Published: February 16th, 2017
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 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.
The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience." 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'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 "pain inhibits pain," 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' 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 (>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.
1. Temporal Summation Protocol
2. Conditioned Pain Modulation Protocol
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'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.
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. Please click here to view a larger version of this figure.
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.
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. Please click here to view a larger version of this figure.
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 °C sequentially. If TSE is above goal, decrease baseline and peak temperatures by 1 °C sequentially. Before the above algorithm, make sure pain rating of the first heat pulse is ≤ 5 by decreasing the baseline and peak pulse temperatures by small (0.5-1 °C) increments. Please click here to view a larger version of this figure.
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. Please click here to view a larger version of this figure.
|# of pulses
|Peak to peak ISI
|Training Trial 1
|Variable (see Table 2)
|Variable (see Table 2)
|Training Trial 2
|from Training Trial 1
|from Training Trial 1
|start with temps from Training Trial 1
|start with temps from Training Trial 1
Table 1: Specifications of Heat Stimuli Used in the TS Protocol (including the training trials).
|Baseline Temperature (°C)
|Peak Temperature (°C)
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 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.
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 °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 °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 authors have no conflicts of interests or any financial interests to disclose.
We acknowledge funding support by K23 AT008477 (Kong), NIH K23 DA031808 (Johnson), and the Chris Redlich Endowment in Pain Research (Mackey, Dixon).
|Medoc Pathway CHEPS system
|Medoc Advanced Medical Systems
|This system includes the machine to generate contact heat (Pathway), the thermode capable of rapid temperature change (CHEPS), and the Medoc software.
|CoVAS accessory hardware with the CHEPS systems
|Medoc Advanced Medical Systems
|This device is a Medoc accessory that allows real-time pain rating by the participant.
|This is the computer that runs the Medoc software and communicates with the Pathway machine.
|Gloves are used to secure the thermode on the participant's thenar eminence.
|Clear plastic box with a perforated dividing wall - filled with Ice and water
|This box provides the cold water bath for the CPM task.
|Aquarium Systems Micro-Jet pump MC 450
|This pump circulates water, to maintain stable, even temperature in the cold water bath.
|Exergen Temporal Scanner, model TAT 2000
|To monitor constantly the temperature of the water bath.
|Any handheld stop watch or stop watch built into a smartphone
|To prompt the participant to rate pain at specific time pointds during the CPM task.
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