Clinical Journal of Pain:
Characteristics of Sensitization Associated With Chronic Pain Conditions
Vierck, Charles J. PhD*; Wong, Fong DDS†; King, Christopher D. PhD‡; Mauderli, Andre P. DMD, PhD†; Schmidt, Siegfried MD, PhD§; Riley, Joseph L. PhD‡
Departments of ‡Behavioral Science
†Prosthodontics, College of Dentistry
Departments of §Community Health and Family Medicine
*Neuroscience, College of Medicine, University of Florida, Gainesville, FL
The authors declare no conflict of interest. Supported by Grant #AG039659 from the National Institute of Aging, NIH, Washington, DC.
Reprints: Charles J. Vierck, PhD, Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610-0244 (e-mail: firstname.lastname@example.org).
Received August 01, 2012
Revision received January 13, 2013
Accepted January 13, 2013
To describe and understand varieties and characteristics of sensitization contributing to hyperalgesia in participants with chronic pain conditions.
Thermal stimulation was delivered to the face, forearm, and calf of pain-free participants and individuals with irritable bowel syndrome, temporomandibular pain disorder (TMD), and fibromyalgia syndrome (FM). Three-second contacts by a preheated thermode occurred at 30-second intervals in ascending and then in descending series (0.7°C steps).
Thermal pain ratings during ascending series were greater at each site in individuals diagnosed with chronic pain. Intense pain at the time of testing further enhanced the ratings at all sites, but mild or moderate clinical pain did not have this effect. Thermal pain in all participants was greater during descending series compared with the ascending series of arm and leg stimulation. The hypersensitivity during the descending series was comparable in pain-free, FM and TMD participants but was increased in duration for arm or leg stimulation of FM participants.
The widespread sensitization for irritable bowel syndrome and TMD participants does not rely on mechanisms of spatial and temporal summation often invoked to explain widespread hyperalgesia associated with chronic pain. Increased sensitivity during descending series of stimulation of an arm or leg but not the face indicates a propensity for sensitization of nociceptive input to the spinal cord. Abnormally prolonged sensitization for FM participants reveals a unique influence of widespread chronic pain referred to deep somatic tissues.
Chronic pain is typically associated with increased sensitivity to somatosensory stimulation. When allodynia and hyperalgesia are present for stimulation of injured tissues, this can be accounted for by a peripheral release of inflammatory mediators, along with central neuronal and glial reactions to partial deafferentation and abnormal input from the injury. In addition, investigations have described hypersensitivity for cutaneous stimulation within the dermatomal distribution of chronic pain localized to deep tissues. Participants with irritable bowel syndrome (IBS; visceral pain) can be hypersensitive to nociceptive stimulation of foot or leg skin.1–6 Similarly, participants with temporomandibular disorder (TMD; facial joint pain) can be hypersensitive to stimulation of cutaneous nociceptors supplying the face.7,8 These effects may result from segmental convergence of input from deep nociceptors and cutaneous nociceptors onto common spinal networks of neurons.6 However, it is difficult to assign mechanisms for hypersensitivity to stimulation outside the dermatomal distribution of regionally referred chronic pain. For example, if convergent interaction underlies central sensitization of cutaneous pain during chronic pain conditions, then sensitization of facial pain should be minimal or absent in IBS participants, and sensitization of pain during stimulation of a leg would be minimal or absent in TMD participants. The trigeminothalamic and spinothalamic projection systems are anatomically distinct and are unlikely to mutually interact to the same extent as can occur between segmentally matched inputs to the central nervous system.
In addition to sensitization of central neurons receiving nociceptive input from injured tissues, pain generates psychological stress, which disrupts autonomic regulation.9,10 Chronic stress in association with chronic pain may constitute a mechanism for extrasegmental sensitization11,12 that is not limited to caudal spinal dermatomes for IBS or to trigeminal areas for TMD. An additional consequence of stress with sympathetic activation is that blood flow to muscles is reduced, which can result in widespread input from nociceptors in ischemic muscles.13–15 Widespread nociceptive input from deep tissues of fibromyalgia syndrome (FM) participants could result in potent and spatially distributed influences of this condition on cutaneous sensitivity, compared with regionally referred pain conditions (IBS and TMD).
Sensitivity to cutaneous thermal stimulation of the face, arm, and leg of FM, IBS, and TMD participants is compared with control participants in the present study to: (1) describe the spatial extent of sensitization in relation to the regional distribution of chronic pain; (2) determine whether sensitization depends upon the presence or intensity of chronic pain at the time of sensory testing; and (3) evaluate whether cutaneous thermal sensitization differs for the 3 pain conditions.
MATERIALS AND METHODS
Twenty-three healthy individuals (average age, 31 y; range, 19 to 66 y), 12 participants with IBS (average age, 32 y; range, 18 to 52 y), 31 participants with TMD (average age, 32 y; range, 20 to 54 y), and 9 participants with FM (average age, 46 y; range, 23 to 66 y), were recruited from the University of Florida. All participants underwent a screening visit to ensure compliance with all inclusion/exclusion criteria for each disorder. The visit included blood pressure measurement, a health questionnaire, and a physical examination. Written informed consent was obtained from all participants once the nature of the study had been thoroughly explained. The procedures were conducted under approval of the University of Florida Institutional Review Board and the Veterans Administration SCI committee.
FM participants met the 1990 American College of Rheumatology criteria for FM, which include widespread pain and the presence of at least 11 tender points.16 Participants of the TMD group met the Research Diagnostic Criteria for an axis I, group I disorder.17 Individuals with TMD were excluded if there was comorbid FM, IBS, or arthrogenic pain. The criteria for the IBS group required a diagnosis based upon the Rome II criteria18 and an absence of other diseases (including chronic pain such as FM). IBS, TMD and FMS participants reported the presence of chronic pain for at least 6 months before the beginning of the study. All participants were instructed to take no pain medication for 1 day before each test session. The criteria for members of the control group required no significant spontaneous pain anywhere in the body, no ongoing pharmacotherapy with opioids or antidepressants, and no disease that might significantly affect pain perception or unduly increase risk of injury (eg, neurological disorders, serious psychiatric disorders, diabetes, hypertension, serious cardiovascular disorders, and chronic pain diseases such as FM).
Thermal stimuli were administered by brief (3 s) contact of a preheated thermode to the face, lateral calf, and volar forearm. This method of stimulation is naturalistic, and it avoids ambiguity presented by effects of ramp rate on thermal sensitivity.19 The thermode had a flat square-shaped copper contact surface of 23×23 mm, which was electronically held at the desired temperature by a Peltier thermoelectric device. It was brought from off the skin onto light contact by solenoid activation. The stimulator assembly was mounted on an adjustable arm for positioning to any desired stimulation site.
The participants were asked to rate pain intensity by moving the slider of an electronic visual analog scale (eVAS) from left to right. Instructions regarding the use of the scale and its end points (“no pain” on the left and “intolerably intense pain” on the right) were given by a standardized video. The slider’s position was recorded as a percentage of its total travel (0 to 100). The eVAS slider was mounted into the surface of a small inclined desk, which was positioned to facilitate a precise operation with minimal fatigue. During the experiment, the participant was separated from the investigator by an equipment rack to prevent nonverbal communication and transmission of bias.
Before each test session, all participants rated the intensity of any ongoing pain, using the 0 to 100 VAS scale, with separate ratings for current pain intensity distributed above and below the umbilicus. Each participant underwent test sessions on 3 nonconsecutive days. During each session, thermal stimuli were presented to the volar forearm, the lateral calf, and the face (over the masseter muscle) in trials separated by 3 minutes. The order of sites was varied between participants and sessions, with equal representation of the 6 sequences. During a trial, 3-second contacts by the Peltier thermode with the skin occurred at intervals of 30 seconds. The initial stimulus in a trial was 43°C, and thermode temperature increased by 0.7°C from one stimulus to the next until an eVAS rating of 40 was reached or exceeded. The defined end point of the ascending series provided stimulus-response functions for low to moderate levels of pain without producing intolerable levels of pain in highly sensitive participants. A descending temperature series was initiated 30 seconds after the last stimulus in the ascending series, beginning with the temperature of the last stimulus in the ascending series and decreasing in 0.7°C increments to 43°C. The participants rated pain intensity within 5 seconds at the end of each stimulus pulse. The slider automatically returned to the left end point at that time.
The following measures of pain sensitivity were analyzed using a 2-way analysis of variances. (1) Ratings of pain during the ascending series of stimulus intensities were averaged across 3 sessions for individual participants. Statistical comparisons of the control group with each patient group (main effects) used eVAS ratings of different temperatures as repeated measures. (2) An influence of the presence or absence of clinical pain on temperatures that elicited pain ratings ≥eVAS 15 for stimulation of the face, arm, or leg was evaluated with t tests. (3) Temperatures that elicited pain ratings ≥15 on the eVAS scale were related to the magnitude of clinical pain on each day of testing, with statistical comparison of clinical pain ranges (main effect) and different sites of stimulation as repeated measures. (4) Ratings of sensation intensity were compared during progressions up to the end of the ascending series and down from the beginning of the descending series, to describe effects of the ascending series on responses to the same temperatures during the descending series. For each group of participants and site of stimulation, ratings during the ascending series were compared with ratings during the descending series (main effect). Intensities relative to the end of ascending series provided repeated measures. (5) Each patient group was compared with control participants (main effect) in terms of differences between the ratings of stimuli in ascending and descending series (repeated measures). Statistical comparisons were conducted with Statistica software (Statsoft Inc., Tulsa, OK). A probability level of 0.05 was corrected to 0.017 in order to establish statistical significance for results from stimulation of a group of participants at 3 sites (the Bonferroni method).
Figure 1 presents eVAS ratings during the ascending series of thermal stimulus intensities for the face, arm, and leg of TMD, IBS, and FM participants, compared with control participants. Statistical analysis used stimulus intensities (43 to 51.4°C) that produced eVAS ratings up to 40 for each group of participants and each stimulation site. For individual participants with an eVAS rating >40 at a temperature <51.4°C, their highest rating was entered for subsequent temperatures up to 51.4°C. This provided a conservative test of differences between participants and the control group. Sensitivity across stimulus intensities was greater at each site of stimulation for the participants with pain (Fig. 1). Three of these differences were not quite significant at the corrected confidence level of 0.017 (Table 1), but the probability that all 12 comparisons would equal or exceed the 0.02 confidence level is quite low.
In order to identify temperatures associated with the maximum hypersensitivity, differences between the eVAS ratings of control participants and all participants with chronic pain for all sites of stimulation were calculated (Fig. 2). The largest differences in sensitivity for participants with pain and controls occurred at temperatures <50°C that were associated with eVAS ratings below 20 for control participants (as shown in Fig. 1). Thus, sensitivity to low levels of nociceptive thermal stimulation was especially enhanced for IBS, TMD, and FM participants. Accordingly, as a basis for evaluation of relationships between cutaneous thermal sensitivity and the presence and intensity of clinical pain, the first temperature in ascending series that produced a rating equal or greater than eVAS 15 was calculated for all participants.
Evidence for an effect of clinical pain magnitude on cutaneous thermal pain sensitivity is provided in Figure 3, where eVAS ranges of maximal clinical pain ratings at the time of testing for all participants are plotted against temperatures sufficient to evoke mild pain (eVAS 15) at the 3 stimulation sites. Statistical evaluation revealed a significant decrease in temperatures that evoked mild thermal pain as a function of 5 ranges of clinical pain intensity (main effect of clinical pain: F=3.23; P=0.014, df=4; differences in sensitivity for stimulation of the face, arm, and leg: F=9.60, P<0.000; interaction between stimulus sites and clinical pain: F=0.28, P=0.97, df=8). The main effect depended upon the presence of high–clinical pain intensity. Post hoc comparison of temperatures that evoked mild thermal pain in the presence of little or no clinical pain (rated as 0 to 4) versus moderate clinical pain (rated as 31 to 50) was insignificant (F=1.52, P=0.22, df=1; interaction F=0.28, P=0.22, df=2). In contrast, comparison of little or no clinical pain (0 to 4) versus intense clinical pain (51 to 100) was significant (F=10.81, P=0.002, df=1; interaction F=0.55, P=0.58, df=2).
The influence of intense clinical pain at the time of sensory testing questions whether widespread hyperalgesia in participants with pain was present during testing sessions not associated with intense clinical pain. This possibility was evaluated by eliminating data from sessions associated with intense clinical pain in the largest group of participants with pain (TMD). Average ratings across the available sessions for each participant at 3 sites and at temperatures from 43 to 51.4°C were compared for control and TMD participants, as in Table 1. These stimulus-response functions revealed hyperalgesia in the TMD participants for stimulation of: the face (main effect: F=13.79, P=0.0005, df=1; interaction: F=2.23, P=0.009, df=12), the arm (main effect: F=5.64, P=021, df=1; interaction: F=1.34, P=0.19, df=12), and the leg (main effect: F=8.52, P=0.005, df=1; interaction: F=1.46, P=0.14, df=12).
Effects of ascending progressions of nociceptive stimulation on sensitivity to subsequent descending progressions were evaluated by comparing eVAS ratings of temperatures presented in the ascending series (up in Fig. 4) and the same temperatures in the descending series (down in Fig. 4). The last stimulus in ascending series elicited an eVAS rating ≥40, and the first stimulus in descending series was a repeat of the last ascending stimulus intensity. For stimulation of the arm and leg of control, TMD, IBS, and FM participants, ratings of pain intensity were significantly increased for the first 6 stimuli in the descending series of stimulus intensities, compared with the last 6 stimuli in the ascending series (Table 2). In contrast, pain ratings were not significantly greater during the descending series of facial stimulation for normal, TMD, IBS, or FM participants. The possibility was considered that the amount of sensitization during the descending series was influenced by the temperatures that elicited an eVAS rating ≥40 in the ascending series. However, comparing across all the groups of participants, the average end temperatures for the ascending series were not consistently low for stimulation of the face (Table 2). Furthermore, correlation of the end temperatures during ascending series with the maximum amounts of sensitization (differences between ratings of the second to last stimulus in the ascending series and the second stimulus in the descending series; Fig. 5) was insignificant (r=−0.026; P=0.68). Thus, for normal participants and participants with pain, a form of sensitization generated by an ascending progression of stimulus intensities (sequence-dependent sensitization) was evident for nociceptive input to central systems of spinal but not trigeminal pain conduction.
In order to evaluate sequence-dependent sensitization, eVAS ratings of stimuli in the ascending series were subtracted from ratings of the corresponding stimulus intensities in the descending series. This analysis showed that sequence-dependent sensitization reached a maximum difference of up to 25 eVAS units for the second and third stimuli of descending series and for stimulation of the arm or leg of controls and participants with pain (Fig. 5). There were no significant differences in the sensitizing effects of ascending series for IBS or TMD participants, compared with control participants. However, sensitization during the descending series was significantly prolonged for arm or leg stimulation of FM participants. Sensitization disappeared by the sixth stimulus in the descending series for control participants, but sensitization was apparent through the eighth stimulus of FM participants’ descending series (4 min from the peak of the ascending series of stimulus intensities). Comparing differences in ratings of ascending and descending stimuli from 2.8 to 4.9°C from the peak of the ascending series for control and FM participants revealed a near significant effect for arm stimulation (F=6.289, P=0.018, df=1), a significant effect for leg stimulation (F=7.724, P=0.009, df=1) but an insignificant effect for face stimulation (F=1.469, P=0.235, df=1).
As expected, ongoing pain was distributed primarily in the upper region in TMD participants and was more often identified as low by IBS participants (Table 3). For FM participants, the frequency, intensity, and/or widespread distribution of clinical pain may have contributed to the unique sensitization observed for these participants during the descending series. The percentage of participants with ongoing pain and the magnitudes of pain in the upper and lower regions were greatest for FM participants. Moreover, clinical pain was equally distributed above and below the umbilicus in FM participants, increasing the probability of convergent interactions with thermal cutaneous input from the arm and leg.
Brief thermal stimulation at a deliberate pace revealed widespread sensitization in TMD, IBS, and FM participants. Widespread sensitization is generally acknowledged to accompany chronic pain and often has been attributed to central mechanisms of synaptic enhancement by tonic nociceptive input to the spinal cord.20,21 For example, temporal summation (windup) of second pain from repetitive thermal stimulation is affected by the presence of FM,22,23 IBS,4 and TMD pain.8,24–26 However, the influences of chronic pain on thermal sensitivity may not be related to windup enhancement. Relatively low-intensity thermal stimulation generates temporal summation for participants with pain but not for controls,4 indicating that the threshold for elicited pain has been lowered by chronic pain. Accordingly, the rate (slope) of temporal summation of thermal pain usually has not been shown to be enhanced in individuals with IBS, TMD, or FM. In these studies, more pain has been elicited throughout a series of stimuli in participants with pain, without a difference in the rate (slope) of temporal summation compared with normal participants.8,20,21,27 Similarly, the rate of temporal summation has not differed between the groups when the temperature is adjusted to accommodate different sensitivities of individual participants.31,28,29 Thus, excessive central amplification as a result of stimulus repetition has been difficult to demonstrate for clinical pain conditions. Further, the NMDA receptor antagonist dextromethorphan does not differentially affect temporal summation of second pain for FM participants relative to controls.30 These findings indicate that increased sensitivity to repetitive thermal stimulation of FM participants represents an increased sensitivity to C-nociceptive input, not an increase in the rate of windup as a measure of central sensitization.
Consistent with the above interpretation, the present study demonstrates an increase in sensitivity to thermal stimulation without a dependency on the rate of repetition. A preheated thermode contacted the skin for 3 seconds, with an interstimulus interval of 30 seconds. Sensitivity to thermal stimulation was enhanced for all sites and all participants with pain. Of particular importance, sensitivity to stimulation of the face was enhanced for IBS participants, and sensitivity to stimulation of the leg was enhanced for TMD participants. In addition, hypersensitivity has been demonstrated for cutaneous stimulation of the arm or hand of IBS participants1,3,5,6,31 and TMD participants.7,8,24–26,28,32 Demonstrations of remote (extrasegmental) hypersensitivity open the possibility that widespread cutaneous sensitization can result from mechanisms other than convergent central input from the viscera or deep somatic tissues and input from the skin.33 The first synaptic targets for chronic input from the gut (IBS) or face (TMD) and cutaneous input from the face or the leg, respectively, are maximally separated along the neuraxis. The spinal and trigeminal pathways subserving pain from the leg and the face originate in the caudal spinal cord or brain stem, relay in separate thalamic nuclei, and terminate at opposite ends of the primary somatosensory cortex.
Irrespective of the relative locations of referred clinical pain and thermal stimulation, high levels of clinical pain (rated >eVAS 50) on the day of psychophysical testing were associated with increased sensitivity to nociceptive thermal stimulation, in contrast to levels of clinical pain from mild to moderate (rated from 5 to 50 on the eVAS scale). This result is consistent with other findings that high levels of clinical pain have sensitizing effects that differ from those observed in the presence of low levels of clinical pain.34,35 However, widespread cutaneous hyperalgesia did not depend upon the presence of intense clinical pain on the day of testing. Thermal pain sensitivity in the cohort of TMD participants was significantly elevated, relative to control participants, for stimulation of the face or the leg on test days without intense clinical pain. Thus, a mechanism other than convergent sensitization from ongoing clinical pain must be identified as responsible for the widespread cutaneous hyperalgesia associated with many pain conditions. Hyperalgesia can be associated with psychological stress,11,36 with mood changes including anxiety, depression, and a perceptual bias toward catastrophizing. Psychological stress is enhanced by pain,11,37,38 setting up a vicious cycle.
Following ascending series of stimulus intensities with descending progressions from a defined eVAS rating revealed a phenomenon of sequence-dependent sensitization. The sensitization was not influenced by the temperatures that produced an eVAS rating ≥40 before the beginning of descending series. Peripheral sensitization is unlikely to have accounted for hyperalgesia after ascending series because of the slow pace of stimulation and the presentation only of stimulus intensities that produced mild to moderate levels of pain. In fact, habituation, rather than sensitization, might have been expected with repeated stimulation of the same peripheral site.39 The sensitization effect is similar to a previous demonstration with continuous stimulation and much shorter intervals (1.7 s) between small changes in temperature that maintained an eVAS setpoint (eg, 40).40 In this study, sensitization was observed after ascending progressions of stimulus intensity, and desensitization was observed after descending progressions of intensity. Alternations of sensitization and desensitization established the importance of intensity sequences, as opposed to mechanisms for these phenomena that depend upon stimulus intensity or duration or repetition rate.
Sequence-dependent sensitization during the descending series was comparable in control participants and participants with regionally referred pain. For IBS and TMD participants and control participants, substantial and comparable increases in eVAS ratings were observed for the first 2 stimuli in the descending series relative to the last 2 stimuli in the ascending series, and then the ratings in both descending and ascending series were equal by the fifth stimulus from the peak (3.5°C from the highest temperature). In contrast, differences in ratings of ascending and descending temperature progressions were significantly greater in FM participants relative to controls. Sensation intensity decayed very little in FM participants as temperatures were reduced in the descending series from the peak of ascending series. For these participants, sensitization remained elevated through the eighth stimulus of the descending series (Fig. 5). Similarly, prolongation of painful after-sensations is characteristic of FM.23 When prolonged sensitization has been observed after stimulation with a windup paradigm, an implicit assumption has been that central NMDA channels have not reset normally.41 However, prolonged sensitization in FM participants during the descending series was observed in the present study for interstimulus intervals of 30 seconds—well beyond those that support windup of thermal second pain.42
Enhanced sequence-dependent sensitization in FM participitants reinforces a need to discriminate between different forms of sensitization and reveal whether and how they are associated with categories of chronic pain.43 For example, NMDA-sensitive windup during repetitive cutaneous thermal stimulation requires activation of C nociceptors at interstimulus intervals for up to 3 seconds.42 In contrast, repetitive compression of muscles produces substantial summation of pain at interstimulus intervals well beyond 3 seconds.44 Consistent with this psychophysical result, stimulation of nociceptors in deep tissues generates a more prolonged response compared with stimulation of cutaneous nociceptors.45 Thus, enhanced pain sensations and after-sensations from repetitive palpation of FM participants muscles46 can be attributed to exaggerated and prolonged discharge from muscle nociceptors rather than windup. Similarly, the sequence-dependent sensitization following ascending series in FM participants might have been increased in duration by widespread input from nociceptors in muscles rendered ischemic from chronic peripheral vasoconstriction.11,47 The clinical pain reported by FM participants was greater in magnitude, more prevalent at the time of testing, and more widespread than the pain reported by IBS and TMD participants (Table 3).
Psychophysical testing of pain sensitivity for stimulation of the face, arm, and leg of participants with chronic pain provided evidence for 4 varieties of sensitization. (1) Near (segmental) and remote (extrasegmental) sensitizations of cutaneous thermal sensitivity were observed for stimulation of the face, arm, and leg of TMD and IBS participants. These widespread effects were not consistent with frequently invoked mechanisms such as temporal summation of convergent inputs from deep structures and the skin onto a common set of central neurons. (2) Sensitization was observed in participants not experiencing intense pain on the day of psychophysical testing, but a more substantial sensitization was observed in the presence of intense clinical pain. (3) Evidence for differences between spinal and trigeminal processing of pain was provided by sequence-dependent sensitization of cutaneous thermal pain, which was observed for stimulation of an arm or leg but not for the face of all participants. (4) For FM participants, the sequence-dependent sensitization for cutaneous thermal stimulation of an arm or leg was considerably prolonged, but FM did not influence ratings of facial stimulation during the descending series.
The limitations of the present study are related to the number of participants with each clinical condition and the number of psychophysical test sessions associated with descriptions of the locations and intensities of clinical pain. Surprisingly, chronic pain was not present or was rated as weak on the majority of test days, limiting evaluation of relationships between the intensity of chronic pain and thermal pain sensitivity. Ideally, this analysis would include both within-subject and between-subject comparisons, permitting a determination of whether the effect of intense clinical pain is related to individual differences or variations in pain intensity over time (or both). Further, determining relationships between the location of clinical pain and thermal sensitivity at different sites requires a large number of participants and testing sessions. For example, correlations between the intensity of clinical pain in all participants and thermal sensitivity at each site indicated that lower body pain is more sensitizing than upper body pain (data not shown). However, the number of participants and clinical pain reports were insufficient to verify this effect with direct statistical comparisons of lower and upper pain effects in each group of participants.
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psychophysics of chronic pain; temporomandibular pain disorder; irritable bowel syndrome; fibromyalgia; sensitization
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