Thermal grill–induced pain, also known as “the thermal grill illusion of pain” (TGIP), is a unique sensory phenomenon described over 120 years ago.2,47 It consists of a burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode (“grill”) consisting of interlaced heated and cooled bars. The TGIP has been investigated in a number of recent studies, which have improved the characterization of the conditions in which it is produced in healthy volunteers.1,4,9,10,12,14,18–20,28,29,33,40 It has been confirmed that stimulation with a thermal grill, with temperatures well below the heat and cold pain thresholds, can generate a paradoxical burning pain sensation in a large proportion (about 70%) of individuals.1,9 The probability of TGIP occurrence and its intensity and unpleasantness have been shown to be directly related to the temperature difference between the warm and cold bars of the grill.9,28,34
The neuropharmacological basis of the TGIP has rarely been investigated, but we have shown that the TGIP can be selectively blocked with a low dose of ketamine, suggesting that it involves the glutamatergic systems acting through the N-methyl-d-aspartate (NMDA) receptors.22 This indirectly suggests that TGIP may have mechanisms in common with pathological pain, including, in particular, central sensitization, which also involves NMDA receptors, and is selectively decreased by NMDA antagonists.27,51 More generally, these data are consistent with the hypothesis that the TGIP may constitute a unique experimental model for investigations of the changes in central pain processing associated with pathological pain, in particular allodynia.13 However, very few studies have investigated the TGIP in patients with chronic pain, and most publications to date were case reports21,30 or concerned studies in small cohorts of heterogeneous patients.39,46,49 The changes to the TGIP occurring in patients with chronic pain and the clinical relevance of the TGIP therefore remain uncertain. We addressed these issues by investigating the TGIP in patients with fibromyalgia or irritable bowel syndrome (IBS). We chose these 2 chronic pain syndromes for study because they are regarded as typical “nociplastic” primary pain syndromes24 and are believed to be related to changes in central pain processing.3,53 In particular, central sensitization and/or alterations to endogenous pain modulation probably play a major pathophysiological role in these syndromes.3,52 These 2 mechanisms, which are not mutually exclusive, result in a sustained hyperexcitability of the central nociceptive systems clinically expressed as widespread hyperalgesia. Diffuse hyperalgesia, characterized by changes in pain thresholds measured with quantitative sensory testing even in body areas without spontaneous pain, is a cardinal clinical feature of fibromyalgia, but it has also been observed in patients with IBS, although these patients do not complain of diffuse pain.35,37,38 As TGIP and central sensitization are both believed to act through NMDA receptors, we hypothesized that the TGIP measured at the hand should be markedly stronger in these patients than that in controls, even in the absence of spontaneous pain in the hand. We used a large range of combinations of temperature differentials to compare the TGIP responses between patients and controls. We also systematically assessed the relationships between the TGIP and clinical characteristics.
This study was performed on a group of 90 women—30 patients with fibromyalgia, 30 patients with irritable bowel syndrome, and 30 healthy controls—with the approval of the local ethics committee (CPP, IDF Ouest). Participants were fully informed about the experimental procedures, and all gave written consent before inclusion in the study.
Consecutive patients aged at least 18 years meeting the American College of Rheumatology criteria for fibromyalgia50 were recruited from the pain centers of the Ambroise Paré (Boulogne-Billancourt) and Cochin (Paris) hospitals. At screening, all patients underwent a physical examination by a pain specialist, followed by laboratory tests (eg, inflammation markers and radiological investigations) if necessary. Patients were excluded if any evidence of inflammatory rheumatic disease, autoimmune disease, or other painful disorders was found that might confound the assessment of fibromyalgia pain. Patients with irritable bowel syndrome, a frequent comorbid disorder in patients with fibromyalgia, were excluded from the fibromyalgia group.
Patients with IBS were recruited from the pain unit of Ambroise Paré Hospital (Boulogne-Billancourt, France) and the gastrointestinal unit of Louis Mourier Hospital (Colombes, France). Patients with diarrhea-predominant or constipation-predominant or mixed bowel habits IBS, as defined by the Rome III criteria,15 were included, and none had any signs of organic gastrointestinal disease or chronic pain, such as fibromyalgia in particular.
Patients were excluded from both groups if they presented a current primary psychiatric condition—including major depression or major personality disorders—or a history of substance abuse, and patients taking analgesics (nonsteroidal anti-inflammatory drugs, paracetamol, or tramadol) were instructed not to use these drugs for 24 hours before the experimental session.
Thirty age-matched healthy female volunteers with a normal clinical examination who were not on medication at the time of testing or during the month preceding testing were recruited as control subjects.
2.2. Experimental session
The participants took part in 1 experimental session. At the start of the session, patients were asked to report their average pain intensity over the past 24 hours on a 100-mm visual analogue scale (VAS; 0 = no pain to 100 = worst pain imaginable), and all participants were asked to complete the self-administered 21-item Hospital Anxiety and Depression Scale (HAD)54 and the Pain Catastrophizing Scale (PCS).45
As in previous studies,1,9,22,23 all of the thermal stimuli were produced by a thermode designed and built by Seicer (Mouy, France). The thermode consisted of 6 bars (1.2 × 16 cm) separated by 2 mm to ensure thermal isolation and covered with a copper plate. The temperature of the bars was controlled by thermoelectric Peltier elements (3 per bar). The temperatures of alternate (even-numbered or odd-numbered) bars were monitored and controlled independently in the 5°C to 50°C range, generating various combinations of temperatures (ie, the patterns of the thermal grill). Thermistors within each bar provided continuous temperature feedback for the thermode–skin interface (resolution ± 0.3°C). All experiments were performed at a constant ambient temperature (21°C). For each combination of cold and warm temperatures, volunteers were asked to place the palm of their dominant hand on the grill, orthogonally to the long axis of the bars, for 30 seconds. An interval of 3 minutes was left between stimuli.
2.2.2. Thermal grill measurements
For each participant, we determined the neutral temperature (ie, neither cold nor warm) with all the bars of the grill at the same temperature. The temperature of the palm was measured with an infrared thermometer (Thermopoint, Agema, Sweden) at the neutral temperature and then systematically before each stimulation.
The stimulation paradigm consisted of a series of systematic combinations of warm and cold temperatures adapted to each subject's thermal pain thresholds, allowing the testing of a large range of differences in temperature between the warm and cold bars of the grill.
The cold pain threshold (CPT) and the heat pain threshold (HPT) were determined with a staircase algorithm. In this procedure, even-numbered bars were kept at the neutral temperature, whereas the temperature of the odd-numbered bars was varied in a random direction (increase or decrease), in steps of 2 to 0.5°C. After each stimulus, the subjects were asked to report whether they perceived the stimulus to be painful or not. If the response was negative, the next temperature step was 2°C. After the first painful stimulus, the temperature of successive stimuli was increased or decreased by 0.5°C, as appropriate, until the first nonpainful sensation was reported.
The series of combinations of temperatures used for each subject consisted of several fixed warm temperatures combined with a series of decreasing cold temperatures. The fixed warm temperatures were HPT-12°C, HPT-10°C, HPT-8°C, HPT-6°C, and HPT-4°C. Each of these fixed warm temperatures was combined with a series of cold temperatures: CPT + 14°C, CPT + 12°C, CPT + 10°C, CPT + 8°C, CPT + 6°C, and CPT + 4°C. Thus, all the temperatures used in the different combinations were clearly in the nonpainful range with at least 4°C from the heat and cold pain thresholds.
For example, if a volunteer had a CPT of 10°C and a HPT of 46°C, the following 5 series of combinations of [warm–cold] temperatures (30 stimuli in total) were applied:
- 1st series: [34°C-24°C], [34°C-22°C], [34°C-20°C], [34°C-18°C], [34°C-16°C], and [34°C-14°C].
- 2nd series: [36°C-24°C], [36°C-22°C], [36°C-20°C], [36°C-18°C], [36°C-16°C], and [36°C-14°C].
- 3rd series: [38°C-24°C], [38°C-22°C], [38°C-20°C], [38°C-18°C], [38°C-16°C], and [38°C-14°C].
- 4th series: [40°C-24°C], [40°C-22°C], [40°C-20°C], [40°C-18°C], [40°C-16°C], and [40°C-14°C].
- 5th series: [42°C-24°C], [42°C-22°C], [42°C-20°C], [42°C-18°C], [42°C-16°C], and [42°C-14°C]
At the end of the 30-second stimulation, the subjects were asked whether the sensation was painful or not. They were asked to describe their painful sensation (burning pain, painful cold, pricking pain, or other) and to rate its intensity and unpleasantness on 2 different visual analogue scales. These 0 to 100 mm visual analogue scales were graduated as follows: “no pain–worst possible pain” and “not unpleasant–very unpleasant.”
Any painful sensation reported by the subjects was considered paradoxical because none of the warm and cold temperatures used in the various series exceeded the heat and cold pain thresholds.
2.2.3. Statistical analysis
Results are expressed as means ± SD. Group comparisons for clinical characteristics, thermal pain thresholds, paradoxical pain intensity, and unpleasantness were performed by one-way analysis of variance, with the Fisher least significant difference post hoc test. Proportions were compared with the Fisher exact test, and the Fisher least significant difference method was used for multiple comparisons. The Spearman rank correlation analysis was performed to assess the relationships between the intensity of paradoxical pain and clinical variables (clinical pain intensity, anxiety, depression, and catastrophizing scores) and cold pain thresholds. A P value <0.05 was considered significant.
3.1. Demographic and clinical characteristics of the participants
Patients with fibromyalgia had a higher body mass index than controls, and patients with IBS were slightly younger than controls (Table 1). Depression, anxiety, and catastrophizing scores were significantly higher in both groups of patients than in controls. The average pain intensity was significantly (P < 0.01) higher in patients with fibromyalgia than in those with IBS.
Table 1 -
Comparisons of demographic and clinical characteristics, including average pain intensity, Hospital Anxiety and Depression Scale anxiety and depression, and catastrophizing (Pain Catastrophizing Scale) scores, between controls and patients with fibromyalgia or irritable bowel syndrome.
||46.8 ± 9
||47.2 ± 8.5
||41.3 ± 11.6*
|Body mass index
||22.9 ± 3.7
||25.9 ± 5.5*
||22.2 ± 4.9
||58.6 ± 18.1†
||37.4 ± 18.0
||1.8 ± 2
||8.2 ± 4.5*
||7.5 ± 4.1*
||6.3 ± 2.5
||11.7 ± 4.9*
||11.8 ± 3.7*
||10.4 ± 10.6
||26.0 ± 12.3*
||33.3 ± 9.2*
|Concomitant treatment (n, %)
| Gabapentin or pregabalin
| NSAIDs or paracetamol
*P < 0.05 for comparison with controls.
†P < 0.001 for comparisons between patients with fibromyalgia and patients with IBS.
HAD, Hospital Anxiety and Depression Scale; IBS, irritable bowel syndrome; NSIAD, nonsteroidal anti-inflammatory drug; PCS, Pain Catastrophizing Scale.
Heat pain thresholds were similar in patients and controls (Fig. 1A). By contrast, the temperatures of cold pain thresholds were significantly higher (ie, cold pain sensitivity was greater) in both patients with fibromyalgia (P < 0.001) and patients with IBS (P < 0.05) than in controls (Fig. 1B) and also differed significantly (P < 0.01) between patients with fibromyalgia and patients with IBS.
3.2. Thermal grill illusion of pain
3.2.1. Percentages of responders
For each group, we applied 150 series of thermal grill stimuli, corresponding to 900 different combinations of warm and cold temperatures. The percentage of responders—ie, participants reporting paradoxical pain (the TGIP response) with at least one of the thermal grill combinations—was significantly (P < 0.05) higher in patients with fibromyalgia (93.3%) than in controls (73.3%), whereas the percentage of responders did not differ between patients with IBS (86.2%) and the other 2 groups.
3.2.2. Effects of the magnitude of the temperature differential
The mean temperature difference in the temperatures of the warm and cold bars of the thermal grill inducing the TGIP was significantly smaller in patients with fibromyalgia than in controls, but did not differ between patients with IBS patients and controls (Fig. 2A). In all 3 groups, the percentage of individuals presenting TGIP responses was directly related to the magnitude of the temperature differential between the warm and cold bars of the thermal grill (Fig. 2B). However, the percentage of responders was significantly higher for patients with fibromyalgia than for controls, for both small and large differentials (Fig. 2B). In patients with IBS, the percentage of TGIP responders was similar to that for controls at smaller differentials, but significantly higher than that of controls for larger temperature differentials (Fig. 2B).
3.2.3. Quality, intensity, and unpleasantness of the thermal grill illusion of pain sensation
Paradoxical pain was mostly described as “burning pain” in the 3 groups of participants: 66.4% in fibromyalgia, 70.6% in IBS, and 78.8% in controls. However, the percentage of paradoxical pain described as “cold pain” was slightly but significantly higher (P < 0.05) in patients with fibromyalgia (25.4%) than in patients with IBS (14.2%) and controls (8.5%).
The mean intensity (Fig. 3A) and unpleasantness (Fig. 3B) of the TGIP were significantly higher in patients with fibromyalgia (P < 0.001) or IBS (P < 0.05) than in controls. The mean intensity of the TGIP, but not its unpleasantness, was also significantly higher (P < 0.05) in patients with fibromyalgia than in patients with IBS.
3.2.4. Correlations between paradoxical pain and clinical characteristics
The intensity of the TGIP was directly correlated with mean clinical pain intensity (rho = 0.36, P < 0.05) in our patients. Significant correlations were also found between the intensities of both paradoxical pain (rho = 0.39; P < 0.001) and clinical pain (rho = 0.30, P < 0.05) and cold pain thresholds. By contrast, there was no correlation between paradoxical pain intensity and anxiety (rho = 0.06, ns), depression (rho = 0.13, ns), or catastrophizing (rho = 0.17; ns).
We found that the paradoxical pain induced by a thermal grill (ie, TGIP) was significantly stronger in patients with fibromyalgia and, albeit to a lesser extent, also in patients with IBS than in controls and that the TGIP was correlated with clinical pain intensity. These results are consistent with our working hypothesis regarding shared mechanisms between paradoxical and clinical pain mechanisms, in particular central sensitization, in patients with nociplastic chronic pain syndromes.
Surprisingly, very few studies have investigated the TGIP in patients with chronic pain. One early case report for a single patient with multiple sclerosis30 reported a decrease in TGIP. By contrast, TGIP was found increased in 1 patient with complex regional pain syndrome.21 Weak TGIP responses have been reported in small cohorts of patients with neuropathic pain related to oxaliplatin treatment49 or multiple sclerosis.39 Another study on 16 patients with chronic pain related to osteoarthritis, sciatic pain, chronic pain, peripheral neuropathy, or fibromyalgia also concluded that these patients had a weaker TGIP.46 However, the group of patients included in this study was highly heterogeneous not only in etiology but also in treatment, with about half the patients receiving strong opioids, which are known to decrease the TGIP.23 In addition, as in the other studies mentioned above, the protocol used was based on the application of fixed combinations of warm and cold temperatures not adapted to the patients' pain thresholds. It was, therefore, unclear whether the pain reported by the patients could be regarded as truly paradoxical. Three other studies have suggested that the TGIP is weaker in patients with schizophrenia,6 major depressive disorder,7 or borderline personality disorder,5 but these patients did not have chronic pain. Our study is, thus, one of the largest to date to focus on the TGIP in patients with chronic pain and is the first to focus specifically on nociplastic pain syndromes. In addition, by contrast to previous studies on patients with chronic pain, the temperature combinations used in this study were adapted to the thermal thresholds of the patients, so the pain sensations reported by our patients can be considered truly paradoxical.
Overall, the changes in the TGIP in patients with fibromyalgia or IBS were more quantitative than qualitative. As in previous studies in healthy volunteers,1,9 the percentages of TGIP responders were directly related to the magnitude of the temperature differences between the warm and cold bars of the grill. Only the proportions of TGIP responders for small and large temperature differentials differed between patients and controls. Furthermore, as in previous studies, the paradoxical pain was predominantly described as “burning” in our patients. However, the percentage of TGIP responses described as “cold pain” was slightly but significantly higher in patients with fibromyalgia than in patients with IBS, suggesting possible qualitative changes in the perception of the TGIP in a subgroup of patients.
We chose to assess the TGIP in patients with fibromyalgia or IBS because, although the pathophysiology of these typical nociplastic (dysfunctional) pain syndromes remains a matter of debate, it is generally agreed that it involves changes in central pain processing.24,53 In particular, central sensitization and alterations to endogenous pain modulation probably play a major pathophysiological role in these syndromes.32,44 These 2 mechanisms are not mutually exclusive because changes in descending pain modulation are probably involved in the development and maintenance of central sensitization.3 The molecular mechanisms of central sensitization have been investigated in detail in animals, and the role of NMDA receptors in the development of the sustained hyperexcitability of nociceptive neurons is well established.27,51 We previously showed that NMDA receptors are also involved in the TGIP. The intravenous injection of a low (subanesthetic) dose of ketamine, a noncompetitive NMDA receptor antagonist, selectively reduced the intensity and unpleasantness of paradoxical pain without affecting normal painful or nonpainful thermal sensations.22 These results suggested that the TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, and that TGIP responses may be stronger in patients with fibromyalgia or IBS. Our results, showing a significant increase in the percentages of TGIP responders and the intensity and unpleasantness of paradoxical pain in our patients, are consistent with this hypothesis. However, the increase in the TGIP was more marked in patients with fibromyalgia, who had a higher TGIP intensity than patients with IBS and stronger TGIP responses for both small and large grill temperature differentials, whereas the increase was only significant for larger temperature differentials in patients with IBS. These differences between our 2 groups of patients may reflect the association of fibromyalgia with more widespread hyperalgesia, and possibly with more severe central sensitization than IBS, as suggested by the higher mean pain intensity and more severe cold allodynia in our patients with fibromyalgia.
The positive, albeit moderate, correlation between TGIP intensity and clinical pain intensity tends to confirm the clinical relevance of this experimental paradoxical pain. Interestingly, we also found moderate correlations between the intensities of both the TGIP and clinical pain and cold pain thresholds (ie, more intense TGIP and clinical pain in patients with higher cold pain sensitivity). A large number of studies using quantitative sensory testing in patients with fibromyalgia or IBS have shown a widespread decrease in pain thresholds, which is generally regarded as a clinical marker of central sensitization.3 The greater cold pain sensitivity in our patients can therefore be seen as an index of widespread hyperalgesia reflecting central sensitization. The (moderate) correlation between clinical pain intensity and the changes in cold pain thresholds in our patients is consistent with this hypothesis. The correlation of TGIP intensity with cold pain thresholds suggests that the TGIP may also reflect central sensitization. However, our results should be interpreted with caution because we measured pain thresholds only for the hand. We cannot, therefore, formally conclude that our patients presented diffuse hyperalgesia. In addition, we only found hypersensitivity to cold, but not to heat, and we did not measure mechanical pain thresholds, which have more frequently been reported to be altered in previous studies.25,26,34,35,42 Another limitation of this study is the absence of assessment of other clinical markers of central sensitization, such as an increase in the effects of the temporal summation of nociceptive stimuli or changes to conditioned pain modulation.3,43,52 It would, therefore, be interesting to combine these approaches in future studies for a more detailed analysis of the relationships between TGIP and central sensitization in patients with chronic pain and to confirm that changes in the TGIP can be used as a new clinical marker of central sensitization. Although the mechanisms of pain in fibromyalgia are mostly regarded as central, a series of studies have suggested that peripheral mechanisms related to alteration of small fibers possibly leading to the development of hyperexcitability of these fibers may play a role in a subgroup of patients.16,31,48 However, it is unlikely that such peripheral mechanisms could explain the increased TGIP in our patients. Patients with fibromyalgia with small fiber pathology present with a hyposensitivity to thermal stimuli,31,48 whereas our patients had rather a hypersensitivity. In addition, the combinations of warm and cold temperatures used here were well below the pain threshold (at least 4°C) and, for a given warm or cold temperature, only a subset of combinations using this temperature were painful. Thus, TGIP was not related to the absolute values of the warm or cold temperatures, as this would be expected in the case of peripheral mechanisms, but, as shown previously,1,9 to the magnitude of the difference between these temperatures.
The neurophysiological mechanisms of the TGIP remain a matter of debate. Peripheral mechanisms have been proposed, but most authors believe that this phenomenon is primarily dependent on central mechanisms. Craig and Bushnell10,12 suggested that the paradoxical burning induced by the thermal grill was due to a reduction of the physiological inhibition of nociceptive pathways exerted by cold afferents. This thermosensory disinhibition hypothesis was based on electrophysiological recordings of spinal dorsal horn neurons in cats, which indicated that stimulation with the cold bars activates 2 populations of lamina I neurons in the spinal cord: the “COLD” cells, responding specifically to nonnoxious cold stimuli, and the multimodal “HPC” cells, activated by noxious heat and mechanical (ie, pinch) stimuli and by nonnoxious cold stimuli.11 The addition of adjacent warm stimuli decreased the activity of COLD cells, but not of HPC neurons, suggesting that the burning pain induced by the grill resulted from changes in the relative activity patterns of the COLD and HPC neurons.10 According to this hypothesis, the increase in TGIP responses in our patients may result from a greater disinhibition of nociceptive pathways by cold afferents. More specifically, an increase in the TGIP may result from an increase in COLD cell inhibition during the simultaneous application of warm stimuli with the thermal grill. However, no data are available concerning the interactions between COLD and HPC neurons in animal models of central sensitization. Alternatively, it has been suggested that the paradoxical sensations induced by the thermal grill may depend on the convergence and addition of the activities of adjacent cold and warm afferents on multireceptive neurons in the central nervous system (ie, wide-dynamic-range neurons) responding to both nociceptive and nonnociceptive stimuli.9,19 Numerous experimental studies have shown that central sensitization is characterized by the development a sustained hyperexcitability and an increase in the responsiveness of spinal nociceptive neurons to both nociceptive and nonnociceptive stimuli,51 potentially explaining the increase in TGIP responses in our patients. More recently, an alternative hypothesis based on population coding models was proposed, according to which the quality and intensity of thermal stimuli are encoded by the mean activity of a range of neuronal populations weighted by the variability within each population.17 However, it is difficult to interpret our data in the framework of this attractive hypothesis because the potential changes in these distributed mechanisms under pathological conditions and their putative pathophysiological role are unknown.
The influence of psychological factors on TGIP responses has also been investigated in several studies, but the results obtained were contradictory. An increase in TGIP responses has been shown to be related to higher rumination and interoceptive accuracy scores41 and to occur during the induction of sad mood in healthy volunteers8,36 and in patients with mild depression.36 However, TGIP responses were found to be weaker in patients with major depressive disorders.7 In our patients, there was no significant correlation between TGIP intensity and anxiety, depression, or catastrophizing scores. It therefore seems unlikely that these psychological factors played a major role in the changes in the TGIP observed in our patients.
In conclusion, our data tend to confirm the clinical relevance of the TGIP, but further studies are required to confirm the value of the TGIP as a potential marker of central sensitization.
Conflict of interest statement
The authors have no conflicts of interest to declare.
This study was supported by Inserm.
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