ADT only ADT only Normal ADT only Normal Normal Normal Normal Normal Normal Normal Normal Normal ADT only Normal ADT only ADT only Normal Normal ADT only ADT only Normal Normal Normal TSP only Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
Curve Type
Table 1 Participants’ demographics, study details, and outcome parameters.
7 6 6 7 8 6 9 7 – – – 8 7 7 8 8 5 8 7 7 7 8 5 8 4 6 9 7 8 6 4 8 4 7 2 4 6 6 7 6 3 7 6 4 3 6 7 7 6 7 7
Initial rating [NRS] 7 6 6 7 7 6 8 7 – – – 8 7 7 8 8 5 8 7 7 7 8 5 8 4 6 9 7 8 6 4 7 4 7 2 5 6 6 7 5 3 7 7 4 3 6 7 7 6 7 7
Final rating [NRS] 0.04 0.03 0.01 0.02 0.01 0.04 0.06 0.04 0.01 0.03 0.02 0.02 0.05 0.02 0.02 0.02 0.02 0.04 0.02 0.06 0.03 0.06 0.04 0.03 0.07 0.31 0.05 0.04 0.03 0.04 0.01 0.06 0.02 0.03 0.01 0.06 0.32 0.06 0.05 – 0.05 0.06 0.01 0.07 0.05 0.15 0.05 0.02 0.01 0.05 0.02
Slope [°C/ s] 1.39 0.98 0.67 1.02 0.33 0.68 1.15 1.35 0.37 1.27 0.89 1.19 1.15 1.00 0.38 0.87 1.46 0.81 0.71 1.57 0.79 1.71 0.81 1.00 1.16 1.18 1.29 1.27 0.99 0.66 0.76 1.78 0.42 0.72 1.28 0.88 0.57 1.14 1.66 – 1.35 0.99 0.20 0.91 1.09 0.61 1.57 1.27 0.75 0.81 1.18
Magnitude [°C]
ADAPTATION
25.92 16.21 18.60 41.42 9.96 6.02 13.63 27.97 5.07 33.53 18.23 37.49 15.80 26.50 5.26 12.18 68.13 7.95 14.69 21.57 12.50 31.09 8.28 25.83 8.81 4.04 4.04 21.49 18.50 6.66 15.91 29.73 7.05 9.96 42.00 6.42 0.53 15.07 32.28 0 22.78 9.77 2.87 7.15 14.16 2.23 31.80 42.09 20.96 7.10 28.22
AUC [°Cs]
0.01 0.01 0 0.02 0 0.16 0.01 0.04 0 0 0.02 0.02 0.01 0.01 0.02 0 0 0.01 0 0.01 0.01 0.01 0.02 0.02 0.01 0.02 0.01 0.01 0 0.01 0 0 0.00 0.03 0 0 0.01 0.02 0.01 0.01 0.01 0.02 0.03 0.01 0.01 0.01 0.01 0.02 0.01 0.01 0.20
Slope [°C/ s] 0.55 0.48 0 0.62 0 0.19 0.68 1.20 0 0 0.48 0.77 0.70 0.37 0.40 0 0 0.59 0.00 0.88 0.52 1.02 0.91 1.03 0.44 1.58 0.91 0.43 0 0.31 0 0 0.19 0.42 0 0 0.99 0.91 0.57 0.89 0.54 0.34 0.97 0.28 0.86 0.45 0.52 0.78 0.22 0.46 0.20
Magnitude [°C]
10.96 7.26 0 10.72 0 0.12 26.99 16.43 0 0 7.66 19.43 18.17 7.96 4.15 0 0 9.40 0.00 32.09 11.71 38.69 16.72 27.90 9.25 85.85 85.85 7.17 0 3.33 0 0 4.69 3.35 0 0 41.14 24.05 13.87 26.94 10.65 2.66 11.93 2.83 28.30 8.78 12.75 19.37 1.93 8.97 0.10
AUC [°Cs]
TEMPORAL SUMMATION
22
53.96 39.01 59.73 58.77 29.09 33.45 64.13 74.83 15.58 101.23 51.87 66.19 48.46 42.09 17.57 42.34 123.10 30.56 65.40 68.88 34.79 72.82 65.03 72.90 42.44 93.33 93.33 58.25 92.88 35.26 55.22 181.75 23.38 25.78 82.01 73.15 53.97 73.19 54.98 26.94 67.84 62.81 44.19 51.08 48.51 39.76 69.12 63.81 38.64 39.66 48.93
AUC Total [°Cs]
(continued on next page)
17.08 15.54 41.13 6.63 19.13 27.31 23.51 30.43 10.51 67.70 25.98 9.27 14.49 7.63 8.16 30.16 54.97 13.21 50.71 15.22 10.58 3.04 40.03 19.17 24.38 3.44 3.44 29.59 74.38 25.27 39.31 152.02 11.64 12.47 40.01 66.73 12.30 34.07 8.83 0.00 34.41 50.38 29.39 41.10 6.05 28.75 24.57 2.35 15.75 23.59 20.61
AUC Plateau [°Cs]
OTHER
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0.15 14.93 20.69 15.25 3.37 2.75 1.68 0 1.46 3.18 0.13 0
21.49 31.06 20.69 14.33 22.45 52.99 74.50 74 3.04 35.48 15.01 15
53.45 75.43 45.69 52.01 51.72 91.07 97.52 74.82 14.25 45.93 28.70 78.89
temperature ≥ 2 clicks. Two was selected a priori as a threshold to ensure a meaningful change in perception. To quantify adaptation and temporal summation of pain, the slope and magnitude of temperature changes were extracted from individual PCT curves in Matlab (Matlab Version R2017a). The overall PCT curve was characterized by measurement of area under the curve (AUC, also extracted in Matlab). Fig. 1C illustrates how these outcomes were defined. In cases where participants did not make temperature changes (i.e., less than two clicks of increases and/or decreases), they were assigned a value of “0” for the respective parameter. 2.5. Statistical analysis
7 8 6 – 9 9 5 9 8 4 8 4
7 8 6 – 8 9 5 9 8 5 8 3
0.02 0.04 0.07 0.03 0.03 0.04 0.08 0.39 0.07 0.03 0.01 0.02
1.06 1.38 1.30 0.98 1.17 1.38 1.47 0.66 1.09 0.63 0.51 1.35
31.81 29.44 13.03 22.43 25.90 35.33 21.34 0.66 9.75 7.27 13.56 64.32
0.19 0.02 0.05 0.01 0.01 0.02 0.02 0.00 0 0.02 0.16 0
0.23 0.71 1.12 0.65 0.41 0.30 0.30 0 0.20 0.54 0.19 0
R Statistical Software version 2.15.3 for Apple Mac was used for all analyses and producing all plots. Alpha was set at 0.05 and multiple comparisons were Bonferroni corrected. Types of PCT curves were determined based on the magnitude of adaptation (increase in temperature, ADT) and temporal summation of pain (decrease in temperature, TSP). All changes in temperature are absolute values. Normal: |ADT magnitude| > 0 AND |TSP magnitude| > 0 ADT only: ADT magnitude| > 0 AND |TSP magnitude| = 0 TSP only: |ADT magnitude| = 0 AND |TSP magnitude| > 0 Spearman correlations were used to determine the effect of adaptation parameters (i.e., slope and magnitude) on temporal summation of pain parameters (magnitude and slope) as well as the relationship between initial rating to the 45 °C stimulation and PCT outcomes. Sex differences were examined with a Mann-Whitney U test. Mixed-effects models were employed to examine the main effect of time (i.e., days between test and retest) on each of the extracted data elements. Random participant and time effects were included in the models. Shapiro-Wilk test was used to confirm that the residuals of the dependent variables are normally distributed. Test–retest reliability of each data element was examined separately by consistency intra-class correlation coefficients (ICC) (single measures, two-way random effect model) (R function: irr) (Koo and Li, 2016). The ICC values were characterized based on previously reported recommendations (Shrout, 1998). Briefly, “fair”, “moderate”, and “substantial” ICCs were considered for ranges of 0.41 to 0.60, 0.61 to 0.80, and 0.81–1.00, respectively. To examine if the mean difference between the test–retest examinations was significantly different from zero, a Wilcoxon rank sums test was performed. Subsequently, a coefficient of reliability (i.e., 2 standard deviations of mean difference between test and re-test, or 95% confidence interval) for all data elements was determined (Bland and Altman, 1986). Bland-Altman plots were produced for all data elements using R package BlandAltmanLeh.
Normal Normal Normal Normal Normal Normal Normal ADT only Normal Normal Normal ADT only
3. Results AUC: Area under the curve, NRS: Numeric rating scale.
22 19 32 32 20 28 28 25 63 23 36 32 C06 C07 C08 C11 C12 C29 C30 C31 C32 C33 C34 C35
2 2 2 2 2 2 2 2 2 2 2 2 Day Day Day Day Day Day Day Day Day Day Day Day f f m m f m f f m m f f
2 2 7 7 7 65 67 25 5 6 59 4
AUC Total [°Cs] AUC [°Cs] Magnitude [°C] Slope [°C/ s] Magnitude [°C] Testing Day Sex Age [years] ID
Table 1 (continued)
Days between sessions
Curve Type
Initial rating [NRS]
Final rating [NRS]
Slope [°C/ s]
ADAPTATION
AUC [°Cs]
TEMPORAL SUMMATION
AUC Plateau [°Cs]
OTHER
C.R. Jutzeler, et al.
3.1. Participants From a total of 50 recruited participants, four had to be excluded due to heat intolerance (n = 2, one male and one female), poor data quality (temperature artefacts (n = 1, male), and did not follow instructions (i.e., forgot to adjust temperature to maintain the intensity of heat pain as initially reported (n = 1, male)). The remaining 46 participants (mean age 28.6 +/- 9.4 yrs [range 19–63]) comprised of 24 women and 22 men. Detailed participants’ characteristics are reported in Table 1. 3.2. Pattern of PCT curves There were two primary PCT curve patterns: 1) initial increase followed by a decrease in temperature (71.7%, n = 33; curve type: normal, i.e., adaptation and temporal summation), and 2) gradual increase in temperature only (26.1%, n = 12; curve type: ADT only, i.e., 23
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47.5
47.5
47.5
47.0
47.0
47.0
46.5
46.5
46.0
46.0
45.5
45.5
45.0
45.0
44.5
44.5
0
20 40 60 80 100 120
0
20 40 60 80 100 120
Fig. 2. Tonic heat curves assessed by Participant-Controlled Temperature (PCT). (A) Average ( ± 1SD) PCT of participants with curve pattern ‘normal’ (adaptation followed by temporal summation), (B) participants with curve pattern ‘ADT only’, and (C) participants with curve pattern ‘TSP only’. ADT: Adaptation, TSP: Temporal summation of pain
0
20 40 60 80 100 120
Adaptation
Temporal Summation of Pain
0.3 0.2 0.1 0.0 -0.1
Magnitude Adaptation
Temporal Summation of Pain
sex
1
0
-1
Area Under the Curve Adaptation
Temporal Summation of Pain
Plateau
Total
0
Fig. 3. Tonic heat outcomes of male and female participants. No sex-differences were found for (A) slope, (B) magnitude, and (C) Area under the curve of adaptation and temporal summation of pain.
pain, and adaptation outcomes between men and women (Fig. 3A–C). The initial rating to the 45 °C stimulus did not have a significant effect on any of the outcomes (Table 2).
adaptation). One participant (2.2% of total sample) only decreased the temperature (curve type: TSP only, i.e., temporal summation). Tonic sensation of heat was confirmed by matched pain ratings from the beginning and end of two minutes of continuous stimulation (Table 1). Grand averages ( ± 1 standard deviation) of each curve type are shown in Fig. 2. The outcomes extracted from each individual tonic heat curve, as outlined in Fig. 1C, are provided in Table 1.
3.4. Effect of time The average time between testing sessions was 15.6 +/- 26.4 days [range 2–67]. Independent of the number of days, the outcomes were comparable between test and retest (Supplementary Tables 1–3). The residuals for the slope of adaptation and temporal summation as well as the AUC of temporal summation were not normally distributed. Thus,
3.3. Effect of sex and rating on tonic heat There were no differences in initial rating, temporal summation of 24
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Laflamme et al., 2008). Our observations agree, in that we found no evidence for sex differences in the modulation of tonic heat stimulation based on a PCT approach. An explanation for the divergence between phasic and tonic heat methods is currently unknown. Given the sheer number of studies applying tonic heat to investigate pain modulation, surprisingly few have evaluated measurement reliability. What little effort has been made indicates preliminary evidence of test-retest reliability of temporal summation of pain according to rating-based techniques (Granot et al., 2006; Naert et al., 2008; Udnesseter et al., 2017). In agreement, PCT demonstrated moderate reliability of the initial rating to the 45 °C stimulus, as well as all temporal summation of pain parameters (i.e., magnitude, slope, and AUC) (Fig. 4). In contrast to temporal summation of pain, adaptation was markedly less reliable, evidenced by larger day to day variations (see Fig. 4). In previous studies applying tonic heat, stimulus intensity was individually adjusted (e.g., pain-60) in order to avoid floor and ceiling effects associated with the measurement of temporal summation based on ratings (Granot et al., 2006; Tousignant-Laflamme et al., 2008). This addresses the concern that higher initial ratings are prone to greater temporal summation of pain (Weissman-Fogel et al., 2015). The difficulty with individually adjusted temperature is two-fold. First, the time required to determined individual thresholds may be limiting in a clinical setting (i.e., applications in patient populations). Second, calibration steps prior to test stimulation may impact the nature of responses to the test stimulus (i.e., thermal carry-over effects). These problems are amplified in experiments incorporating the measurement of tonic heat into the evaluation of other forms of modulation, for example conditioned pain modulation (i.e., multiple applications of tonic heat are required as part of the test). Thus, a tonic heat paradigm that is unaffected by perceived intensity is preferred. To this end, the measurement of temporal summation of pain based on PCT was independent of rating differences. One explanation for the robustness of our PCT approach is that 45 °C resulted in ratings of 5 or greater for the vast majority of participants. A lower temperature that results more variable ratings may yield larger and correlated effects. The original application of a participant-controlled approach to assess fluctuations in heat sensation dates back to 1962 (Greene and Hardy, 1962). At this time, investigators were addressing the notion of pain adapting over time. Paradoxically, Greene and Hardy found instead that “pain tends to increase in intensity with constant low-level stimulation”, which, in retrospect, provides seminal evidence for the temporal summation of pain (Mendell and Wall, 1965; Price et al., 1994). While the concept of evaluating the modulation of tonic heat by way of PCT is not, itself, a novel approach, here we have re-examined the methodology using a modern, safe, and controlled contact heat stimulator. Beyond the original application to assess adaptation, we have demonstrated that PCT can be used to reliably examine temporal summation of pain.
Table 2 Correlation between pain rating and the tonic heat parameter (Spearman). Parameter Adaptation Slope Magnitude AUC Temporal Summation of Pain Slope Magnitude AUC Other AUC Plateau AUC Total AUC: Area under the curve
rho-value
p-value
−0.06 0.16 −0.07
0.66 0.29 0.65
0.16 0.16 0.10
0.30 0.35 0.54
−0.07 0.03
0.64 0.81
data was log transformed, which resulted in normally distributed residuals. Using a mixed-effects model, a sensitivity analyses confirmed that the number of days between test and retest did not affect any of the outcomes. 3.5. Test-retest reliability of PCT data elements All ICC values for PCT data elements and initial rating to the 45 °C stimulation are presented in Fig. 4A. Fair to substantial test-retest reliability was observed for the slope, magnitude, and AUC of temporal summation of pain. The adaptation outcomes were not reliable. BlandAltman plots for each outcome are shown in Fig. 4B. 4. Discussion A previously adopted method of evaluating modulation to noxious stimulation was re-examined using a modern contact heat stimulator. Participants were instructed to use a controller to keep their pain perception to heat constant for a period of two minutes. In agreement with rating-based methods, PCT revealed evidence of temporal summation of pain in 73% of participants of the current study (i.e., temperature was decreased after an initial period of adaptation). Temporal summation of pain (or lack thereof) was reliably captured on separate days as a change in magnitude, slope, and AUC. Collectively, our observations suggest that PCT may be a useful method to quantify temporal summation of pain. Several studies have applied continuous tonic heat of long durations (i.e., > 1 min) to assess temporal summation of pain (Granot et al., 2003, 2006; Eisenberg et al., 2015; Schulz et al., 2015; Weissman-Fogel et al., 2015; Devoize et al., 2016). These studies typically require participants to either continuously report pain perception using a computerized visual analogue scale or provide some verbal report of pain perception at fixed time-points (e.g., every 10 s). All but one participant in our study increased temperature in order to maintain their perception in the initial 30–60 s of stimulation. This is consistent with decreasing perception and was followed by reductions in temperature, paralleling that widely reported for rating based tonic heat techniques (i.e., increased ratings). Also similar to a rating based approach, approximately 25% of participants failed to demonstrate evidence of temporal summation of pain (Zheng et al., 2014; Weissman-Fogel et al., 2015; Devoize et al., 2016). Sex differences in pain perception have been the source of considerable debate. Generally speaking, women are more sensitive than men in response to a variety of test stimuli, including heat (Mogil, 2012). Based on ratings, studies applying phasic heat pulses have consistently demonstrated greater temporal summation of pain in women compared to men (Fillingim et al., 1998; Robinson et al., 2004; George et al., 2007). In contrast, temporal summation of tonic heat stimulation, with the exception of one study (Suzan et al., 2015), is unaffected by sex (Granot et al., 2003; Naert et al., 2008; Tousignant-
4.1. Future directions and limitations There are a number of limitations that warrant discussion. First, our study was performed in a relatively small sample of healthy participants. Future studies incorporating a larger number of participants are needed to examine participant-level factors, including psychological variables, that may influence temporal summation of pain. Second, with regards to our test-retest reliability, future studies should directly compare PCT to rating based tonic heat methodologies. A head-to-head comparison is needed to determine which method is most reliable and best suited to detect the modulating effect of conditioning stimuli on the temporal summation of pain. Although speculative at this time, PCT may also have other advantages compared to rating-based methods of evaluating tonic heat. For example, the sex of the examiner has been shown to impact the outcome of the pain testing (e.g., male participants report lower pain rating and higher pain tolerance in the presence of a 25
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Slope
Slope
Magnitude
Magnitude
Rating
AUC Total
Fair Moderate Substantial
AUC
AUC
-.6 -.4 -.2 0 .2 .4 .6 .8 1
AUC Plateau
-.6 -.4 -.2 0 .2 .4 .6 .8 1
-.6 -.4 -.2 0 .2 .4 .6 .8 1
Intraclass Correlation Coefficient
ADAPTATION
TEMPORAL SUMMATION OF PAIN
Slope [ºC/s]
Slope [ºC/s]
0.2
0.2
0.0
0.0
-0.2
-0.2
-0.4
-0.4 0
0.05
0.10
0.15
0.20
-0.15
-0.10
Magnitude [ºC] 1.0
0.5
0.5
0.0
0.0
-0.5
-0.5
-1.0 1
1.50
95 % Confidence intervals Mean
-1.0 -1.2
-0.9
AUC [ºCs] 40
20
20
0
0
-20
-20
0
10
20
30
-0.6
-0.3
0
AUC [ºCs]
40
-40
0
Magnitude [ºC]
1.0
0.50
-0.05
40
50
-40
0
5
10
15
20
Fig. 4. Test-retest reliability of PCT data elements. (A) Intra-class correlations revealed moderate reliability for all temporal summation parameters, namely slope, magnitude, and are under the curve (AUC) as well as for the initial rating to the 45 °C stimulation. (B) Bland-Altmann plots for all adaptation and temporal summation parameters. Blue: Participants with intervals > 50 days between testing day 1 and 2.
4.2. Conclusion
female compared to a male experimenter)(Kállai et al., 2004; Campbell et al., 2006; Aslaksen et al., 2007). In large part, the effect of the examiner on pain is related to gender roles and a reluctance to subjectively describe a stimulus as painful to a member of the opposing sex (Robinson and Wise, 2003). In terms of evaluating temporal summation, this may create an unwillingness of participants to report increasing pain intensity. To this end, PCT could serve as a covert measure of temporal summation of pain, independent of the examiner and influence of gender.
In this study, we demonstrated the feasibility of PCT to detect changes in pain perception. While the reliability to assess adaption was poor, PCT reliably allowed for detection of temporal summation of pain through measurement with a physical construct (i.e., temperature). Conclusively, PCT could be useful in future studies for detecting (spinal) endogenous pain modulation in healthy individuals and patient populations.
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Conflict of interest statement
Devoize, L., et al., 2016. Relationship between adaptation and cardiovascular response to tonic cold and heat pain Adaptability to tonic pain and cardiovascular responses. Eur. J. Pain 20 (5), 731–741. https://doi.org/10.1002/ejp.799. Eisenberg, E., et al., 2015. Spinal cord stimulation attenuates temporal summation in patients with neuropathic pain. Pain 156 (3), 381–385. https://doi.org/10.1097/01. j.pain.0000460342.69718.a2. Fillingim, R.B., et al., 1998. Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain. https://doi.org/10.1016/S03043959(97)00214-5. George, S.Z., et al., 2007. Sex and pain-related psychological variables are associated with thermal pain sensitivity for patients with chronic low back pain. J. Pain. https://doi. org/10.1016/j.jpain.2006.05.009. Granot, M., Sprecher, E., Yarnitsky, D., 2003. Psychophysics of phasic and tonic heat pain stimuli by quantitative sensory testing in healthy subjects’. Eur. J. Pain 7 (2), 139–143. https://doi.org/10.1016/S1090-3801(02)00087-3. Granot, M., et al., 2006. Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation. Pain 122 (3), 295–305. https://doi.org/10.1016/j.pain. 2006.02.003. Greene, L.C., Hardy, J.D., 1962. Adaptation of thermal pain in the skin. J. Appl. Physiol. 1985 (17), 693–696. Kállai, I., Barke, A., Voss, U., 2004. The effects of experimenter characteristics on pain reports in women and men. Pain. https://doi.org/10.1016/j.pain.2004.08.008. Kleinböhl, D., et al., 1999. Psychophysical measures of sensitization to tonic heat discriminate chronic pain patients. Pain 81 (1–2), 35–43. Koo, T.K., Li, M.Y., 2016. A guideline of selecting and reporting intraclass correlation coefficients for reliability research. J. Chiropr. Med. https://doi.org/10.1016/j.jcm. 2016.02.012. Mendell, L.M., Wall, P.D., 1965. Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature 206, 97–99. Mogil, J.S., 2012. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nature Publishing Group 13 (12), 859–866. https://doi. org/10.1038/nrn3360. Naert, A.L.G., Kehlet, H., Kupers, R., 2008. Characterization of a novel model of tonic heat pain stimulation in healthy volunteers. Pain 138 (1), 163–171. https://doi.org/10. 1016/j.pain.2007.11.018. Price, D.D., et al., 1977. Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3 (1), 57–68. Price, D.D., et al., 1994. The N-methyl-d-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain. https://doi. org/10.1016/0304-3959(94)90069-8. Robinson, M.E., Wise, E.A., 2003. Gender bias in the observation of experimental pain. Pain. https://doi.org/10.1016/S0304-3959(03)00014-9. Robinson, M.E., et al., 2004. Influences of gender role and anxiety on sex differences in temporal summation of pain. J. Pain. https://doi.org/10.1016/j.jpain.2003.11.004. Schulz, E., et al., 2015. Prefrontal gamma oscillations encode tonic pain in humans. Cereb. Cortex 25 (11), 4407–4414. https://doi.org/10.1093/cercor/bhv043. Severin, F., Lehmann, W.P., Strian, F., 1985. Subjective sensitization to tonic heat as an indicator of thermal pain. Pain 21 (4), 369–378. Shrout, P.E., 1998. Measurement reliability and agreement in psychiatry. Stat. Methods Med. Res. 7 (3), 301–317. https://doi.org/10.1177/096228029800700306. Staud, R., et al., 2001. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. https://doi.org/10.1016/ S0304-3959(00)00432-2. Staud, R., et al., 2003. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 101 (1–2), 167–174. Staud, R., et al., 2014. Slow temporal summation of pain for assessment of central pain sensitivity and clinical pain of fibromyalgia patients. PLoS One. https://doi.org/10. 1371/journal.pone.0089086. Suzan, E., et al., 2015. Individually based measurement of temporal summation evoked by a noxious tonic heat paradigm. J. Pain Res. 8, 409–415. https://doi.org/10.2147/ JPR.S83352. Tousignant-Laflamme, Y., et al., 2008. An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res. 1230, 73–79. https://doi.org/10. 1016/j.brainres.2008.06.120. Udnesseter, M., et al., 2017. A tonic heat test stimulus yields a larger and more reliable conditioned pain modulation effect compared to a phasic heat test stimulus. Pain Rep. 0, 1–8. https://doi.org/10.1097/PR9.0000000000000626. Weissman-Fogel, I., Dror, A., Defrin, R., 2015. Temporal and spatial aspects of experimental tonic pain: understanding pain adaptation and intensification. Eur. J. 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The authors declare no competing financial interests. Authors contributions Catherine Jutzeler contributed substantially to the conception and design of the study, the data acquisition, analysis, and interpretation. Furthermore, she was chiefly involved in drafting the manuscript. Laura Sirucek led the development of the algorithm for the data preprocessing and extracting data elements. She was further involved in drafting the manuscript. Paulina Scheuren contributed to the development of the data extraction algorithm, data analysis, and revised the manuscript for intellectual content. Bobo Tong contributed substantially to the data acquisition and revised the research article for important intellectual content. Eitan Anenberg contributed substantially to the data acquisition and revised the research article for important intellectual content. Oscar Ortiz substantially contributed to the development of the algorithm for the data preprocessing and data elements extraction as well as revised the research article for important intellectual content. Jan Rosner was involved in the data analysis and revising the research article. Michèle Hubli was involved in the data analysis and revised the research article for important intellectual content. John Kramer contributed substantially to the conception and design of the study, data analysis and interpretation, and was involved in drafting the research article. Acknowledgments We would like to thank all of the individuals participating in the study. The study was supported by an NSERC Discovery grant (John Kramer, #1502). Catherine Jutzeler is supported by postdoctoral research fellowship from the Craig H. Neilsen Foundation (#460378). Paulina Scheuren was supported by a Blusson Integrated Cures Partnership International Award (Rick Hansen Foundation and International Collaboration On Repair Discoveries [ICORD]). Jan Rosner is supported through funding from the Hartmann MüllerStiftung für Medizinische Forschung (grant number 1997) and supported by the Swiss Spinal Cord Injury Cohort Study Nested Project Grant (Rosner and Jutzeler, 2016-N-005). John Kramer is supported by a Michael Smith Foundation for Health Research and Rick Hansen Scholar Award. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jneumeth.2019.04. 003. References Aslaksen, P.M., et al., 2007. The effect of experimenter gender on autonomic and subjective responses to pain stimuli. Pain. https://doi.org/10.1016/j.pain.2006.10.011. Bland, J.M., Altman, D.G., 1986. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 327, 307–310. https://doi.org/10.1016/ S0140-6736(86)90837-8. Campbell, T.S., Holder, M.D., France, C.R., 2006. The effects of experimenter status and cardiovascular reactivity on pain reports. Pain. https://doi.org/10.1016/j.pain.2006. 06.002.
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Contents lists available at ScienceDirect
Journal of Neuroscience Methods journal homepage: www.elsevier.com/locate/jneumeth
New life for an old idea: Assessing tonic heat pain by means of participant controlled temperature
T
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Catherine R. Jutzelera,b,c,1, , Laura Siruceka, Paulina S. Scheurenb, Tong Bobob, Eitan Anenbergb, Oscar Ortizb, Jan Rosnera, Michèle Hublia, John L.K. Kramerb,c a
Spinal Cord Injury Center, University Hospital Balgrist, University of Zurich, Zurich, Switzerland ICORD, University of British Columbia, Vancouver, British Columbia, Canada c School of Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada b
A R T I C LE I N FO
A B S T R A C T
Keywords: Tonic heat pain Temporal summation of pain Participant-controlled temperature Test-retest reliability Experimental model of pain
Background: Temporal changes of pain perception to prolonged tonic heat pain are conventionally assessed using a computerized visual analog scale. Such a rating-based approach is, however, prone to floor and ceiling effects, which limit the assessment of temporal changes in perception. Thus, alternative methods that overcome these shortcomings are warranted. New method: The aim of this study was to assess the feasibility and reliability of a psychophysical approach, i.e., participant-controlled temperature (PCT), to evaluate ongoing human perception of tonic heat pain. Fifty participants were presented with a 45 °C stimulus on the non-dominant hand, and were instructed to maintain their initial sensation for two minutes via a feedback controller in the dominant hand. A subset of participants (n = 17) performed PCT tonic heat protocols on two different days to determine the test-retest reliability. As participants controlled temperature to maintain a stable pain perception, any adjustments made reflected shifts in their perception of heat. Results: In 33 (71.7%) participants, we observed an initial adaptation (participant increased temperature) followed by temporal summation of pain (participant decreased temperature). Twelve participants (26.1%) showed only adaptation and one (2.2%) only temporal summation. No sex differences were observed, nor did the initial rating of pain have an effect on PCT outcomes. Temporal summation of pain showed moderate to substantial reliability upon retest. Conclusions: PCT represents can be reliably performed using a contact heat stimulator to measure the temporal summation of pain. The standardized setup and overall good reliability of the outcome measures facilitate a sound implementation into the clinical work-up of patients with pain conditions.
1. Introduction Tonic heat stimulation has been proposed as a physiologically relevant alternative to noxious, phasic, stimuli, suitable for the assessment of wind-up in humans – so-called temporal summation of pain (Price et al., 1977; Granot et al., 2006; Suzan et al., 2015). Conventional tonic heat stimulation paradigms apply a fixed heat stimulus over a one to two-minute period and acquire intermittent or continuous ratings of perceived intensity. An individual’s perception is characterized by initial decreases, promptly followed by increased ratings. The latter is thought to represent central wind-up of noxious stimuli, which
is believed to occur at the level of the spinal cord (Price et al., 1977; Staud et al., 2003). Emphasizing a need for a valid and reliable assessment, studies have reported increased temporal summation of pain as a characteristic of chronic pain (Staud et al., 2001, 2014). The earliest studies examining responses to tonic heat reported changes in temporal summation of pain, not based on rating, but rather on changes in temperature. Applying a “thermal radiation” instrument, Greene and Hardy instructed participants to adjust stimulus energy so as to maintain a constant intensity (Greene and Hardy, 1962). The focus of this study was on adaptation and to what extent adaptation occurred during presentation of a noxious stimulus. To our knowledge, no study
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Corresponding author at: 818W 10th Ave, Vancouver, BC, V5Z 1M9, Canada. E-mail addresses: [email protected] (C.R. Jutzeler), [email protected] (L. Sirucek), [email protected] (P.S. Scheuren), [email protected] (T. Bobo), [email protected] (E. Anenberg), [email protected] (O. Ortiz), [email protected] (J. Rosner), [email protected] (M. Hubli), [email protected] (J.L.K. Kramer). 1 URL: www.icord.org. https://doi.org/10.1016/j.jneumeth.2019.04.003 Received 2 November 2018; Received in revised form 20 March 2019; Accepted 5 April 2019 Available online 06 April 2019 0165-0270/ © 2019 Elsevier B.V. All rights reserved.
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PCT
45
32
0
Dominant Hand
120 Time [sec]
+ +
46.0
45.5
AUC ADT AUC Plateau
slope TSP slope ADT ADT Magnitude
AUC Total
AUC TSP
TSP Magnitude
Fig. 1. Study design details. (A) Tonic heat was applied from a baseline temperature of 32 °C and ramped up to 45 °C using a heating rate of 70 °C/s. Upon reaching 45 °C, thermode temperature control was relinquished to the participant for two minutes. Participants rated their pain perception using a numeric rating scale (NRS, 0–10, 0 - ‘no pain at all’, 10 - ‘worst pain imaginable’) at the beginning and end of this two-minute period. (B) Individuals were instructed to maintain their initial sensation for two minutes via a feedback controller in the dominant hand. Temperature change increments/decrements were nominally set at 0.1 °C per participant response (i.e., one “click”). (C) Model representing the interpretation of tonic heat using the participant-controlled temperature (PCT) approach, where increases in temperature demonstrate an adaptation to the stimulus, and any decreases in temperature represent sensitization (temporal summation of pain). AUC: Area under the curve, ADT: Adaptation, TSP: Temporal summation of pain.
45.0
reliability. Three trained experimenters (2 male and 1 female) performed the assessments.
since has adopted this approach or evaluated such a technique to measure the temporal summation of pain. Here, we reintroduce a psychophysical approach using a common quantitative sensory testing device to assess adaptation and temporal summation of pain based on continuous adjustments in temperature. Similar to the method proposed by Hardy and colleagues, participants were in control of stimulus temperature and instructed to maintain their initially perceived pain evoked by the 45 °C stimulus. Alterations in temperature were then extracted to reflect individual pain modulation in a participants’ perception – termed participant-controlled temperature (PCT). The primary aim of the study was to assess the feasibility and reliability of the PCT approach.
2.3. Data acquisition
A total of 50 (25 male and 25 female) participants were recruited for this study through advertisement at the research and academic institutions. Inclusion criteria included age of 18–40 years and native language being English. Exclusion criteria comprised pregnancy, intake of any medication (except birth control), and any obvious neurological and/or pain conditions.
For all procedures, the Pathway (Medoc Advanced Medical Systems, Ramat Yishai, Israel) ATS thermode (30 x 30 mm) was placed firmly against the posterior radial cutaneous area of the dominant hand (C6 dermatome) allowing for a good contact surface. Tonic heat was applied from a baseline temperature of 32 °C and ramped up to 45 °C using a heating rate of 70 °C/s (Fig. 1A). Upon reaching 45 °C, thermode temperature control was relinquished to the participant for two minutes. Participants rated their pain perception using a numeric rating scale (NRS, 0–10, 0 - ‘no pain at all’, 10 - ‘worst pain imaginable’) at the beginning and end of this two-minute period. It was explained to participants, with standardized instructions, that their goal was to use a controller with their dominant hand to maintain the temperature such that they would maintain the intensity of heat pain as initially reported. No statement was made to suggest that without participant control the thermode temperature remained constant or changed. Temperature change increments were nominally set at 0.1 °C per participant response (i.e., one “click”) (Fig. 1B). Left clicks on the controller resulted in an increase in temperature, while right clicks reduced it. It was made clear to participants that the stimulator had a built-in safety that would not allow temperatures to reach harmful intensities. This technique was conceptualized based on the original publication by Hardy and colleagues (Greene and Hardy, 1962). All signals were recorded using a builtin software at 200 Hz.
2.2. Experimental design
2.4. Data extraction
Tonic heat was always applied to the base of the thumb on the dorsum of the non-dominant hand. Participants were asked to control the temperature with the dominant hand using a commercially available device (Medoc Advanced Medical Systems, Ramat Yishai, Israel). A randomly selected subset of participants (n = 17) performed PCT tonic heat protocols on two different days to determine the test-retest
Based on what is known about behavioral responses to tonic heat (Greene and Hardy, 1962; Severin et al., 1985; Kleinböhl et al., 1999; Granot et al., 2006), PCT curves were divided into an adaptation and temporal summation of pain phase. Adaptation is characterized by a reduction in perception, conveyed as an increase in temperature of ≥ 2 clicks. In contrast, temporal summation is represented as a decrease in
2. Methods The Clinical Research Ethics Board of the University of British Columbia approved all experimental procedures. Furthermore, study procedures were in accordance with the Declaration of Helsinki and all participants provided written informed consent. 2.1. Individuals
21
Age [years]
20 20 29 21 27 22 19 32 21 21 32 20 21 29 24 26 30 30 25 23 24 24 24 32 46 25 26 27 28 28 25 63 23 36 32 36 39 28 41 28 22 23 62 34 27 21 20 20 29 21 27
ID
C01 C02 C03 C04 C05 C06 C07 C08 C09 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 C29 C30 C31 C32 C33 C34 C35 C36 C37 C38 C39 C40 C41 C42 C43 C44 C45 C46 C01 C02 C03 C04 C05
f m f f f f f m f f m f f m m f m f f f m f f m m f m f m f m m m f f m m m m f m m m m f f f m f f f
Sex
Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2
Testing Day
2 2 2 2 2 2 2 7 7 – 7 – – – – – – – – – – – – – – – – – 65 67 25 5 6 59 4 – – – – – – – – – – – 2 2 2 2 2
Days between sessions Normal Normal ADT only Normal ADT only Normal Normal Normal ADT only ADT only Normal Normal Normal Normal Normal ADT only ADT only Normal ADT only Normal Normal Normal Normal Normal Normal Normal Normal Normal ADT only Normal ADT only ADT only Normal Normal ADT only ADT only Normal Normal Normal TSP only Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
Curve Type
Table 1 Participants’ demographics, study details, and outcome parameters.
7 6 6 7 8 6 9 7 – – – 8 7 7 8 8 5 8 7 7 7 8 5 8 4 6 9 7 8 6 4 8 4 7 2 4 6 6 7 6 3 7 6 4 3 6 7 7 6 7 7
Initial rating [NRS] 7 6 6 7 7 6 8 7 – – – 8 7 7 8 8 5 8 7 7 7 8 5 8 4 6 9 7 8 6 4 7 4 7 2 5 6 6 7 5 3 7 7 4 3 6 7 7 6 7 7
Final rating [NRS] 0.04 0.03 0.01 0.02 0.01 0.04 0.06 0.04 0.01 0.03 0.02 0.02 0.05 0.02 0.02 0.02 0.02 0.04 0.02 0.06 0.03 0.06 0.04 0.03 0.07 0.31 0.05 0.04 0.03 0.04 0.01 0.06 0.02 0.03 0.01 0.06 0.32 0.06 0.05 – 0.05 0.06 0.01 0.07 0.05 0.15 0.05 0.02 0.01 0.05 0.02
Slope [°C/ s] 1.39 0.98 0.67 1.02 0.33 0.68 1.15 1.35 0.37 1.27 0.89 1.19 1.15 1.00 0.38 0.87 1.46 0.81 0.71 1.57 0.79 1.71 0.81 1.00 1.16 1.18 1.29 1.27 0.99 0.66 0.76 1.78 0.42 0.72 1.28 0.88 0.57 1.14 1.66 – 1.35 0.99 0.20 0.91 1.09 0.61 1.57 1.27 0.75 0.81 1.18
Magnitude [°C]
ADAPTATION
25.92 16.21 18.60 41.42 9.96 6.02 13.63 27.97 5.07 33.53 18.23 37.49 15.80 26.50 5.26 12.18 68.13 7.95 14.69 21.57 12.50 31.09 8.28 25.83 8.81 4.04 4.04 21.49 18.50 6.66 15.91 29.73 7.05 9.96 42.00 6.42 0.53 15.07 32.28 0 22.78 9.77 2.87 7.15 14.16 2.23 31.80 42.09 20.96 7.10 28.22
AUC [°Cs]
0.01 0.01 0 0.02 0 0.16 0.01 0.04 0 0 0.02 0.02 0.01 0.01 0.02 0 0 0.01 0 0.01 0.01 0.01 0.02 0.02 0.01 0.02 0.01 0.01 0 0.01 0 0 0.00 0.03 0 0 0.01 0.02 0.01 0.01 0.01 0.02 0.03 0.01 0.01 0.01 0.01 0.02 0.01 0.01 0.20
Slope [°C/ s] 0.55 0.48 0 0.62 0 0.19 0.68 1.20 0 0 0.48 0.77 0.70 0.37 0.40 0 0 0.59 0.00 0.88 0.52 1.02 0.91 1.03 0.44 1.58 0.91 0.43 0 0.31 0 0 0.19 0.42 0 0 0.99 0.91 0.57 0.89 0.54 0.34 0.97 0.28 0.86 0.45 0.52 0.78 0.22 0.46 0.20
Magnitude [°C]
10.96 7.26 0 10.72 0 0.12 26.99 16.43 0 0 7.66 19.43 18.17 7.96 4.15 0 0 9.40 0.00 32.09 11.71 38.69 16.72 27.90 9.25 85.85 85.85 7.17 0 3.33 0 0 4.69 3.35 0 0 41.14 24.05 13.87 26.94 10.65 2.66 11.93 2.83 28.30 8.78 12.75 19.37 1.93 8.97 0.10
AUC [°Cs]
TEMPORAL SUMMATION
22
53.96 39.01 59.73 58.77 29.09 33.45 64.13 74.83 15.58 101.23 51.87 66.19 48.46 42.09 17.57 42.34 123.10 30.56 65.40 68.88 34.79 72.82 65.03 72.90 42.44 93.33 93.33 58.25 92.88 35.26 55.22 181.75 23.38 25.78 82.01 73.15 53.97 73.19 54.98 26.94 67.84 62.81 44.19 51.08 48.51 39.76 69.12 63.81 38.64 39.66 48.93
AUC Total [°Cs]
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17.08 15.54 41.13 6.63 19.13 27.31 23.51 30.43 10.51 67.70 25.98 9.27 14.49 7.63 8.16 30.16 54.97 13.21 50.71 15.22 10.58 3.04 40.03 19.17 24.38 3.44 3.44 29.59 74.38 25.27 39.31 152.02 11.64 12.47 40.01 66.73 12.30 34.07 8.83 0.00 34.41 50.38 29.39 41.10 6.05 28.75 24.57 2.35 15.75 23.59 20.61
AUC Plateau [°Cs]
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0.15 14.93 20.69 15.25 3.37 2.75 1.68 0 1.46 3.18 0.13 0
21.49 31.06 20.69 14.33 22.45 52.99 74.50 74 3.04 35.48 15.01 15
53.45 75.43 45.69 52.01 51.72 91.07 97.52 74.82 14.25 45.93 28.70 78.89
temperature ≥ 2 clicks. Two was selected a priori as a threshold to ensure a meaningful change in perception. To quantify adaptation and temporal summation of pain, the slope and magnitude of temperature changes were extracted from individual PCT curves in Matlab (Matlab Version R2017a). The overall PCT curve was characterized by measurement of area under the curve (AUC, also extracted in Matlab). Fig. 1C illustrates how these outcomes were defined. In cases where participants did not make temperature changes (i.e., less than two clicks of increases and/or decreases), they were assigned a value of “0” for the respective parameter. 2.5. Statistical analysis
7 8 6 – 9 9 5 9 8 4 8 4
7 8 6 – 8 9 5 9 8 5 8 3
0.02 0.04 0.07 0.03 0.03 0.04 0.08 0.39 0.07 0.03 0.01 0.02
1.06 1.38 1.30 0.98 1.17 1.38 1.47 0.66 1.09 0.63 0.51 1.35
31.81 29.44 13.03 22.43 25.90 35.33 21.34 0.66 9.75 7.27 13.56 64.32
0.19 0.02 0.05 0.01 0.01 0.02 0.02 0.00 0 0.02 0.16 0
0.23 0.71 1.12 0.65 0.41 0.30 0.30 0 0.20 0.54 0.19 0
R Statistical Software version 2.15.3 for Apple Mac was used for all analyses and producing all plots. Alpha was set at 0.05 and multiple comparisons were Bonferroni corrected. Types of PCT curves were determined based on the magnitude of adaptation (increase in temperature, ADT) and temporal summation of pain (decrease in temperature, TSP). All changes in temperature are absolute values. Normal: |ADT magnitude| > 0 AND |TSP magnitude| > 0 ADT only: ADT magnitude| > 0 AND |TSP magnitude| = 0 TSP only: |ADT magnitude| = 0 AND |TSP magnitude| > 0 Spearman correlations were used to determine the effect of adaptation parameters (i.e., slope and magnitude) on temporal summation of pain parameters (magnitude and slope) as well as the relationship between initial rating to the 45 °C stimulation and PCT outcomes. Sex differences were examined with a Mann-Whitney U test. Mixed-effects models were employed to examine the main effect of time (i.e., days between test and retest) on each of the extracted data elements. Random participant and time effects were included in the models. Shapiro-Wilk test was used to confirm that the residuals of the dependent variables are normally distributed. Test–retest reliability of each data element was examined separately by consistency intra-class correlation coefficients (ICC) (single measures, two-way random effect model) (R function: irr) (Koo and Li, 2016). The ICC values were characterized based on previously reported recommendations (Shrout, 1998). Briefly, “fair”, “moderate”, and “substantial” ICCs were considered for ranges of 0.41 to 0.60, 0.61 to 0.80, and 0.81–1.00, respectively. To examine if the mean difference between the test–retest examinations was significantly different from zero, a Wilcoxon rank sums test was performed. Subsequently, a coefficient of reliability (i.e., 2 standard deviations of mean difference between test and re-test, or 95% confidence interval) for all data elements was determined (Bland and Altman, 1986). Bland-Altman plots were produced for all data elements using R package BlandAltmanLeh.
Normal Normal Normal Normal Normal Normal Normal ADT only Normal Normal Normal ADT only
3. Results AUC: Area under the curve, NRS: Numeric rating scale.
22 19 32 32 20 28 28 25 63 23 36 32 C06 C07 C08 C11 C12 C29 C30 C31 C32 C33 C34 C35
2 2 2 2 2 2 2 2 2 2 2 2 Day Day Day Day Day Day Day Day Day Day Day Day f f m m f m f f m m f f
2 2 7 7 7 65 67 25 5 6 59 4
AUC Total [°Cs] AUC [°Cs] Magnitude [°C] Slope [°C/ s] Magnitude [°C] Testing Day Sex Age [years] ID
Table 1 (continued)
Days between sessions
Curve Type
Initial rating [NRS]
Final rating [NRS]
Slope [°C/ s]
ADAPTATION
AUC [°Cs]
TEMPORAL SUMMATION
AUC Plateau [°Cs]
OTHER
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3.1. Participants From a total of 50 recruited participants, four had to be excluded due to heat intolerance (n = 2, one male and one female), poor data quality (temperature artefacts (n = 1, male), and did not follow instructions (i.e., forgot to adjust temperature to maintain the intensity of heat pain as initially reported (n = 1, male)). The remaining 46 participants (mean age 28.6 +/- 9.4 yrs [range 19–63]) comprised of 24 women and 22 men. Detailed participants’ characteristics are reported in Table 1. 3.2. Pattern of PCT curves There were two primary PCT curve patterns: 1) initial increase followed by a decrease in temperature (71.7%, n = 33; curve type: normal, i.e., adaptation and temporal summation), and 2) gradual increase in temperature only (26.1%, n = 12; curve type: ADT only, i.e., 23
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47.5
47.5
47.5
47.0
47.0
47.0
46.5
46.5
46.0
46.0
45.5
45.5
45.0
45.0
44.5
44.5
0
20 40 60 80 100 120
0
20 40 60 80 100 120
Fig. 2. Tonic heat curves assessed by Participant-Controlled Temperature (PCT). (A) Average ( ± 1SD) PCT of participants with curve pattern ‘normal’ (adaptation followed by temporal summation), (B) participants with curve pattern ‘ADT only’, and (C) participants with curve pattern ‘TSP only’. ADT: Adaptation, TSP: Temporal summation of pain
0
20 40 60 80 100 120
Adaptation
Temporal Summation of Pain
0.3 0.2 0.1 0.0 -0.1
Magnitude Adaptation
Temporal Summation of Pain
sex
1
0
-1
Area Under the Curve Adaptation
Temporal Summation of Pain
Plateau
Total
0
Fig. 3. Tonic heat outcomes of male and female participants. No sex-differences were found for (A) slope, (B) magnitude, and (C) Area under the curve of adaptation and temporal summation of pain.
pain, and adaptation outcomes between men and women (Fig. 3A–C). The initial rating to the 45 °C stimulus did not have a significant effect on any of the outcomes (Table 2).
adaptation). One participant (2.2% of total sample) only decreased the temperature (curve type: TSP only, i.e., temporal summation). Tonic sensation of heat was confirmed by matched pain ratings from the beginning and end of two minutes of continuous stimulation (Table 1). Grand averages ( ± 1 standard deviation) of each curve type are shown in Fig. 2. The outcomes extracted from each individual tonic heat curve, as outlined in Fig. 1C, are provided in Table 1.
3.4. Effect of time The average time between testing sessions was 15.6 +/- 26.4 days [range 2–67]. Independent of the number of days, the outcomes were comparable between test and retest (Supplementary Tables 1–3). The residuals for the slope of adaptation and temporal summation as well as the AUC of temporal summation were not normally distributed. Thus,
3.3. Effect of sex and rating on tonic heat There were no differences in initial rating, temporal summation of 24
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Laflamme et al., 2008). Our observations agree, in that we found no evidence for sex differences in the modulation of tonic heat stimulation based on a PCT approach. An explanation for the divergence between phasic and tonic heat methods is currently unknown. Given the sheer number of studies applying tonic heat to investigate pain modulation, surprisingly few have evaluated measurement reliability. What little effort has been made indicates preliminary evidence of test-retest reliability of temporal summation of pain according to rating-based techniques (Granot et al., 2006; Naert et al., 2008; Udnesseter et al., 2017). In agreement, PCT demonstrated moderate reliability of the initial rating to the 45 °C stimulus, as well as all temporal summation of pain parameters (i.e., magnitude, slope, and AUC) (Fig. 4). In contrast to temporal summation of pain, adaptation was markedly less reliable, evidenced by larger day to day variations (see Fig. 4). In previous studies applying tonic heat, stimulus intensity was individually adjusted (e.g., pain-60) in order to avoid floor and ceiling effects associated with the measurement of temporal summation based on ratings (Granot et al., 2006; Tousignant-Laflamme et al., 2008). This addresses the concern that higher initial ratings are prone to greater temporal summation of pain (Weissman-Fogel et al., 2015). The difficulty with individually adjusted temperature is two-fold. First, the time required to determined individual thresholds may be limiting in a clinical setting (i.e., applications in patient populations). Second, calibration steps prior to test stimulation may impact the nature of responses to the test stimulus (i.e., thermal carry-over effects). These problems are amplified in experiments incorporating the measurement of tonic heat into the evaluation of other forms of modulation, for example conditioned pain modulation (i.e., multiple applications of tonic heat are required as part of the test). Thus, a tonic heat paradigm that is unaffected by perceived intensity is preferred. To this end, the measurement of temporal summation of pain based on PCT was independent of rating differences. One explanation for the robustness of our PCT approach is that 45 °C resulted in ratings of 5 or greater for the vast majority of participants. A lower temperature that results more variable ratings may yield larger and correlated effects. The original application of a participant-controlled approach to assess fluctuations in heat sensation dates back to 1962 (Greene and Hardy, 1962). At this time, investigators were addressing the notion of pain adapting over time. Paradoxically, Greene and Hardy found instead that “pain tends to increase in intensity with constant low-level stimulation”, which, in retrospect, provides seminal evidence for the temporal summation of pain (Mendell and Wall, 1965; Price et al., 1994). While the concept of evaluating the modulation of tonic heat by way of PCT is not, itself, a novel approach, here we have re-examined the methodology using a modern, safe, and controlled contact heat stimulator. Beyond the original application to assess adaptation, we have demonstrated that PCT can be used to reliably examine temporal summation of pain.
Table 2 Correlation between pain rating and the tonic heat parameter (Spearman). Parameter Adaptation Slope Magnitude AUC Temporal Summation of Pain Slope Magnitude AUC Other AUC Plateau AUC Total AUC: Area under the curve
rho-value
p-value
−0.06 0.16 −0.07
0.66 0.29 0.65
0.16 0.16 0.10
0.30 0.35 0.54
−0.07 0.03
0.64 0.81
data was log transformed, which resulted in normally distributed residuals. Using a mixed-effects model, a sensitivity analyses confirmed that the number of days between test and retest did not affect any of the outcomes. 3.5. Test-retest reliability of PCT data elements All ICC values for PCT data elements and initial rating to the 45 °C stimulation are presented in Fig. 4A. Fair to substantial test-retest reliability was observed for the slope, magnitude, and AUC of temporal summation of pain. The adaptation outcomes were not reliable. BlandAltman plots for each outcome are shown in Fig. 4B. 4. Discussion A previously adopted method of evaluating modulation to noxious stimulation was re-examined using a modern contact heat stimulator. Participants were instructed to use a controller to keep their pain perception to heat constant for a period of two minutes. In agreement with rating-based methods, PCT revealed evidence of temporal summation of pain in 73% of participants of the current study (i.e., temperature was decreased after an initial period of adaptation). Temporal summation of pain (or lack thereof) was reliably captured on separate days as a change in magnitude, slope, and AUC. Collectively, our observations suggest that PCT may be a useful method to quantify temporal summation of pain. Several studies have applied continuous tonic heat of long durations (i.e., > 1 min) to assess temporal summation of pain (Granot et al., 2003, 2006; Eisenberg et al., 2015; Schulz et al., 2015; Weissman-Fogel et al., 2015; Devoize et al., 2016). These studies typically require participants to either continuously report pain perception using a computerized visual analogue scale or provide some verbal report of pain perception at fixed time-points (e.g., every 10 s). All but one participant in our study increased temperature in order to maintain their perception in the initial 30–60 s of stimulation. This is consistent with decreasing perception and was followed by reductions in temperature, paralleling that widely reported for rating based tonic heat techniques (i.e., increased ratings). Also similar to a rating based approach, approximately 25% of participants failed to demonstrate evidence of temporal summation of pain (Zheng et al., 2014; Weissman-Fogel et al., 2015; Devoize et al., 2016). Sex differences in pain perception have been the source of considerable debate. Generally speaking, women are more sensitive than men in response to a variety of test stimuli, including heat (Mogil, 2012). Based on ratings, studies applying phasic heat pulses have consistently demonstrated greater temporal summation of pain in women compared to men (Fillingim et al., 1998; Robinson et al., 2004; George et al., 2007). In contrast, temporal summation of tonic heat stimulation, with the exception of one study (Suzan et al., 2015), is unaffected by sex (Granot et al., 2003; Naert et al., 2008; Tousignant-
4.1. Future directions and limitations There are a number of limitations that warrant discussion. First, our study was performed in a relatively small sample of healthy participants. Future studies incorporating a larger number of participants are needed to examine participant-level factors, including psychological variables, that may influence temporal summation of pain. Second, with regards to our test-retest reliability, future studies should directly compare PCT to rating based tonic heat methodologies. A head-to-head comparison is needed to determine which method is most reliable and best suited to detect the modulating effect of conditioning stimuli on the temporal summation of pain. Although speculative at this time, PCT may also have other advantages compared to rating-based methods of evaluating tonic heat. For example, the sex of the examiner has been shown to impact the outcome of the pain testing (e.g., male participants report lower pain rating and higher pain tolerance in the presence of a 25
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Slope
Slope
Magnitude
Magnitude
Rating
AUC Total
Fair Moderate Substantial
AUC
AUC
-.6 -.4 -.2 0 .2 .4 .6 .8 1
AUC Plateau
-.6 -.4 -.2 0 .2 .4 .6 .8 1
-.6 -.4 -.2 0 .2 .4 .6 .8 1
Intraclass Correlation Coefficient
ADAPTATION
TEMPORAL SUMMATION OF PAIN
Slope [ºC/s]
Slope [ºC/s]
0.2
0.2
0.0
0.0
-0.2
-0.2
-0.4
-0.4 0
0.05
0.10
0.15
0.20
-0.15
-0.10
Magnitude [ºC] 1.0
0.5
0.5
0.0
0.0
-0.5
-0.5
-1.0 1
1.50
95 % Confidence intervals Mean
-1.0 -1.2
-0.9
AUC [ºCs] 40
20
20
0
0
-20
-20
0
10
20
30
-0.6
-0.3
0
AUC [ºCs]
40
-40
0
Magnitude [ºC]
1.0
0.50
-0.05
40
50
-40
0
5
10
15
20
Fig. 4. Test-retest reliability of PCT data elements. (A) Intra-class correlations revealed moderate reliability for all temporal summation parameters, namely slope, magnitude, and are under the curve (AUC) as well as for the initial rating to the 45 °C stimulation. (B) Bland-Altmann plots for all adaptation and temporal summation parameters. Blue: Participants with intervals > 50 days between testing day 1 and 2.
4.2. Conclusion
female compared to a male experimenter)(Kállai et al., 2004; Campbell et al., 2006; Aslaksen et al., 2007). In large part, the effect of the examiner on pain is related to gender roles and a reluctance to subjectively describe a stimulus as painful to a member of the opposing sex (Robinson and Wise, 2003). In terms of evaluating temporal summation, this may create an unwillingness of participants to report increasing pain intensity. To this end, PCT could serve as a covert measure of temporal summation of pain, independent of the examiner and influence of gender.
In this study, we demonstrated the feasibility of PCT to detect changes in pain perception. While the reliability to assess adaption was poor, PCT reliably allowed for detection of temporal summation of pain through measurement with a physical construct (i.e., temperature). Conclusively, PCT could be useful in future studies for detecting (spinal) endogenous pain modulation in healthy individuals and patient populations.
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Conflict of interest statement
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The authors declare no competing financial interests. Authors contributions Catherine Jutzeler contributed substantially to the conception and design of the study, the data acquisition, analysis, and interpretation. Furthermore, she was chiefly involved in drafting the manuscript. Laura Sirucek led the development of the algorithm for the data preprocessing and extracting data elements. She was further involved in drafting the manuscript. Paulina Scheuren contributed to the development of the data extraction algorithm, data analysis, and revised the manuscript for intellectual content. Bobo Tong contributed substantially to the data acquisition and revised the research article for important intellectual content. Eitan Anenberg contributed substantially to the data acquisition and revised the research article for important intellectual content. Oscar Ortiz substantially contributed to the development of the algorithm for the data preprocessing and data elements extraction as well as revised the research article for important intellectual content. Jan Rosner was involved in the data analysis and revising the research article. Michèle Hubli was involved in the data analysis and revised the research article for important intellectual content. John Kramer contributed substantially to the conception and design of the study, data analysis and interpretation, and was involved in drafting the research article. Acknowledgments We would like to thank all of the individuals participating in the study. The study was supported by an NSERC Discovery grant (John Kramer, #1502). Catherine Jutzeler is supported by postdoctoral research fellowship from the Craig H. Neilsen Foundation (#460378). Paulina Scheuren was supported by a Blusson Integrated Cures Partnership International Award (Rick Hansen Foundation and International Collaboration On Repair Discoveries [ICORD]). Jan Rosner is supported through funding from the Hartmann MüllerStiftung für Medizinische Forschung (grant number 1997) and supported by the Swiss Spinal Cord Injury Cohort Study Nested Project Grant (Rosner and Jutzeler, 2016-N-005). John Kramer is supported by a Michael Smith Foundation for Health Research and Rick Hansen Scholar Award. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jneumeth.2019.04. 003. References Aslaksen, P.M., et al., 2007. The effect of experimenter gender on autonomic and subjective responses to pain stimuli. Pain. https://doi.org/10.1016/j.pain.2006.10.011. Bland, J.M., Altman, D.G., 1986. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 327, 307–310. https://doi.org/10.1016/ S0140-6736(86)90837-8. Campbell, T.S., Holder, M.D., France, C.R., 2006. The effects of experimenter status and cardiovascular reactivity on pain reports. Pain. https://doi.org/10.1016/j.pain.2006. 06.002.
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