We acknowledge funding support by K23 AT008477 (Kong), NIH K23 DA031808 (Johnson), and the Chris Redlich Endowment in Pain Research (Mackey, Dixon).

1. Temporal Summation Protocol
<ol>
	<li>Equipment
	<ol>
		<li>Heat pulse delivery and location:
		<ol>
			<li>Used a circular thermode with a diameter of 2.9 cm. This thermode has a microprocessor driven, automated control system, and a peltier element that enables rapid temperature change. Place thermode on the thenar eminence of the subject and use a glove to secure the placement.</li>
		</ol>
		</li>
		<li>Computer Interface:
		<ol>
			<li>Interface the thermode with a software program on a laptop that precisely controls the temperature delivery. Preprogram the appropriate heat stimuli for each stage of the protocol (training 1 and 2 only, as the optimization and final trials follow the same pulse structure as training 2) according to specifications listed in Table 1.</li>
			<li>Execute the delivery of the heat pulses by selecting the heat stimulus program appropriate for each stage on the software, adjust the temperatures and hit &#34;start&#34; on the user interface.</li>
		</ol>
		</li>
		<li>Pain rating device:
		<ol>
			<li>Use the Computerized Visual Analog Scale (CoVAS). 
			NOTE: The CoVAS is a box with a mobile lever on a horizontal bar that represents the visual analog scale (VAS). It is an accessory to the main thermode.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Training
	<ol>
		<li>Define the visual analog scale (VAS) on the CoVAS:
		<ol>
			<li>Present the CoVAS to the participant and define the anchoring points on the VAS: 0 means no pain and 10 means the worst pain imaginable. Ascertain that the participant is comfortable moving the lever left and right with ease.</li>
		</ol>
		</li>
		<li>Define second pain:
		<ol>
			<li>Instruct the participant to focus on second pain from a heat pulse. Define second pain as &#34;a slow, burning, achy pain that takes place about one second after the heat pulse.&#34;</li>
		</ol>
		</li>
		<li>Rate SECOND pain from a single heat pulse (training trial 1):
		<ol>
			<li>Secure the thermode on the participant&#39;s thenar eminence. Instruct the participant to use CoVAS to rate second pain from each single pulse delivered through the thermode.</li>
			<li>Begin the pre-programed test on the laptop by hitting the &#34;start&#34; button on the software menu. Each heat pulse lasts 0.5 second and has an inter-stimulus interval of 10 s (see Fig. 1). Sequentially increase the baseline and peak temperatures of the heat pulse per Table 2.</li>
			<li>Observe closely the participants&#39; rating of second pain. As soon as the participant rates the second pain as more than 2/10, stop the training trial 1 by pressing the stop button on the software. Remove the thermode and record the final heat pulse parameters (i.e. baseline and peak temperatures).</li>
		</ol>
		</li>
		<li>Rate pain continuously from a TS trial (training trial 2):
		<ol>
			<li>Secure the thermode on the opposite hand. Inform the participant that they will receive a series of 10 rapid pulses. Instruct the participant to rate second pain only, and not focus on the faster heat pain sensation that immediately accompanies each pulse (first pain). Explain to the participant that the second pain may increase, decrease, or remain the same between each pulse.</li>
			<li>Begin the pre-programmed test on the laptop. Use the final baseline and peak temperatures recorded from step 1.2.3 above. Keep the pulse width at 0.5 s and the inter-stimulus interval at 2 s (Fig. 2). Switch hand and repeat this training trial if necessary until the participant is comfortable rating second pain continuously in response to rapid heat pulses.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Optimization
	<ol>
		<li>Define P1, Pmax and TSE:
		<ol>
			<li>Define P1 as the pain rating at approximately 2 s after the delivery of the peak temperature from the first pulse (See Fig. 3).11,21 
			NOTE: TSE is the estimated difference between the pain P1 and the maximum pain (Pmax).</li>
		</ol>
		</li>
		<li>Adjusting pulse temperature. Aim to achieve TSE between 30 and 70/100 by sequentially adjusting the peak and baseline temperature according to Figure 4. 
		NOTE: See Fig. 4 for optimization algorithm.</li>
		<li>Secure thermode: Using a surgical glove, secure the thermode to the participant&#39;s thenar eminence. Switch hand between each trial.</li>
		<li>Deliver heat pulses: Instruct the participant to only rate their second pain from the heat pulses. Confirm that the participant is ready to begin and then start the pre-programed test on laptop.</li>
		<li>Iterations: Repeat steps 1.3.2 -1.3.4 until the participant&#39;s pain rating at P1 is &#60;50/100 VAS and their TSE is between 30/100 and 70/100 VAS. Conduct no more than 5 optimization trials and ensure that there is a 3 min rest between each trial. Take the parameters from the very last trial as the final parameters.</li>
	</ol>
	</li>
	<li>Final Trials
	<ol>
		<li>Rest for 5 min between the optimization trial and the final trials. Repeat 1.3.3 and 1.3.4. using the final parameters from step 1.3.5 above. Have the participant rest for 3 min and then repeat again.</li>
	</ol>
	</li>
</ol>
2. Conditioned Pain Modulation Protocol
<ol>
	<li>Overview and equipment:
	<ol>
		<li>Test stimulus: 30 s contact heat (delivered by the same thermode as above) calibrated to 6 out of 10 pain (Heat-6). See 2.2 for details.</li>
		<li>Conditioning stimulus:
		<ol>
			<li>Construct the cold-water bath using a clear plastic box with a perforated dividing wall, and filling it with ice and water on one side and just water on the other. Gently agitate then insert thermometer to water-only side to ensure temperature is stable at 10 &#176;C.</li>
			<li>If unable to obtain stable temperature, attach a hydro pump to the side with ice to maintain stable temperature by circulating water constantly. Turn on the pump and make sure water side temperature is stable at 10 &#176;C.</li>
		</ol>
		</li>
		<li>Timing and computing CPM:
		<ol>
			<li>Apply the test stimulus to the participant once before and once during the last 30 s of the conditioning cold bath. Compute CPM as the difference in the pain level of the Heat-6 stimulus applied before and during the last 30 s of the cold bath.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Calibrating for Heat-6:
	<ol>
		<li>Estimating Heat-6 via heat ramp:
		<ol>
			<li>Secure the thermode to the thenar eminence of the non-dominant hand of the participant. Starting at 32 &#176;C, increase the temperature at a rate of 0.3 &#176;C per second. 
			NOTE: A slow ramp rate is used to preferentially activate C-fibers20 which are responsible for CPM.12</li>
			<li>Stop whenever the participant reaches thermal tolerance or at 51 &#176;C maximum. Instruct the participant to rate the pain continuously during the heat ramp. Repeat 3 times and compute the average temperature where the pain rating is 6/10.</li>
		</ol>
		</li>
		<li>Fine thresholding: Apply the Heat-6 and instruct the participant to rate the pain. If the rating is between 5 and 7/10, proceed to 2.3.2. If it is &#62;7 or &#60;5, apply a series of 30 s thermal heat stimuli to the participant (alternating hands between each stimuli), ranging from 44 &#176;C to 49 &#176;C and changing in increments of 0.5-1 &#176;C, until the rating is between 5-7, allowing a 30 s rest between each stimulus.</li>
		<li>Finalizing Heat-6 and rating of the pre-conditioning, test stimulus:
		<ol>
			<li>End the fine thresholding once the participant&#39;s pain rating is between 5 and 7/10. NOTE: Use this final, within-range pain as the rating of the pre-conditioning testing stimulus for the computation of CPM. Also, record the temperature of the final Heat-6 that resulted in this rating.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>CPM protocol
	<ol>
		<li>Pre-condition test stimulus as per step 2.2.3.</li>
		<li>Conditioning stimulus:
		<ol>
			<li>Apply the cold-water bath at 10 &#176;C to the contralateral foot for 2 min. Instruct the participant to rate the pain from the cold-water bath at 0, 30, and 90 s.</li>
		</ol>
		</li>
		<li>Repeating the test stimulus during conditioning stimulus:
		<ol>
			<li>Apply the final Heat-6 stimulus from fine thresholding (2.2.3) to the same hand again during the last 30 s of the cold-water bath. Instruct the participant to rate the pain from Heat-6 at the end of the 30-second heat stimulus, which is also the end of the 120 s cold bath. 
			NOTE: CPM is computed as the difference in the pain rating of the testing stimulus reported before and during the cold bath.</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>

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The authors have no conflicts of interests or any financial interests to disclose.

Critical Steps within the Protocol
The TS protocol includes the following in key steps in chronological order: multi-step training (using the visual analog scale to rate pain, rating of second pain from a single heat pulse, and rating second pain from rapid heat pulse trains); optimization of pulse temperatures; obtain TS in 2-3 trials with the optimized temperatures. As with most psychophysical measures, participant training is extremely critical to ensure that pain ratings are consistent across trials and are as accurate as possible. The optimization step is equally important, where both the baseline and peak pulse temperatures are adjusted such that the rating of the first heat pulse is less than 5/10, and the approximated TS is between 3 to 7.
The key steps of CPM include training of pain rating on visual analog scale, obtaining Heat-6 from slow heat ramps, confirming Heat-6 and fine thresholding if necessary, applying a cold bath to contralateral distal extremity and reapplying confirmed Heat-6 during the last 30 s of cold bath. Similar to the TS protocol, both the training and the individualization of the heat stimulus (Heat-6) are critical in the CPM protocol. Additionally, from experience as well as from the literature, repeating the Heat-6 stimulus during the last 30 s of the cold bath is critical and yields a greater magnitude of CPM compared to applying the heat stimulus after the cold bath.26 However, given that some individuals cannot tolerate the full 2 min of cold pressor at 10 degree Celsius, it might be reasonable to consider applying the testing stimulus immediately after the completion of the conditioning stimulus to standardize data collection across all individuals.
Modifications and Troubleshooting
The most common problem with the TS protocol is the inability to obtain TS, which can be due to 3 main causes. First, and most commonly, the pain rating from the first heat pulse may be so strong that it overwhelms the perception of any increase in pain with subsequent pulses (TS). The best way to minimize this problem is to follow the protocol and sequentially decrease the baseline and peak stimulus temperature until the pain rating of the first pulse is less than 5 (out of 10) before optimizing the magnitude of TS. The second cause, opposite to the first one, is when the participant perceives no pain whatsoever at the end of the 10 pulses even at the highest temperature settings. In such situations, one may consider increasing the baseline pulse temperature by 1 or 2&#160;&#176;C. Occasionally, an individual may simply have a hard time discerning and rating second pain, possibly due to both peripheral and central factors. Without reliable perception of second pain, it is very difficult to capture TS. In such situations, we find the best set of the temperatures that an individual can tolerate and record TS as zero.
The most common barriers to a successful CPM protocol are the instability of Heat-6 and the inability to tolerate a cold bath (10&#160;&#176;C) for 2min. Use the fine thresholding in the current protocol to address the first problem by adjusting heat stimulus temperature step-wise until the pain rating is between 5 and 7. For the second issue, note that the literature suggests the inhibitory effect from the conditioning stimulus is saturable.27 As such, even if a person cannot keep his or her foot in cold bath for 2 min, a sufficient CPM effect should occur with this intensely painful cold stimulus. Modify the protocol to record the duration of the foot submerged in cold water bath and deliver the heat stimulus immediately after the participant withdraw his or her foot from the cold bath. CPM is then calculated as the pain rating of the heat stimulus before subtracted by the pain rating of the heat stimulus applied immediately after the cold bath (not during, as the general protocol indicates).
Limitations of Technique
This method is not without limitations. First, despite our best effort, we were not able to elicit TS and CPM in every individual (missed 1 participant in TS and 1 in CPM, respectively). This, in part, may be due to the large between-individual variability in these parameters.5,15,16,28,29 However, the success rate was 94%, which was better than the 50-60% success rate quoted from the literature.22,28 Second, researchers should take caution when interpreting between-individual differences in TS generated by this method since we use different heat pulse temperatures to generate TS in each individual. Therefore, when comparing TS in a cross-sectional sample, one should consider both the differences in the magnitude of TS and in the temperatures used to generate it. The individualized TS method is best suited for longitudinal studies where the focus is on the changes in the same individual overtime. The same concern does not apply to the individualized CPM because the same conditioning stimulus is used for all individuals and only the change in the pain perception of individualized Heat-6 is recorded and not the raw score of Heat-6 pain. Although this method allows broad capturing of TS and CPM, it does take more time compared to methods where universal parameters are used. Finally, this technique requires an experienced operator and advanced heat testing machines, both of which are not practical for immediate adaption to busy clinical settings. We encourage future efforts to simplify the methods.
Significance of the Technique with Respect to Existing /Alternative Methods
Our method of individualizing TS and CPM parameters aim to remove influence of floor and ceiling effect due to variations in peripheral heat sensitivity. The methods presented improved on previous methods published by our group with the goals of both broader capturing and time efficiency.11,30 The advantage of individualizing TS and CPM is the ability to capture the state of ascending and descending pain processing in a broad range of individuals, thereby allowing the use of these parameters as a reasonable outcome measure for longitudinal studies.
Future Applications or Directions after Mastering the Technique
Future studies should focus on additional modifications to save time, collecting of TS and CPM data on large populations to characterize the range of these parameters in individuals who are pain free vs those with chronic pain, and on the correlation of the diversity in the TS and CPM response to specific physiologic processes in addition to windup and DNIC.

The International Association for the Study of Pain (IASP) defines pain as &#34;an unpleasant sensory and emotional experience.&#34; Chronic pain refers to pain that persists beyond 6 months. Chronic pain is a significant problem in the United States, affecting more than 100 million American adults at a cost upwards of $635 billion per annum.1 Due to the subjective nature of pain, it is difficult for researchers and clinicians to objectively measure a person&#39;s painful experience(s), therefore making it challenging to assess and treat pain. For this reason, it is important that we develop standardized tests to quantify pain as objectively as possible. One such test is QST, where standardized sensory stimuli are administered to and rated by the test subject.2 There are static and dynamic QST. The former typically assesses the sensory thresholds to or the rating of a single stimulus, while the latter assesses the response to a number of stimuli.3 Recently, dynamic QST has gained increasing attention because it offers the opportunity to probe the central processing of incoming nociceptive signals.4,5,6
Two key components of dynamic QST are temporal summation (TS) and conditioned pain modulation (CPM). Temporal summation refers to the increased perception of pain from repetitive, noxious stimuli. TS is a behavioral correlate of wind-up, the phenomenon where spinal secondary neurons display increased firing due to repetitive c-fiber input.7,8 Generally, TS can be induced by using various noxious stimuli, such as heat, electricity, and tactile methods (i.e. pressure or pinprick), provided that the frequency of the repetitive stimulus is greater than 0.3Hz, the natural frequency of c-fibers.9,10 Many researchers use repetitive heat pulses to generate TS because of the ease in producing and standardizing the noxious heat stimuli.11
CPM refers to the phenomenon of &#34;pain inhibits pain,&#34; where the presence of a second noxious stimulus decreases the pain perception from an initial noxious stimulus.12 The initial noxious stimulus, which is measured before and after (or during) the application of the second stimulus, is referred to as the test stimulus. The test stimulus can be thermal, electrical or tactile. Here thermal stimulus is often used as the testing stimulus because of its ease in adjustment and standardization.13 The second stimulus, called the conditioning stimulus, typically consists of a cold or hot water bath applied to a distal extremity.13 CPM is the behavioral correlate of Diffuse Noxious Inhibitory Control (DNIC), a physiological phenomenon where input from peripheral c-fibers results in diffuse inhibition from the brainstem of all incoming stimuli mediated by c-fiber from heterotopic fields.12,14
While TS and CPM both have the potential to reflect states and changes in central pain processing, limitations exist in both.4,5 For example, because there is a large variability in individuals&#39; sensitivity to heat, the application of a universal stimulus can result in lack of TS in up to 50% of individuals tested.11,15 Similarly, a thermal test stimulus often results in widely different pain ratings that may render CPM test impossible due to floor or ceiling effects.16 Therefore, to capture TS and CPM broadly, a protocol that adjusts the heat stimulus to the individual is needed. For TS, we adjust the heat pulse temperatures so that they can generate adequate increase in pain rating with each successive pulse; while for the CPM, we adjust the thermal test stimulus to moderately painful (6 out 10) for each individual so that adequate pain ratings may still exist after the application of a conditioning stimulus.
For all psychophysical tests, training of the participant in the proper rating of painful stimuli is crucial to the accuracy and reproducibility of these behavioral tests.17 This is particularly relevant for TS when multiple stimuli are presented at a rapid rate and, in the case of CPM, when two different stimuli are applied simultaneously to the participant. Furthermore, for TS from heat pulses, it is especially important to train the participant to rate the c-fiber mediated second pain (slow, burning, usually comes on about 1 second after the heat pulse) and not the first pain (mediated by A-delta fibers and come on immediately with the heat pulse).18,19 This is less an issue in CPM as the stimuli there are much longer (&#62;30 s) and C-fiber mediated sensation would dominate the noxious perception in these situations.19,20 In the protocol below, we will go over proper training of participants in detail.

<table><tbody><tr><td>Medoc Pathway CHEPS system</td><td>Medoc Advanced Medical Systems&amp;nbsp;&amp;nbsp;</td><td></td><td>This system includes the machine to generate contact heat (Pathway), the thermode capable of rapid temperature change (CHEPS), and the Medoc software.&amp;nbsp;</td></tr><tr><td>CoVAS accessory hardware with the CHEPS systems</td><td>Medoc Advanced Medical Systems&amp;nbsp;&amp;nbsp;</td><td></td><td>This device is a Medoc accessory that allows real-time pain rating by the participant.&amp;nbsp;</td></tr><tr><td>Laptop Computer</td><td>Lenovo</td><td></td><td>This is the computer that runs the Medoc software and communicates with the Pathway machine.&amp;nbsp;</td></tr><tr><td>Glove</td><td>Kimberly-Clark</td><td></td><td>Gloves are used to secure the thermode on the participant&#039;s thenar eminence.&amp;nbsp;</td></tr><tr><td>Clear plastic box with a perforated dividing wall - filled with Ice and water</td><td></td><td></td><td>This box provides the cold water bath for the CPM task.&amp;nbsp;</td></tr><tr><td>Aquarium pump&amp;nbsp;</td><td>Aquarium Systems Micro-Jet pump MC 450</td><td></td><td>This pump circulates water, to maintain stable, even temperature in the cold water bath.&amp;nbsp;</td></tr><tr><td>Infrared Thermometer</td><td>Exergen Temporal Scanner, model TAT 2000&amp;nbsp;</td><td></td><td>To monitor constantly the temperature of the water bath.&amp;nbsp;</td></tr><tr><td>Stop Watch</td><td>Any handheld stop watch or stop watch built into a smartphone</td><td></td><td>To prompt the participant to rate pain at specific time pointds during the CPM task.&amp;nbsp;</td></tr></tbody></table>

dynamic quantitative sensory testing to characterize central pain processing

Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain processing is present in many chronic pain conditions and can influence responses to specific therapies. Thus, the ability to precisely describe the state of central pain processing has profound clinical significance in both prognosis and prediction. Because it is not practical to record neuronal firings directly in the human spinal cord, surrogate behavior tests become an important tool to assess the state of central pain processing. Dynamic QST is one such test, and can probe both the ascending facilitation and descending modulation of incoming nociceptive signals via TS and CPM, respectively. Due to the large between-individual variability in the sensitivity to noxious signals, standardized TS and CPM tests may not yield any meaningful data in up to 50% of the population due to floor or ceiling effects. We present methodologies to individualize TS and CPM so we can capture these measures in a broader range of individuals than previously possible. We have used these methods successfully in several studies at the lab, and data from one ongoing study will be presented to demonstrate feasibility and potential applications of the methods.

In an on-going clinical trial where we performed deep phenotyping of patients with chronic axial low back pain, we included dynamic QST as an integral part of the assessment. Table 3 below summarizes baseline data from the first 15 patients where the exact TS and CPM protocol above was used. Note that the data includes patient #19 because not all 19 recruited patients showed up for their evaluation due to scheduling conflicts and other circumstance. Figure 5 visually displays the TS and CPM data side-by-side to reveal patterns of central pain processing changes in these patients.
As shown above, using an individualized optimization protocol, we obtained TS at the thenar eminence with an average of 2.7 on a 0-10 VAS scale. We were able to obtain TS in all 19 participants except for Participant 1, who was not able to reliably identify second pain without being overwhelmed by sensation from the first pain. Participant 13 needed to leave early thus did not undergo the CPM task. Otherwise all 18 participants demonstrated CPM, the average of which is about 3.1. We were successful in achieving some degree of TS and CPM in most of the subjects; and the magnitude of the TS and CPM is consistent with that from the literature.13,15,22
Furthermore, as demonstrated in Figure 4, the simultaneous measurement of TS and CPM can lead to insight on a patient&#39;s profile in central pain processing. To put it in simplified terms, high TS may indicate abnormally augmented ascending facilitation while a low CPM suggests impaired descending inhibition of nociceptive transmission. For example, Participant 10, showed high TS of 7.7 (out of 10), while Participant 18 demonstrated an essentially absent CPM (-0.5/10). Several pioneer studies have shown that such different profiles of central pain processing may predict different rates of development of chronic pain after surgery, and different responses to drugs that act on specific central pain pathways.4,23,24,25 In this example here, it is reasonable to speculate that Participant 10 might respond to Gabapentin, a calcium channel blocker while Participant 18, who has impaired CPM might respond to Duloxetine, a serotonin-norepinephrine reuptake inhibitor. Clearly more data and studies are needed to verify the hypotheses. The interventional trial is ongoing and will assess the response of these back-pain patients to verum and sham electroacupuncture. The individualized QST method presented here would allow us to accurately and longitudinally track the changes in TS and CPM in as many individuals as possible.
<img alt="Figure 1" src="/files/ftp_upload/54452/54452fig1.jpg" /> 
Figure 1. Single Heat Pulses Used in Training Trial 1. Each heat pule lasts 0.5 s and is 10 s apart from the next heat pulse. The baseline and peak temperatures of each pulse gradually increase according to Table 2. As soon as the participant perceives second pain from any of the pulses, the endpoint of training trial 1 is reached and the temperature settings of the pulse that leads to perception of second pain are recorded and used in Training Trial 2. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/54452/54452fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" src="/files/ftp_upload/54452/54452fig2.jpg" /> 
Figure 2. Heat Pulse Train Used in Training Trial 2, Optimization and Final TS Trials. Ten heat pulses, each 0.5 s long, and 2 s apart, is delivered in a standard TS trial.
<img alt="Figure 3" src="/files/ftp_upload/54452/54452fig3.jpg" /> 
Figure 3. Defining P1, Pmax and TSE. P1: rating of the second pain from the first pulse; Pmax: maximum rating of second pain of the entire 10-pulse train; TSE: estimated magnitude of temporal summation. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/54452/54452fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" src="/files/ftp_upload/54452/54452fig4.jpg" /> 
Figure 4. Algorithms to Individually Optimize Temporal Summation. The objective here is to find baseline and peak pulse temperatures that result in estimated temporal summation (TSE) between 3 and 7 out 10 VAS. If TSE is below goal, increase peak and baseline temperatures by 1 &#176;C sequentially. If TSE is above goal, decrease baseline and peak temperatures by 1 &#176;C sequentially. Before the above algorithm, make sure pain rating of the first heat pulse is &#8804; 5 by decreasing the baseline and peak pulse temperatures by small (0.5-1 &#176;C) increments. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/54452/54452fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" src="/files/ftp_upload/54452/54452fig5.jpg" /> 
Figure 5. TS and CPM Profiles in Patients from an Ongoing Clinical Trial. Baseline measurement of TS and CPM in the first 19 patients with chronic low back pain from an ongoing clinical trial. The various patterns of relative TS and CPM magnitude reveals potential differences in central pain processing. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/54452/54452fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Trial</td>
			<td># of pulses</td>
			<td>Stimulus Duration</td>
			<td>Peak to peak ISI</td>
			<td>Ramp Rate</td>
			<td>Baseline Temp</td>
			<td>Max Temp</td>
		</tr>
		<tr>
			<td>Training Trial 1</td>
			<td>1 pulse</td>
			<td>0.5 s</td>
			<td>10 s</td>
			<td>40 &#176;C/s</td>
			<td>Variable (see Table 2)</td>
			<td>Variable (see Table 2)</td>
		</tr>
		<tr>
			<td>Training Trial 2</td>
			<td>10 pulses</td>
			<td>0.5 s</td>
			<td>2 s</td>
			<td>40 &#176;C/s</td>
			<td>from Training Trial 1</td>
			<td>from Training Trial 1</td>
		</tr>
		<tr>
			<td>Optimization Trials</td>
			<td>10 pulses</td>
			<td>0.5 s</td>
			<td>2 s</td>
			<td>40 &#176;C/s</td>
			<td>start with temps from Training Trial 1</td>
			<td>start with temps from Training Trial 1</td>
		</tr>
		<tr>
			<td>Final Trials&#160;</td>
			<td>10 pulses</td>
			<td>0.5 s</td>
			<td>2 s</td>
			<td>40 &#176;C/s</td>
			<td>Individualized</td>
			<td>Individualized&#160;</td>
		</tr>
	</tbody>
</table>
Table 1: Specifications of Heat Stimuli Used in the TS Protocol (including the training trials).
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Pulse Number</td>
			<td>Baseline Temperature (&#176;C)</td>
			<td>Peak Temperature (&#176;C)</td>
		</tr>
		<tr>
			<td>1</td>
			<td>36</td>
			<td>45</td>
		</tr>
		<tr>
			<td>2</td>
			<td>36</td>
			<td>46</td>
		</tr>
		<tr>
			<td>3</td>
			<td>37</td>
			<td>47</td>
		</tr>
		<tr>
			<td>4</td>
			<td>38</td>
			<td>48</td>
		</tr>
		<tr>
			<td>5</td>
			<td>39</td>
			<td>49</td>
		</tr>
		<tr>
			<td>6</td>
			<td>40</td>
			<td>50</td>
		</tr>
		<tr>
			<td>7</td>
			<td>41</td>
			<td>51</td>
		</tr>
		<tr>
			<td>8</td>
			<td>42</td>
			<td>51</td>
		</tr>
		<tr>
			<td>9</td>
			<td>43</td>
			<td>51</td>
		</tr>
		<tr>
			<td>10</td>
			<td>44</td>
			<td>51</td>
		</tr>
	</tbody>
</table>
Table 2: Temperature Settings Used to Capture Second Pain in Training Trial 1. Refer to Figure 1 for shape of single heat pulses delivered with these temperature parameters.
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Subj ID</td>
			<td>Base T</td>
			<td>Peak T</td>
			<td>TS</td>
			<td>Heat-6</td>
			<td>CPM</td>
		</tr>
		<tr>
			<td></td>
			<td>Celsius</td>
			<td>Celsius</td>
			<td>VAS</td>
			<td>Celsius</td>
			<td>VAS</td>
		</tr>
		<tr>
			<td>1</td>
			<td></td>
			<td></td>
			<td>0</td>
			<td>44</td>
			<td>4.4</td>
		</tr>
		<tr>
			<td>2</td>
			<td>41</td>
			<td>51</td>
			<td>0.43</td>
			<td>47.6</td>
			<td>4.717</td>
		</tr>
		<tr>
			<td>3</td>
			<td>40</td>
			<td>50</td>
			<td>0.5</td>
			<td>44.7</td>
			<td>4.42</td>
		</tr>
		<tr>
			<td>4</td>
			<td>38</td>
			<td>49</td>
			<td>0.45</td>
			<td>44</td>
			<td>4.355</td>
		</tr>
		<tr>
			<td>5</td>
			<td>42</td>
			<td>51</td>
			<td>3.287</td>
			<td>44</td>
			<td>4.0713</td>
		</tr>
		<tr>
			<td>6</td>
			<td>44</td>
			<td>51</td>
			<td>0.415</td>
			<td>45.5</td>
			<td>4.5085</td>
		</tr>
		<tr>
			<td>7</td>
			<td>44</td>
			<td>51</td>
			<td>4.2495</td>
			<td>45.5</td>
			<td>4.12505</td>
		</tr>
		<tr>
			<td>8</td>
			<td>41</td>
			<td>51</td>
			<td>2.575</td>
			<td>45</td>
			<td>4.2425</td>
		</tr>
		<tr>
			<td>9</td>
			<td>44</td>
			<td>51</td>
			<td>3.435</td>
			<td>48</td>
			<td>4.4565</td>
		</tr>
		<tr>
			<td>10</td>
			<td>43</td>
			<td>51</td>
			<td>7.713</td>
			<td>44</td>
			<td>3.6287</td>
		</tr>
		<tr>
			<td>11</td>
			<td>39</td>
			<td>51</td>
			<td>4.59</td>
			<td>42.5</td>
			<td>3.791</td>
		</tr>
		<tr>
			<td>12</td>
			<td>39</td>
			<td>49</td>
			<td>5.395</td>
			<td>43.3</td>
			<td>3.7905</td>
		</tr>
		<tr>
			<td>13</td>
			<td>44</td>
			<td>51</td>
			<td>2.165</td>
			<td></td>
			<td>0</td>
		</tr>
		<tr>
			<td>14</td>
			<td>39</td>
			<td>49</td>
			<td>2.55</td>
			<td>44.1</td>
			<td>4.155</td>
		</tr>
		<tr>
			<td>15</td>
			<td>40</td>
			<td>51</td>
			<td>4.0635</td>
			<td>44</td>
			<td>3.99365</td>
		</tr>
		<tr>
			<td>16</td>
			<td>42</td>
			<td>51</td>
			<td>3.45665</td>
			<td>45.5</td>
			<td>4.204335</td>
		</tr>
		<tr>
			<td>17</td>
			<td>40</td>
			<td>51</td>
			<td>0.953</td>
			<td>46.1</td>
			<td>4.5147</td>
		</tr>
		<tr>
			<td>18</td>
			<td>37.5</td>
			<td>49</td>
			<td>0.21</td>
			<td>45.5</td>
			<td>4.529</td>
		</tr>
		<tr>
			<td>19</td>
			<td>40</td>
			<td>51</td>
			<td>2.2135</td>
			<td>46.6</td>
			<td>4.43865</td>
		</tr>
	</tbody>
</table>
Table 3. Results of TS and CPM from an Ongoing Clinical Trial. See Figure 4 for the TS and CPM from the same participants graphed side by side to reveal pain modulation profiles.

Watch this Scientific Journal Video about Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing at JoVE.com

Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing

By assessing pain in response to repetitive or different types of standardized stimuli, dynamic quantitative sensory testing (QST) can reveal changes in the central processing of pain. We present methods to optimize and individualize two dynamic QST measures: temporal summation (TS) and conditioned pain modulation (CPM).

Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain ...

dynamic-quantitative-sensory-testing-to-characterize-central-pain

Nanyang Technological University

Research

JoVE Journal

Neuroscience

16.9K Views.  Stanford University School of Medicine. By assessing pain in response to repetitive or different types of standardized stimuli, dynamic quantitative sensory testing (QST) can reveal changes in the central processing of pain. We present methods to optimize and individualize two dynamic QST measures: temporal summation (TS) and conditioned pain modulation (CPM).

Video: Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing

Acute and Chronic Tactile Sensory Testing after Spinal Cord Injury in Rats

Spinal cord injury (SCI) impairs sensory systems causing allodynia1-8. To identify cellular and molecular causes of allodynia, sensitive and valid sensory testing in rat SCI models is needed. However, until recently, no single testing approach had been validated for SCI so that standardized methods have not been implemented across labs. Additionally, available testing methods could not be implemented acutely or when severe motor impairments existed, preventing studies of the development of SCI-induced allodynia3. Here we present two validated sensory testing methods using von Frey Hair (VFH) monofilaments which quantify changes in tactile sensory thresholds after SCI4-5. One test is the well-established Up-Down test which demonstrates high sensitivity and specificity across different SCI severities when tested chronically5. The other test is a newly-developed dorsal VFH test that can be applied acutely after SCI when allodynia develops, prior to motor recovery4-5. Each VFH monofilament applies a calibrated force when touched to the skin of the hind paw until it bends. In the up-down method, alternating VFHs of higher or lower forces are used on the plantar L5 dermatome to delineate flexor withdrawal thresholds. Successively higher forces are applied until withdrawal occurs then lower force VFHs are used until withdrawal ceases. The tactile threshold reflects the force required to elicit withdrawal in 50% of the stimuli. For the new test, each VFH is applied to the dorsal L5 dermatome of the paw while the rat is supported by the examiner. The VFH stimulation occurs in ascending order of force until at least 2 of 3 applications at a given force produces paw withdrawal. Tactile sensory threshold is the lowest force to elicit withdrawal 66% of the time. Acclimation, testing and scoring procedures are described. Aberrant trials that require a retest and typical trials are defined. Animal use was approved by Ohio State University Animal Care and Use Committee.

We describe two tactile sensory testing methods for acute or chronic periods of spinal cord injury in rats. These validated procedures can detect the development and maintenance of allodynia-like sensations.

Spinal cord injury (SCI) impairs sensory systems causing allodynia1-8. To identify cellular and molecular causes of allodynia, sensitive and valid sensory ...

Medicine

Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of the population1,2. Symptoms include spontaneous (tingling, burning, electric-shock like) pain, dysaesthesia, paraesthesia, allodynia (pain resulting from normally non-painful stimuli) and hyperalgesia (an increased response to painful stimuli). The sensory symptoms are co-morbid with behavioural disabilities, such as insomnia and depression. To study chronic neuropathic pain several animal models mimicking peripheral nerve injury have been developed, one of the most widely used is Bennett and Xie's (1988) unilateral sciatic nerve chronic constriction injury (CCI)3 (Figure 1). Here we present a method for performing CCI and testing pain hypersensitivity.
CCI is performed under anaesthesia, with the sciatic nerve on one side exposed by making a skin incision, and cutting through the connective tissue between the gluteus superficialis and biceps femoris muscles. Four chromic gut ligatures are tied loosely around the sciatic nerve at 1 mm intervals, to just occlude but not arrest epineural blood flow. The wound is closed with sutures in the muscle and staples in the skin. The animal is then allowed to recover from surgery for 24 hrs before pain hypersensitivity testing begins.
For behavioural testing, rats are placed into the testing apparatus and are allowed to habituate to the testing procedure. The area tested is the mid-plantar surface of the hindpaw (Figure 2), which falls within the sciatic nerve distribution. Mechanical withdrawal threshold is assessed by mechanically stimulating both injured and uninjured hindpaws using an electronic dynamic plantar von Frey aesthesiometer or manual von Frey hairs4. The mechanical withdrawal threshold is the maximum pressure exerted (in grams) that triggers paw withdrawal. For measurement of thermal withdrawal latency, first described by Hargreaves et al (1988), the hindpaw is exposed to a beam of radiant heat through a transparent glass surface using a plantar analgesia meter5,6. The withdrawal latency to the heat stimulus is recorded as the time for paw withdrawal in both injured and uninjured hindpaws. Following CCI, mechanical withdrawal threshold, as well as thermal withdrawal latency in the injured paw are both significantly reduced, compared to baseline measurements and the uninjured paw (Figure 3). The CCI model of peripheral nerve injury combined with pain hypersensitivity testing provides a model system to investigate the effectiveness of potential therapeutic agents to modify chronic neuropathic pain. In our laboratory, we utilise CCI alongside thermal and mechanical sensitivity of the hindpaws to investigate the role of neuro-immune interactions in the pathogenesis and treatment of neuropathic pain.

Due to the simplicity of surgery and the robust behavioural outcome, chronic constriction of the sciatic nerve is one of the pre-eminent animal models of neuropathic pain. Within 24 hrs following surgery, pain hypersensitivity is established and can be quantitatively measured using a von Frey aesthesiometer (mechanical test) and plantar analgesia meter (thermal test).

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of ...

Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug&#39;s pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task&#160;battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action.

Human pain models are valuable tools used to assess the analgesic potential of novel compounds and predict their clinical efficacy, especially when used in an integrated manner. Although implementation of these models is complex, with proper execution, the pain models described in this protocol can provide predictive and reliable results.

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug&#39;s pharmacology and identify ...

Behavior

A Protocol of Manual Tests to Measure Sensation and Pain in Humans

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study demonstrates a quantitative sensory testing protocol using techniques to measure tactile sensation and pain threshold for pressure and heat using portable and easily accessed equipment. These techniques and equipment are ideal for new laboratories and clinics where cost is a concern or a limiting factor. We demonstrate measurement techniques for the following: cutaneous mechanical sensitivity on the arms and legs (von-Frey filaments), radiant and contact heat sensitivity (with both threshold and qualitative assessments using the Visual Analog Scale (VAS)), and mechanical pressure sensitivity (algometer, with both threshold and the VAS). The techniques and equipment described and demonstrated here can be easily purchased, stored, and transported by most clinics and research laboratories around the world. A limitation of this approach is a lack of automation or computer control. Thus, these processes can be more labor intensive in terms of personnel training and data recording than the more sophisticated equipment. We provide a set of reliability data for the demonstrated techniques. From our description, a new laboratory should be able to set up and run these tests and to develop their own internal reliability data.

The goal of this procedure is to demonstrate a battery of quantitative techniques for sensory and pain measurement in humans. The equipment and techniques described are commonly found in pain clinics or are easy to obtain.

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study ...

Psychophysically-anchored, Robust Thresholding in Studying Pain-related Lateralization of Oscillatory Prestimulus Activity

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the intra-individual sensation magnitude that is evoked by stimulation over multiple trials. This requires a robust mapping of stimulus magnitude to perceived intensity and is commonly achieved by psychophysical estimation methods such as the staircase procedure. Newer, more efficient procedures like the QUEST algorithm fit a psychophysical function to the data in real time while at the same time maximizing the efficiency of data collection. A robust estimate of the threshold intensity between painful and nonpainful perceptions can then be used to reduce the influence of variations in sensory input in subsequent analyses of oscillatory brain activity. By stimulating at a constant threshold intensity determined by an adaptive estimation procedure, the variance in the ratings can be directly attributed to perceptual processes. Oscillatory activity can then be contrasted between &#34;pain&#34; and &#34;no-pain&#34; trials directly, yielding activity that closely relates to perceptual classification processes in nociception.

Psychophysical methods such as the QUEST estimation procedure can efficiently yield robust estimates of the stimulation intensity at which nonpainful sensations transition into painful sensations. By stimulating repeatedly at the threshold intensity, the variability in rating responses can directly be attributed to perceptual classifications in subsequent analyses.

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the ...

Determining heat and mechanical pain threshold in inflamed skin of human subjects

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific nociceptive and inflammatory biochemicals in humans. In this article we will show pain-testing paradigms that are often used in tandem with microdialysis procedures. Combining pain tests with microdialysis provides the critical link between behavioral and biochemical data that allows identifying key biochemicals responsible for generating and propagating pain.
Two models of evoking pain in inflamed skin of human study participants are shown. The first model evokes pain with aid of heat stimuli. Heat evoked pain as described here is predominantly mediated by small, non-myelinated peripheral nociceptive nerve fibers (C-fibers). The second model evokes pain via punctuated pressure stimuli. Punctuated pressure evoked pain is predominantly mediated by small, myelinated peripheral nociceptive nerve fibers (A-delta fibers). The two models are mechanistically distinct and independently examine nociceptive processing by the two major peripheral nerve fiber populations involved in pain signaling.
Heat pain is evoked with aid of the TSA II, a commercially available thermo-sensory analyzer (Medoc Advanced Medical Systems, Durham, NC). Stimulus configuration and delivery is handled with aid of specific software. Thermodes vary in size and shape but in principle consist of a metal plate that can be heated or cooled at various rates and for different periods of time. Algorithms assessing heat-evoked pain are manifold. In the experiments shown here, study participants are asked to indicate at what point they start experiencing pain while the thermode in contact with skin is heated at a predetermined rate starting at a temperature that does not evoke pain. The thermode temperature at which a subject starts experiencing pain constitutes the heat pain threshold.
Mechanical pain is evoked with punctuated probes. Such probes are commercially available from several manufacturers (von Frey hairs). However, the accuracy of von Frey hairs has been criticized and many investigators use custom made punctuated pressure probes. In the experiments shown here eight custom-made punctuated probes of different weights are applied in consecutive order, a procedure called up-down algorithm, to identify perceptional deflection points, i.e., a change from feeling no pain to feeling pain or vice versa. The average weight causing a perceptional deflection constitutes the mechanical pain threshold.

Algorithms assessing heat and mechanical pain thresholds in experimentally inflamed skin of human study subjects are shown. The two pain testing paradigms independently examine nociceptive processing by the two major peripheral nerve fiber populations transmitting pain, i.e., non-myelinated C fibers and small myelinated A-delta fibers.

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific ...

Biology

Chronic Post-Ischemia Pain Model for Complex Regional Pain Syndrome Type-I in Rats

Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical condition. However, the underlying mechanisms of CRPS-I have yet to be revealed. It is known that ischemia/reperfusion is one of the leading factors that causes CRPS-I. By means of prolonged ischemia and reperfusion of the hind limb, the rat chronic post-ischemia pain (CPIP) model has been established to mimic CRPS-I. The CPIP model has become a well-recognized animal model for studying the mechanisms of CRPS-I. This protocol describes the detailed procedures involved in the establishment of the rat model of CPIP, including anesthesia, followed by ischemia/reperfusion of the hind limb. Characteristics of the rat CPIP model are further evaluated by measuring the mechanical and thermal hypersensitivities of the hind limb as well as the nocifensive responses to acute capsaicin injection. The rat CPIP model exhibits several CRPS-I-like manifestations, including hind limb edema and hyperemia in the early stage after establishment, persistent thermal and mechanical hypersensitivities, and increased nocifensive responses to acute capsaicin injection. These characteristics render it a suitable animal model for further investigation of the mechanisms involved in CRPS-I.

Provided here is a protocol that details steps to establish an animal model of chronic post-ischemia pain (CPIP). This is a well-recognized model mimicking human complex regional pain syndrome type-I. Mechanical and thermal hypersensitivities are further evaluated, as well as capsaicin-induced nocifensive behaviors observed in the CPIP rat model.

Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical ...

Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain perception in rodents. Withdrawal thresholds can be measured first at baseline and then following drug, venom, injury, allergen,&#160;or otherwise evoked inflammation by applying an accurate force on very specific areas of the skin. An electronic von Frey apparatus allows precise assessment of mouse hind paw withdrawal thresholds that are not limited by the available filament sizes in contrast to classical von Frey measurements. The ease and rapidity of measurements allow for incorporation of assessment of tactile sensitivity outcomes in diverse models of rapid-onset inflammatory and neuropathic pain as multiple measurements can be taken within a short time period. Experimental measurements for individual rodent subjects can be internally controlled against individual baseline responses and exclusion criteria easily established to standardize baseline responses within and across experimental groups. Thus, measurements using an electronic von Frey apparatus represent a useful modification of the well-established classical von Frey filament-based assays for rodent mechanical allodynia that may also be applied to other nonhuman mammalian models.

Electronic von Frey measurements are an effective and improved alternative to classical von Frey filaments, as they allow rapid and precise measurement of changes in rodent mechanical withdrawal thresholds to continuously applied pressure stimuli before and after an inflammatory event.

Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain ...

Back Mechanical Sensitivity Assessment in the Rat for Mechanistic Investigation of Chronic Back Pain

Low back pain is the leading cause of disability worldwide, with dramatic personal, economic, and social consequences. To develop novel therapeutics, animal models are needed to examine the mechanisms and effectiveness of novel therapies from a translational perspective. Several rodent models of back pain are used in current investigations. Surprisingly, however, no standardized behavioral test was validated to assess mechanical sensitivity in back pain models. This is critical to confirm that animals with presumed back pain present local hypersensitivity to nociceptive stimuli, and to monitor sensitivity during interventions designed to relieve back pain. The objective of this study is to lay down a simple and accessible test to assess mechanical sensitivity in the back of rats. A test cage was fabricated specifically for this method; length x width x height: 50 x 20 x 7 cm, having a stainless-steel mesh on the top. This test cage allows the application of mechanical stimuli to the back. To perform the test, the back of the animal is shaved in the region of interest, and the test area is marked to repeat the test on different days, as needed. The mechanical threshold is determined with Von Frey filaments applied to the paraspinal muscles, utilizing the up-down method described previously. The positive responses include (1) muscle twitching, (2) arching (back extension), (3) rotation of the neck (4) scratching or licking the back, and (5) escaping. This behavioral test (Back Mechanical Sensitivity (BMS) test) is useful for mechanistic research with rodent models of back pain for the development of therapeutic interventions for the prevention and management of back pain.

To develop novel therapeutic interventions for the prevention and management of back pain, animal models are required to examine the mechanisms and effectiveness of these therapies from a translational perspective. The present protocol describes the BMS test, a standardized method to assess back mechanical sensitivity in the rat.

Low back pain is the leading cause of disability worldwide, with dramatic personal, economic, and social consequences. To develop novel therapeutics, ...

A Quantitative Sensory Testing Paradigm to Obtain Measures of Pain Processing in Patients Undergoing Breast Cancer Surgery

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and lower quality of life. Persistent postsurgical pain is relatively refractory to treatment hence generating a high need for preventive strategies and treatments. Therefore, the identification of patients at risk of developing persistent pain is an area of active ongoing research. Recently it was demonstrated that peri-operative disruptions in central pain processing may be able to predict persistent postsurgical pain at long term follow-up in breast cancer patients. The aim of the current report is to present a short protocol to obtain pain thresholds to different stimuli at multiple sites and a measure of endogenous analgesia in breast cancer patients. We have used this method successfully in a clinical context and detail some representative results from a clinical study.

Persistent postsurgical pain may be related to changes in pain processing. By assessing pain in response to standardized stimuli, changes in pain processing can be elucidated. We present methods to obtain pain thresholds to different stimuli and a measure of endogenous analgesia in patients undergoing breast cancer surgery.

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and ...

Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing

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