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Clinical identification of the stimulus intensity to measure temporal summation of second pain


To assess CS, a gold standard for TSSP protocols is required. This is the first study that has examined the clinical identification of TSSP protocols with the stimulus intensity adjusted individually to the patient’s pain thresholds. This study has provided an evidence for a practical clinical paradigm to set the stimulus intensity for measuring TSSP.

In this study, the null hypothesis was rejected. Therefore: 1. In healthy volunteers with no pain, TSSP was measured at PT + 2 °C more significantly than at PT °C and PT + 1 °C; and 2. TSSP differences between chronic pain patients and healthy volunteers with no pain were observed at PT + 2 °C more significantly than at PT °C and PT + 1 °C.

Wind-up, TSSP, and CS share common characteristics and their definitions are complex, but they should be distinguished. TSSP refers to increased pain perception from repetitive, noxious stimuli4,10,11. The neurophysiological underpinnings of this phenomenon probably result from enhancements of a central N-methyl-d-aspartate (NMDA) receptor mechanism within the spinal dorsal horn (brain stem) nociceptive neurons, which is termed “wind-up”4. The wind-up process measured from dorsal horn wide-dynamic range neurons in animals is a progressive increase in neuronal output during the course of a train of identical afferent nociceptive stimuli11. This repeated high intensity afferent barrage will cause the increased neuronal output to last after the end of the repeated stimuli11. In humans, psychological or electrophysiological responses are used as proxies for the initial part of the wind-up process11. This phase translates into TSSP, which is so-called wind-up like pain11. TSSP is an essential index for evaluating CS.

Wind-up has been first proposed as the increased firings of excitatory postsynaptic potential (EPSP) within the dorsal horn (brain stem) induced by repetitive electrical stimuli of peripheral C-fibers at train frequencies of more than 0.33 Hz36. The pathway of input of nociceptive impulses in the trigeminal nervous system is different from that in the spinal nervous system37. Nociceptive impulses arising from the face and oral structures are carried by the primary afferent neuron of the mandibular or maxillary division of the trigeminal nerve (V2, V3) through the gasserian ganglion into the subnucleus caudalis region of the trigeminal spinal tract. It synapses with a second-order neuron, and the input is carried to the thalamus and the cortex37. However, there has been no evidence that the skin overlying the masseter of TMD pain patients presents peripheral sensitization. Future studies should be assessed through a stimulus applied to the muscle and not the surface.

TSSP magnitude (PImax − PI1) is popular and useful for a TSSP parameter, but this could not reveal a process of TSSP. There is a risk that TSSP magnitude could be the same despite the different TSSP processes (whether a subjective pain intensity is gradually increased by repeated stimulation or a subjective pain intensity is momentarily increased by a single stimulation). So, in this study, TSSP frequency (Numbers of times Pn + 1 > PIn) was added for TSSP parameters.

The stimulus intensity was needed to ensure a painful sensation at the start of the stimulus for measuring TSSP, so the stimulus intensity in this study was set to PT °C or higher. To investigate at what higher stimulus intensities TSSP should cease to occur due to a ceiling effect, it is needed to measure TSSP at PT + 3 °C or higher. However, in the pilot study, five participants were tested at PT + 3 °C, and they felt too much pain that the test was discontinued. Therefore, measuring TSSP at PT + 3 °C might be unethical. This study’s results of TSSP in healthy volunteers with no pain revealed that PT + 2 °C was enough for the stimulus intensity for measuring TSSP, as described later. Thus, this study did not measure TSSP at PT + 3 °C or higher.

When an interstimulus interval is more than 0.33 Hz, a wind-up phenomenon could occur, that is, TSSP could occur36. So, an interstimulus interval should be more than 0.33 Hz for measuring TSSP. In this study, an interstimulus interval was set to two seconds because most of the earlier studies set an interstimulus interval to 2 s14,16,21,22.

There is no gold standard for protocols to set the number of stimuli for measuring TSSP. Earlier studies set the number of stimuli to 1014,16 or 1521 or 2022 etc. in an arbitrary way. In an earlier study in which the number of stimuli was set to 20, TSSP was clearly measured at 10 stimulus times22. Of course, TSSP was clearly measured in earlier studies when the number of stimuli was set to 1014,16. In this study, the number of stimuli was set to 10 because TSSP was measured clearly when 10 consecutive heat stimuli were applied in the pilot study. Future studies are needed to identify the appropriate numbers of stimuli for measuring TSSP.

In this study, nociceptive stimuli were applied to the spinal nervous system (hands) to exclude potential confounding from peripheral sensitization and to assess CS more directly. In many studies, such as the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA)38, nociceptive stimuli were also applied to the spinally innervated areas in TMD patients.

TSSP could be facilitated using various noxious stimuli, such as electrical, mechanical, and heat stimuli11,17. There are equally valid and reliable techniques to measure TSSP in orofacial pain conditions39, and it is not clear what is the advantage of the proposed one, in particular, because there is no comparator protocol. TSSP depends on spinal processes driven by the activation of C-fibers. Participants must rate the second pain evoked by C-fibers activation and not the first pain evoked by A-delta-fibers activation40.

TSSP in healthy volunteers with no pain

Generalized Linear Mixed Models to examine TSSP response patterns at each stimulus intensity revealed that TSSP decreased significantly at PT °C. This result suggests that measuring TSSP at PT °C could not avoid a floor effect. PT °C was too weak for the stimulus intensity to measure TSSP. So, the stimulus intensity should be set to more than PT °C to assure a mild painful sensation that could avoid a floor effect. Although there has been no clear rationale, earlier studies set the stimulus intensity to more than PT °C. Zhou et al. set the stimulus intensity to PT + 2 °C22. Janal et al. set the stimulus intensity to a magnitude of TSSP adjusted to VAS 0/100 or more21. Kong and Mackey et al. set the stimulus intensity to a magnitude of TSSP adjusted to VAS 30/100 to 70/10014,16.

TSm and TSf at PT + 2 °C increased significantly more than those at PT + 1 °C. This result suggests that the stimulus intensity should be set to PT + 2 °C rather than PT + 1 °C to measure TSSP more clearly.

TSSP in chronic pain patients

Generalized Linear Mixed Models to examine TSSP response patterns at each stimulus intensity revealed that TSSP did not increase significantly at PT °C and that TSSP increased significantly at PT + 1 °C and PT + 2 °C. TSSP response patterns in chronic pain patients were higher than those in healthy volunteers with no pain at all stimulus intensities. Besides, at PT + 2 °C, TSm and TSf were significantly higher in chronic pain patients than in healthy volunteers with no pain. These results might indicate that the differences between chronic pain patients and healthy volunteers with no pain could be observed only at PT + 2 °C. The stimulus intensity should be individually adjusted to 2 °C above the patient’s pain thresholds to measure TSSP. Earlier studies do not contrast with our study. Maixner et al. reported that TSSP response patterns in TMD patients with chronic pain enhanced more than those in healthy volunteers with no pain and TSm in TMD patients with chronic pain was significantly higher than that in healthy volunteers with no pain27. In the OPPERA study, which was a large-scale study that demonstrated pain sensitivity risk factors for chronic TMD, TSm in TMD patients with chronic pain was not significantly higher than that in healthy volunteers with no pain, but TSSP response patterns in TMD patients with chronic pain enhanced more than those in healthy volunteers with no pain38. But, these studies applied a fixed stimulus intensity for measuring TSSP. In studies with individualized protocols suited for within-individual monitoring, TSSP response patterns in TMD patients with chronic pain enhanced more than those in healthy volunteers with no pain at every stimulus (PT + 2 °C; first, fifth, 10th, 15th, 20th) and TSm in TMD patients with chronic pain was significantly higher than that in healthy volunteers with no pain22. In a case–control study with fibromyalgia patients, Staud et al. reported that TSSP response patterns in fibromyalgia patients with chronic pain was enhanced more than those in healthy volunteers with no pain and TSm in fibromyalgia patients with chronic pain was significantly higher than that in healthy volunteers with no pain19,41,42. In various chronic pain conditions, such as neuropathic, musculoskeletal, joint, and visceral pain, TSSP is significantly facilitated11. TSSP might be an index suggestive of CS since TSSP was facilitated more within CS-related disorders11. There is an evidence that chronic pain patients enhanced experimental pain sensitivity that appears to be facilitated by alteration in central nervous system processes that regulate the temporal processing of pain11.

Notwithstanding the significant advantages of the present study, a few limitations also should be acknowledged and discussed. The main limitation could be significant differences in age between healthy volunteers with no pain and chronic pain patients. Experimental data on age-related changes in TSSP are contradictory due to the methodologic differences between studies. Some studies showed that TSSP in the middle-aged and older-aged groups was significantly higher compared to that in the younger-aged group40,43, while some studies showed no effects of age on TSSP44. However, age-matched controls should be identified in future studies. Experimental pain perception was found between male and female38. But, in this study, participants were composed of only female. So, additional studies should investigate TSSP differences by sex.



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