ORIGINAL ARTICLE
Relationship between Personality Traits and Endogenous Analgesia: The Role of Harm Avoidance Hadas Nahman-Averbuch, MSc*; David Yarnitsky, MD, PhD*,†; Elliot Sprecher, PhD*; Yelena Granovsky, PhD*,†; Michal Granot, PhD*,‡ *The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa; †Department of Neurology, Rambam Medical Center, Haifa, ; ‡Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
& Abstract Background: Whether psychological factors such as anxiety and pain catastrophizing levels influence the expression of endogenous analgesia in general and, more specifically, the conditioned pain modulation (CPM) response is still under debate. It may be assumed that other psychological characteristics also play a role in the CPM response. The neurotransmitters serotonin, dopamine, and norepinephrine are involved both in CPM, as well as personality traits such as harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), which can be obtained by the Tridimensional Personality Questionnaire (TPQ). However, the associations between these traits (HA, NS, and RD) with endogenous analgesia revealed by CPM have not yet been explored. Methods: Healthy middle-age subjects (n = 28) completed the TPQ, Spielberger’s State Anxiety Inventory, and the Pain Catastrophizing Scale and were assessed for CPM paradigms using thermal phasic temporal summation as the “test stimulus” and hand immersion into hot water bath (CPM
Address correspondence and reprint requests to: Hadas NahmanAverbuch, MSc, The Clinical Neurophysiology Laboratory, Technion-Israel Institute of Technology, Technion City, Haifa, 3200003, Israel. E-mail: [email protected]. There are no funding sources and no conflict of interest. Submitted: June 1, 2014; Revision accepted: September 1, 2014 DOI. 10.1111/papr.12256
© 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume , Issue , 2014 –
water) or contact heat (CPM contact) for “conditioning stimulus.” Results: Higher levels of HA were associated with lessefficient CPM responses obtained by both paradigms: CPM water (r = 0.418, P = 0.027) and CPM contact (r = 0.374, P = 0.050). However, NS and RD were not associated with the other measurements. No significant relationship was observed between state anxiety and pain catastrophizing levels and the CPM responses. Conclusions: The relationship between the capacity of endogenous analgesia and the tendency to avoid aversive experience can be explained by mutual mechanisms involving similar neurotransmitters or brain areas. These findings illuminate the key role of harm avoidance obtained by the TPQ in determining the characteristics of pain modulation profile. & Key Words: harm avoidance, conditioned pain modulation, Tridimensional Personality Questionnaire, anxiety, pain catastrophizing
INTRODUCTION Endogenous analgesia acts through several mechanisms that are mediated mainly by the neurotransmitters serotonin, norepinephrine, and dopamine.1,2 Conditioned pain modulation (CPM) response, a pain-inhibits-pain phenomenon that represents features of diffuse noxious inhibitory control, is one expression of endogenous analgesia that was found to be mediated by the
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above-mentioned neurotransmitters.3–5 The CPM response is manifested as a decrease in pain sensation evoked by a “test stimulus” during or following the application of another noxious stimulus, termed the “conditioning stimulus” (CS). The CPM response has been found to predict the development of acute and chronic pain following surgery and outcome after treatment.6–8 Given its clinical relevance, there is a need to better understand which factors may influence the efficiency of CPM. It has been proposed that the CPM response is influenced by psychological factors, such as anxiety, depression, and pain catastrophizing levels. However, these results are controversial as most studies have not shown any associations between the CPM response and these psychological factors.9–18 Therefore, there is a need to explore whether other, pain-related psychological factors may be more relevant to the CPM response. As serotonin, norepinephrine, and dopamine also were found to be associated with particular personality temperament traits as characterized by Cloninger’s tridimensional personality theory,19 we hypothesized that these traits may affect the CPM response. This biopsychosocial theory states that 3 specific traits are associated with each individual personality: (1) Novelty seeking (NS), which is described as a tendency to respond with intense excitement to novel stimuli leading to the pursuit of rewards and escape from punishment, is associated with dopamine, (2) Harm avoidance (HA), which is defined as a tendency to respond intensely to previously established signals of aversive stimuli and to learn passively to avoid punishment, novelty, and frustrating nonreward, is associated with serotonin, (3) Reward dependence (RD), which is characterized as a tendency to respond intensely to signals of reward and to maintain behavior previously associated with reward or with relief from punishment, is associated with norepinephrine.19 In the past decade, several reports applied Cloninger’s theory to explore individual variation in pain perception using pain psychophysical tests. These studies have found that higher HA scores were associated with enhanced pain response obtained by higher pain ratings and lower pain tolerance in healthy subjects20–22 and the presence of cutaneous allodynia in migraine patients.23 Moreover, higher HA and RD scores were associated with lower pain thresholds and higher pain ratings in women who suffer from provoked vestibulodynia.24 Nevertheless, Ziv et al., (2010) did not find associations between HA scores and pain ratings or the temperature
which induced painful sensation in healthy subjects.25 To our knowledge, the effect of personality traits assessed by the Tridimensional Personality Questionnaire (TPQ) on endogenous analgesia capacity has not been yet determined. We hypothesized that both Cloninger’s personality traits and CPM responses are mediated by the similar neurotransmitters serotonin, norepinephrine and dopamine and thus, may be related. This study aimed to explore whether or not personality traits representing these particular neurotransmitters as well as anxiety or pain catastrophizing are involved in the expression of the CPM response.
METHODS Subjects The study was approved by the local Ethics Committee, and informed consent was obtained from all subjects. Participants were 28 healthy subjects (14 women and 14 men), with mean age of 51.0 6.4, who met the following inclusion criteria: (1) the absence of chronic pain, neurological or psychiatric disease history, (2) no use of analgesic or psychiatric medication on a regular basis, and (3) ability to communicate and understand the instructions of the study. Subjects were asked to refrain from pain relief medications 24 hours before the experimental trial. Subjects were recruited through advertisements and were compensated for their participation (the Israeli shekel equivalent of about 25 US$). This study was a part of a larger research project that tested the effect of various stimulation parameters on CPM response.
Assessment of Psychological Factors
Tridimensional Personality Questionnaire is a 100-item true/false self-report inventory constructed according to Cloninger’s 3-dimensional personality theory.19 This questionnaire measures the 3 primary personality temperament dimensions that are considered to be involved in the mediation of particular types of response to stimuli: HA (34 items); NS (34 items), and RD (30 items). According to the instructions of the TPQ calculation, 2 items that are included in the questionnaire are excluded from the total score of each dimension. This questionnaire has been
Personality Traits and Endogenous Analgesia 3
translated into several languages, including Hebrew,26 and used in a variety of studies. Anxiety level was assessed by the state part of the Spielberger’s State-Trait Anxiety Inventory,27 using the validated Hebrew version.28 This questionnaire has 2 parts; anxiety state and anxiety trait. Each part includes 20 items and the subjects were asked to rate their feelings about each statement on a 4-point scale (1 to 4). This questionnaire has a very good reliability (alpha score > 0.89).29 We used the state part of this questionnaire to assess the anxiety level of the subjects obtained at the time of experimental session. Pain catastrophizing level was assessed by the Pain Catastrophizing Scale30 using the validated Hebrew version (alpha score of 0.86).31 This questionnaire includes 13 items representing the 3 components of pain catastrophizing: rumination (eg “I can’t seem to keep it out of my mind”); magnification (eg “I wonder whether something serious may happen”); and helplessness (eg “There is nothing I can do to reduce the intensity of pain”). Subjects were asked to complete the questionnaire and to relate the conditioning stimulus obtained by the contact heat stimulation (situational pain catastrophizing scale—sPCS).
The Assessment of CPM The “test stimulus”. Thermal temporal summation served as the “test stimulus” and was induced by a series of 10 brief repetitive suprathreshold thermal stimuli that were applied at the pain60 intensity.32,33 The intensity of this stimulus was determined first for each individual using a short series of ascending and descending thermal stimuli, culminating in identification of the temperature that induced a pain experience score of 60 on a 0 to 100 numerical pain scale (NPS) in which 0 represent “no pain at all” and 100 “most pain imaginable”. NPS is a widely used tool for assessing pain levels. It has good reliability/validity and is easy to use.34 The stimulation temperature was determined individually. Stimuli were delivered to the thenar eminence of the dominant hand using a Contact HeatEvoked Potential Stimulator (CHEPS, Medoc, Ramat Yishay, Israel). This device generates heat stimuli using a flat disk probe surface of 27 mm in diameter. The thermode is comprised of 2 layers: an external heating
thermofoil (Minco Products, Inc., Minneapolis, MN) and a cover comprised of a 25-mm layer of thermoconductive plastic (Kaptonâ, with a thermal conductivity of 0.1 to 0.35 W/m/K at 23°C). The stimulus plateau duration was 0.7 seconds, with an ISI of 2 seconds. The baseline temperature was 39°C, the increase rate was 20°C/seconds, and the decrease rate was 40°C/seconds. The Conditioning Stimuli. To reveal the role of different types of thermal CS on the CPM response, 2 stimulations of 46.5°C that lasted for 60 seconds were applied. (1) Immersion of the nondominant hand into a hot water bath (Heto CBN 8-30 Lab equipment, Allerod, Denmark) up to the wrist level (CPM water). The water bath is temperature-controlled with a maximum temperature variance of 0.5°C and continuous stirring action to ensure the maintenance of an even temperature throughout the bath, (2) Contact heat stimulus that was applied to the nondominant thenar eminence (CPM contact). This was performed using a Thermal Sensory Analyzer (TSA) 2001 system (Medoc, Ramat Yishay, Israel), with a 30 9 30 mm Peltier surface stimulator. The baseline temperature was 32.0°C, temperature rates of increase and decrease were 2°C/seconds. Study Design Subjects completed the TPQ and state anxiety. Then, the individual pain60 temperature was determined for each subject. After 10 minutes break, the temporal summation “test stimulus” was applied (“test stimulus”_alone). The participants were asked to rate their pain level of the 1st, 5th, and 10th stimuli using NPS. After a 15-minute break, the CS was delivered. Throughout this stimulation, subjects were asked to score their pain intensity induced by the CS 4 times, at 0, 10, 20, and 30 seconds, and the mean scores of the CS were calculated. During the second half-minute, and subsequent to the last pain scoring of CS, the “test stimulus” was repeated and subject rated the pain of the “test stimulus” (“test stimulus”_water or “test stimulus”_contact). After a 15-minute break, the second CS was delivered in the same way as described above and the “test stimulus” was repeated. The CSs were delivered in a random order. Both the “test stimulus” pain60 intensity and the CS-chosen temperature of 46.5°C are standard and widely used in our laboratory.7–9,32,33 The subjects were asked to complete the sPCS referring to the pain evoked by the CS delivered by the contact heat stimulus.
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Statistical Analysis Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA, version 15). For the “test stimulus,” the temporal summation value was calculated as the difference between the pain scores obtained for the last vs. the first stimuli. The CPM response was calculated as the difference between the “test stimulus”_water and the “test stimulus”_contact (scores of the temporal summation values) obtained during the CS vs. “test stimulus”_alone (the same “test stimulus” was used for both CPM assessments). Thus, negative CPM values would indicate an inhibitory response. We first examined the characteristics of the CPM paradigms, to determine whether temporal summation was induced before and during the CS application for both CPM paradigms, using ANOVA with test (“test stimulus”_alone, “test stimulus”_water, and “test stimulus”_contact) and time (1st, 5th, and 10th pain ratings) interaction. Thereafter, a paired t-test was used to confirm that CPM responses were induced by comparing the temporal summation values obtained before and during each of the CS, and the correlation between the 2 CPM responses was examined. The next step was to explore the role of the CS type on the CPM responses; t-test analyses were used to compare (1) the pain ratings of the CS obtained for hot water immersion and the contact heat, (2) the CPM magnitudes for both paradigms. Finally, Pearson correlations were conducted to examine the associations between psychological factors and the CPM responses. Data are presented as means standard deviation. Statistical significance was defined as P ≤ 0.05.
RESULTS Characteristics of the CPM Paradigms Pain ratings of the 1st, 5th, and 10th “test stimuli” as well as the calculated TS values and CPM responses are presented in Table 1. ANOVA revealed a significant effect of time (P < 0.0001) such that the pain ratings of the 1st stimulus were significantly different from the
pain ratings of the 5th (P = 0.0004) and the 10th (P < 0.0001) stimuli. In addition, the pain ratings of the 5th and the 10th stimuli were different (P = 0.026). These indicated that the repetitive thermal stimuli evoked robust temporal summation effects which were observed regardless the CS administration. The test (P = 0.502) or time X test (P = 0.337) interaction were not significantly different, indicating that the pain ratings of the 1st, 5th, and 10th obtained during the “test stimulus”_alone were not different from the pain ratings of the 1st, 5th, and 10th obtained during the “test stimulus”_water and “test stimulus”_contact. No gender or age effect was found on pain modulation measures. Lower temporal summation values were obtained during the CS as compared with temporal summation values before the exposure to CS, indicating that a significant CPM response was evoked. This was observed for both CPM contact and CPM water paradigms (P = 0.042 and P = 0.002, respectively). Comparing the 2 CPM paradigms, revealed that significant higher pain ratings were reported for the CS induced by the water bath immersion compared with the contact heat (71.8 20.7 vs. 53.9 23.2, P < 0.001). However, no difference was found between the CPM responses (P = 0.188) evoked by the 2 different types of CS. Moreover, positive correlation was observed between the CPM contact and the CPM water response (r = 0.530, P = 0.001), indicating that individuals who demonstrated less-efficient CPM response in one paradigm also exhibited similar CPM response in the other paradigm. No correlations were found between the pain ratings of the CS and the CPM response. This was observed for both the CPM water (r = 0.171, P = 0.341) and for the CPM contact (r = 0.091, P = 0.615), thus, the possibility that greater pain reports of the CS induced greater CPM responses may be ruled out. Associations between Psychological Factors and Pain Psychophysical Measures The scores of the HA, RD, and NS are presented in Table 2. As can be observed, there were no gender
Table 1. The Pain Ratings, TS, and CPM Values of the 2 Paradigms
“test stimulus”_alone “test stimulus”_water “test stimulus”_contact
1st Pain Rating
5th Pain Rating
10th Pain Rating
45.9 19.4 52.6 20.3 53.0 20.1
61.1 14.9 60.0 22.8 63.3 19.9
72.4 18.3 64.6 24.4 70.0 18.9
TS Value 26.5 21.3 12.0 16.6 17.0 19.6
CPM Response 14.6 22.1 9.6 22.6
Personality Traits and Endogenous Analgesia 5
Table 2. Comparison of Psychological Factors between Men and Women Men (n = 14)
All HA NS RD Anxiety state sPCS
11.0 14.2 19.5 29.1 21.8
5.6 4.1 3.5 7.8 9.9
11.6 14.6 19.0 29.4 20.2
5.6 4.7 3.0 8.5 8.4
Women (n = 14)
P Value
0.557 0.652 0.489 0.869 0.407
10.4 13.9 19.9 28.8 23.5
5.8 3.5 3.9 7.4 11.3
A
HA, harm avoidance; NS, novelty seeking; RD, reward dependent; sPCS, situational pain catastrophizing scale.
Table 3. Correlations between Psychological Factors and the Conditioned Pain Modulation Response HA CPM water CPM contact
0.418* 0.374*
NS 0.157 0.123
RD 0.161 >0.001
Anxiety State
sPCS
0.170 0.239
0.339 0.230
B
HA, harm avoidance; NS, novelty seeking; RD, reward dependent; sPCS, situational pain catastrophizing scale; CPM, conditioned pain modulation. *P ≤ 0.05.
differences in the personality trait scores. Among all the assessed measures, only the HA dimension of the TPQ traits was associated with the CPM responses. This association was observed for both CPM paradigms (see Table 3). Higher levels of HA were associated with lessefficient CPM responses obtained for both the CPM water (r = 0.418, P = 0.027, Figure 1A) and the CPM contact (r = 0.374, P = 0.050, Figure 1B) paradigms. The levels of sPCS and state anxiety were not associated with CPM magnitude. Temporal summation value was not correlated with any of the Tridimensional Personality Questionnaire traits, indicating that the effect of HA was specific to CPM.
DISCUSSION Despite the growing number of publications indicating that pain modulation responses are affected by a variety of pain-related psychological variables, no study has yet focused on the possible role of the personality traits, as assessed by the TPQ, on the pain modulation capacity. The main finding of the present study was that higher scores of HA trait were associated with less-efficient inhibitory pain modulation responses induced by 2 CPM paradigms. This may suggest that greater predisposition to react intensely to signals of aversive stimuli and learning to avoid punishment, innovation and frustrating nonreward, may be related to lower endogenous analgesia. Accordingly, it may be assumed that pronociceptive pain modulation profile35 as expressed by the
Figure 1. Positive correlations between harm avoidance and (A) conditioned pain modulation (CPM) water (r = 0.418, P = 0.027) as well as with (B) CPM contact (r = 0.374, P = 0.050).
less-efficient CPM response, characterized the individuals with higher HA. The results of the current study give a better understanding of the factors that can affect the CPM efficiency. CPM was found to be less efficient among chronic pain patients10,12,17,35 and to predict the development of chronic and acute pain following a surgery.6,7 Thus, according to our findings, it can be suggested that individuals with high HA levels may be prone to develop chronic pain and therefore may need to be treated differently to prevent chronic pain development. Brain imaging studies provide evidence for the possible effect of HA on the processing of nociceptive input. It has been reported in fMRI studies that higher HA levels were associated with greater brain activation during expectations and processing of noxious stimulus. This was observed in brain areas involved in pain modulation such as medial prefrontal cortex, premotor cortex, anterior and posterior cingulate cortex, thalamus, and amygdala.25 In addition, in healthy subjects, HA was negatively correlated with gray matter volume
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in frontal, occipital, and parietal structures.36 The previously mentioned brain regions such as the thalamus, anterior and posterior cingulate cortex, and prefrontal cortex, all of which have been found to be related to the HA trait, are also known to be involved in pain modulation, particularly CPM.37,38 Thus, we can conceptualize that the same brain areas which are involved in both inhibitory pain response and aversive stimulus avoidance may explain our findings. Another possible explanation for such relations may be attributed to the fact that serotonin plays a significant role in both CPM and HA. Variation in the serotonin transporter (5-HTT) gene explained interindividual differences in pain modulation, such that subjects with low 5-HTT expression exhibited less-efficient CPM response,4,39 although another study failed to find this effect.40 Yarnitsky et al. (2012) reported that pretreatment CPM efficiency predicted treatment success with duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in patients with diabetic neuropathy. Moreover, the extent of pain alleviation in these patients was linked to the extent of CPM modification following treatment that modified the serotonin levels.8 According to Cloninger’s suggestion that higher HA is related to higher synaptic levels of serotonin,19 it was expected that higher HA scores will characterize individuals with more efficient CPM responses. However, our findings revealed an opposite direction of associations in which higher HA was correlated with less-efficient CPM responses. Previous studies indeed reported that high activity in the serotonergic system characterized individuals with high HA,41–44 however, others did not find these relationships.45–47 Furthermore, one study reported findings in the opposite direction: low basal levels of central serotonin were related to higher HA scores.48 Additionally, use of tricyclic antidepressants (TCA) or selective serotonin reuptake inhibitors (SSRI) was followed by reduction in HA scores in studies of patients with depression and generalized anxiety disorders.49,50 This suggests that the pattern of relationships between serotonin and HA is more complex and may be mediated by an interaction between serotonin and dopamine51 or norepinephrine.52 Therefore, our observation that higher HA was associated with less-efficient CPM may be explained by an involvement of other neurotransmitters that intervene between serotonin and HA or CPM. Our findings may also illuminate the role of the CS on CPM response. We applied 2 types of thermal tonic noxious stimuli for the CS delivered at the same intensity
and duration. Although both represent the same pain modality, the water immersion evokes higher pain reports, which may be attributed to the different quality of pain experience activated by water and/or to the larger area of stimulation compared with the contact heat. As a positive correlation between the 2 CPM responses was observed, it can be assumed that if the CS is painful, then its particular characteristics have minor effect on the CPM magnitude. This notion is further supported by the lack of correlation between the pain ratings reported for the CS and the CPM response magnitude in both paradigms. This is in line with previous studies that demonstrated no association between CPM responses and pain intensity of the CS.32,53 It has been assumed that CPM response is influenced by psychological factors such as anxiety and pain catastrophizing. While some studies found associations between CPM responses and these factors9-11, the majority of the studies found no associations.12–18 Similarly, this study found no associations between the 2 CPM responses and the levels of state anxiety and situational pain catastrophizing. The sPCS is a relatively new measure which has been examined in only a few studies in relation to the CPM response. Although one study which controlled for gender found a significant relationship between sPCS and the CPM response,54 the other study found no significant correlation,6 similar to our result. Still, there are other psychological factors that were not included in this study and may affect the CPM response. The major limitation of our study is the relative small number of subjects that were tested. Still, this study is the first to suggest that HA and CPM responses are related. Nevertheless, there is a need to further explore the association between the TPQ traits and the CPM response in larger samples and other populations, especially for HA.
CONCLUSIONS The lower capacity of pain inhibition which characterized individuals with greater tendency to avoid aversive experience can be explained by mutual mechanisms involving modulation processes invoked by nociceptive input and behavioral features of pain perception. These findings illuminate the key role of pain-related psychological factors in determining the characteristics of pain modulation profile. Therefore, an assessment of CPM should encompass the evaluation of these psychological factors, mainly via tools that represent biopsychosocial facets of pain.
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44. Melke J, Westberg L, Nilsson S, et al. A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women. Arch Gen Psychiatry. 2003;60:1017–1023. 45. Blairy S, Massat I, Staner L, et al. 5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait. Am J Med Genet. 2000;96:360–364. 46. Hillert L, Jovanovic H, Ahs F, Savic I. Women with multiple chemical sensitivity have increased harm avoidance and reduced 5-HT(1A) receptor binding potential in the anterior cingulate and amygdala. PLoS ONE. 2013;8:54781. 47. Kusumi I, Suzuki K, Sasaki Y, Kameda K, Sasaki T, Koyama T. Serotonin 5-HT(2A) receptor gene polymorphism, 5-HT(2A) receptor function and personality traits in healthy subjects: a negative study. J Affect Disord. 2002;68:235–241. 48. Peirson AR, Heuchert JW, Thomala L, Berk M, Plein H, Cloninger CR. Relationship between serotonin and the temperament and character inventory. Psychiatry Res. 1999;89:29–37. 49. Allgulander C, Cloninger CR, Przybeck TR, Brandt L. Changes on the Temperament and Character Inventory after paroxetine treatment in volunteers with generalized anxiety disorder. Psychopharmacol Bull. 1998;34:165–166. 50. Joffe RT, Bagby RM, Levitt AJ, Regan JJ, Parker JD. The Tridimensional Personality Questionnaire in major depression. Am J Psychiatry. 1993;150:959–960. 51. Kim SJ, Kim YS, Lee HS, Kim SY, Kim CH. An interaction between the serotonin transporter promoter region and dopamine transporter polymorphisms contributes to harm avoidance and reward dependence traits in normal healthy subjects. J Neural Transm. 2006;113:877–886. 52. Suzuki A, Matsumoto Y, Oshino S, Kamata M, Goto K, Otani K. Combination of the serotonin transporter and norepinephrine transporter gene promoter polymorphisms might influence harm avoidance and novelty seeking in healthy females. Neurosci Lett. 2008;439:52–55. 53. Nir RR, Granovsky Y, Yarnitsky D, Sprecher E, Granot M. A psychophysical study of endogenous analgesia: the role of the conditioning pain in the induction and magnitude of conditioned pain modulation. Eur J Pain. 2011;15:491–497. 54. Goodin BR, McGuire L, Allshouse M, et al. Associations between catastrophizing and endogenous pain-inhibitory processes: sex differences. J Pain. 2009;10:180–190.
Relationship between Personality Traits and Endogenous Analgesia: The Role of Harm Avoidance Hadas Nahman-Averbuch, MSc*; David Yarnitsky, MD, PhD*,†; Elliot Sprecher, PhD*; Yelena Granovsky, PhD*,†; Michal Granot, PhD*,‡ *The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa; †Department of Neurology, Rambam Medical Center, Haifa, ; ‡Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
& Abstract Background: Whether psychological factors such as anxiety and pain catastrophizing levels influence the expression of endogenous analgesia in general and, more specifically, the conditioned pain modulation (CPM) response is still under debate. It may be assumed that other psychological characteristics also play a role in the CPM response. The neurotransmitters serotonin, dopamine, and norepinephrine are involved both in CPM, as well as personality traits such as harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), which can be obtained by the Tridimensional Personality Questionnaire (TPQ). However, the associations between these traits (HA, NS, and RD) with endogenous analgesia revealed by CPM have not yet been explored. Methods: Healthy middle-age subjects (n = 28) completed the TPQ, Spielberger’s State Anxiety Inventory, and the Pain Catastrophizing Scale and were assessed for CPM paradigms using thermal phasic temporal summation as the “test stimulus” and hand immersion into hot water bath (CPM
Address correspondence and reprint requests to: Hadas NahmanAverbuch, MSc, The Clinical Neurophysiology Laboratory, Technion-Israel Institute of Technology, Technion City, Haifa, 3200003, Israel. E-mail: [email protected]. There are no funding sources and no conflict of interest. Submitted: June 1, 2014; Revision accepted: September 1, 2014 DOI. 10.1111/papr.12256
© 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume , Issue , 2014 –
water) or contact heat (CPM contact) for “conditioning stimulus.” Results: Higher levels of HA were associated with lessefficient CPM responses obtained by both paradigms: CPM water (r = 0.418, P = 0.027) and CPM contact (r = 0.374, P = 0.050). However, NS and RD were not associated with the other measurements. No significant relationship was observed between state anxiety and pain catastrophizing levels and the CPM responses. Conclusions: The relationship between the capacity of endogenous analgesia and the tendency to avoid aversive experience can be explained by mutual mechanisms involving similar neurotransmitters or brain areas. These findings illuminate the key role of harm avoidance obtained by the TPQ in determining the characteristics of pain modulation profile. & Key Words: harm avoidance, conditioned pain modulation, Tridimensional Personality Questionnaire, anxiety, pain catastrophizing
INTRODUCTION Endogenous analgesia acts through several mechanisms that are mediated mainly by the neurotransmitters serotonin, norepinephrine, and dopamine.1,2 Conditioned pain modulation (CPM) response, a pain-inhibits-pain phenomenon that represents features of diffuse noxious inhibitory control, is one expression of endogenous analgesia that was found to be mediated by the
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above-mentioned neurotransmitters.3–5 The CPM response is manifested as a decrease in pain sensation evoked by a “test stimulus” during or following the application of another noxious stimulus, termed the “conditioning stimulus” (CS). The CPM response has been found to predict the development of acute and chronic pain following surgery and outcome after treatment.6–8 Given its clinical relevance, there is a need to better understand which factors may influence the efficiency of CPM. It has been proposed that the CPM response is influenced by psychological factors, such as anxiety, depression, and pain catastrophizing levels. However, these results are controversial as most studies have not shown any associations between the CPM response and these psychological factors.9–18 Therefore, there is a need to explore whether other, pain-related psychological factors may be more relevant to the CPM response. As serotonin, norepinephrine, and dopamine also were found to be associated with particular personality temperament traits as characterized by Cloninger’s tridimensional personality theory,19 we hypothesized that these traits may affect the CPM response. This biopsychosocial theory states that 3 specific traits are associated with each individual personality: (1) Novelty seeking (NS), which is described as a tendency to respond with intense excitement to novel stimuli leading to the pursuit of rewards and escape from punishment, is associated with dopamine, (2) Harm avoidance (HA), which is defined as a tendency to respond intensely to previously established signals of aversive stimuli and to learn passively to avoid punishment, novelty, and frustrating nonreward, is associated with serotonin, (3) Reward dependence (RD), which is characterized as a tendency to respond intensely to signals of reward and to maintain behavior previously associated with reward or with relief from punishment, is associated with norepinephrine.19 In the past decade, several reports applied Cloninger’s theory to explore individual variation in pain perception using pain psychophysical tests. These studies have found that higher HA scores were associated with enhanced pain response obtained by higher pain ratings and lower pain tolerance in healthy subjects20–22 and the presence of cutaneous allodynia in migraine patients.23 Moreover, higher HA and RD scores were associated with lower pain thresholds and higher pain ratings in women who suffer from provoked vestibulodynia.24 Nevertheless, Ziv et al., (2010) did not find associations between HA scores and pain ratings or the temperature
which induced painful sensation in healthy subjects.25 To our knowledge, the effect of personality traits assessed by the Tridimensional Personality Questionnaire (TPQ) on endogenous analgesia capacity has not been yet determined. We hypothesized that both Cloninger’s personality traits and CPM responses are mediated by the similar neurotransmitters serotonin, norepinephrine and dopamine and thus, may be related. This study aimed to explore whether or not personality traits representing these particular neurotransmitters as well as anxiety or pain catastrophizing are involved in the expression of the CPM response.
METHODS Subjects The study was approved by the local Ethics Committee, and informed consent was obtained from all subjects. Participants were 28 healthy subjects (14 women and 14 men), with mean age of 51.0 6.4, who met the following inclusion criteria: (1) the absence of chronic pain, neurological or psychiatric disease history, (2) no use of analgesic or psychiatric medication on a regular basis, and (3) ability to communicate and understand the instructions of the study. Subjects were asked to refrain from pain relief medications 24 hours before the experimental trial. Subjects were recruited through advertisements and were compensated for their participation (the Israeli shekel equivalent of about 25 US$). This study was a part of a larger research project that tested the effect of various stimulation parameters on CPM response.
Assessment of Psychological Factors
Tridimensional Personality Questionnaire is a 100-item true/false self-report inventory constructed according to Cloninger’s 3-dimensional personality theory.19 This questionnaire measures the 3 primary personality temperament dimensions that are considered to be involved in the mediation of particular types of response to stimuli: HA (34 items); NS (34 items), and RD (30 items). According to the instructions of the TPQ calculation, 2 items that are included in the questionnaire are excluded from the total score of each dimension. This questionnaire has been
Personality Traits and Endogenous Analgesia 3
translated into several languages, including Hebrew,26 and used in a variety of studies. Anxiety level was assessed by the state part of the Spielberger’s State-Trait Anxiety Inventory,27 using the validated Hebrew version.28 This questionnaire has 2 parts; anxiety state and anxiety trait. Each part includes 20 items and the subjects were asked to rate their feelings about each statement on a 4-point scale (1 to 4). This questionnaire has a very good reliability (alpha score > 0.89).29 We used the state part of this questionnaire to assess the anxiety level of the subjects obtained at the time of experimental session. Pain catastrophizing level was assessed by the Pain Catastrophizing Scale30 using the validated Hebrew version (alpha score of 0.86).31 This questionnaire includes 13 items representing the 3 components of pain catastrophizing: rumination (eg “I can’t seem to keep it out of my mind”); magnification (eg “I wonder whether something serious may happen”); and helplessness (eg “There is nothing I can do to reduce the intensity of pain”). Subjects were asked to complete the questionnaire and to relate the conditioning stimulus obtained by the contact heat stimulation (situational pain catastrophizing scale—sPCS).
The Assessment of CPM The “test stimulus”. Thermal temporal summation served as the “test stimulus” and was induced by a series of 10 brief repetitive suprathreshold thermal stimuli that were applied at the pain60 intensity.32,33 The intensity of this stimulus was determined first for each individual using a short series of ascending and descending thermal stimuli, culminating in identification of the temperature that induced a pain experience score of 60 on a 0 to 100 numerical pain scale (NPS) in which 0 represent “no pain at all” and 100 “most pain imaginable”. NPS is a widely used tool for assessing pain levels. It has good reliability/validity and is easy to use.34 The stimulation temperature was determined individually. Stimuli were delivered to the thenar eminence of the dominant hand using a Contact HeatEvoked Potential Stimulator (CHEPS, Medoc, Ramat Yishay, Israel). This device generates heat stimuli using a flat disk probe surface of 27 mm in diameter. The thermode is comprised of 2 layers: an external heating
thermofoil (Minco Products, Inc., Minneapolis, MN) and a cover comprised of a 25-mm layer of thermoconductive plastic (Kaptonâ, with a thermal conductivity of 0.1 to 0.35 W/m/K at 23°C). The stimulus plateau duration was 0.7 seconds, with an ISI of 2 seconds. The baseline temperature was 39°C, the increase rate was 20°C/seconds, and the decrease rate was 40°C/seconds. The Conditioning Stimuli. To reveal the role of different types of thermal CS on the CPM response, 2 stimulations of 46.5°C that lasted for 60 seconds were applied. (1) Immersion of the nondominant hand into a hot water bath (Heto CBN 8-30 Lab equipment, Allerod, Denmark) up to the wrist level (CPM water). The water bath is temperature-controlled with a maximum temperature variance of 0.5°C and continuous stirring action to ensure the maintenance of an even temperature throughout the bath, (2) Contact heat stimulus that was applied to the nondominant thenar eminence (CPM contact). This was performed using a Thermal Sensory Analyzer (TSA) 2001 system (Medoc, Ramat Yishay, Israel), with a 30 9 30 mm Peltier surface stimulator. The baseline temperature was 32.0°C, temperature rates of increase and decrease were 2°C/seconds. Study Design Subjects completed the TPQ and state anxiety. Then, the individual pain60 temperature was determined for each subject. After 10 minutes break, the temporal summation “test stimulus” was applied (“test stimulus”_alone). The participants were asked to rate their pain level of the 1st, 5th, and 10th stimuli using NPS. After a 15-minute break, the CS was delivered. Throughout this stimulation, subjects were asked to score their pain intensity induced by the CS 4 times, at 0, 10, 20, and 30 seconds, and the mean scores of the CS were calculated. During the second half-minute, and subsequent to the last pain scoring of CS, the “test stimulus” was repeated and subject rated the pain of the “test stimulus” (“test stimulus”_water or “test stimulus”_contact). After a 15-minute break, the second CS was delivered in the same way as described above and the “test stimulus” was repeated. The CSs were delivered in a random order. Both the “test stimulus” pain60 intensity and the CS-chosen temperature of 46.5°C are standard and widely used in our laboratory.7–9,32,33 The subjects were asked to complete the sPCS referring to the pain evoked by the CS delivered by the contact heat stimulus.
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Statistical Analysis Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA, version 15). For the “test stimulus,” the temporal summation value was calculated as the difference between the pain scores obtained for the last vs. the first stimuli. The CPM response was calculated as the difference between the “test stimulus”_water and the “test stimulus”_contact (scores of the temporal summation values) obtained during the CS vs. “test stimulus”_alone (the same “test stimulus” was used for both CPM assessments). Thus, negative CPM values would indicate an inhibitory response. We first examined the characteristics of the CPM paradigms, to determine whether temporal summation was induced before and during the CS application for both CPM paradigms, using ANOVA with test (“test stimulus”_alone, “test stimulus”_water, and “test stimulus”_contact) and time (1st, 5th, and 10th pain ratings) interaction. Thereafter, a paired t-test was used to confirm that CPM responses were induced by comparing the temporal summation values obtained before and during each of the CS, and the correlation between the 2 CPM responses was examined. The next step was to explore the role of the CS type on the CPM responses; t-test analyses were used to compare (1) the pain ratings of the CS obtained for hot water immersion and the contact heat, (2) the CPM magnitudes for both paradigms. Finally, Pearson correlations were conducted to examine the associations between psychological factors and the CPM responses. Data are presented as means standard deviation. Statistical significance was defined as P ≤ 0.05.
RESULTS Characteristics of the CPM Paradigms Pain ratings of the 1st, 5th, and 10th “test stimuli” as well as the calculated TS values and CPM responses are presented in Table 1. ANOVA revealed a significant effect of time (P < 0.0001) such that the pain ratings of the 1st stimulus were significantly different from the
pain ratings of the 5th (P = 0.0004) and the 10th (P < 0.0001) stimuli. In addition, the pain ratings of the 5th and the 10th stimuli were different (P = 0.026). These indicated that the repetitive thermal stimuli evoked robust temporal summation effects which were observed regardless the CS administration. The test (P = 0.502) or time X test (P = 0.337) interaction were not significantly different, indicating that the pain ratings of the 1st, 5th, and 10th obtained during the “test stimulus”_alone were not different from the pain ratings of the 1st, 5th, and 10th obtained during the “test stimulus”_water and “test stimulus”_contact. No gender or age effect was found on pain modulation measures. Lower temporal summation values were obtained during the CS as compared with temporal summation values before the exposure to CS, indicating that a significant CPM response was evoked. This was observed for both CPM contact and CPM water paradigms (P = 0.042 and P = 0.002, respectively). Comparing the 2 CPM paradigms, revealed that significant higher pain ratings were reported for the CS induced by the water bath immersion compared with the contact heat (71.8 20.7 vs. 53.9 23.2, P < 0.001). However, no difference was found between the CPM responses (P = 0.188) evoked by the 2 different types of CS. Moreover, positive correlation was observed between the CPM contact and the CPM water response (r = 0.530, P = 0.001), indicating that individuals who demonstrated less-efficient CPM response in one paradigm also exhibited similar CPM response in the other paradigm. No correlations were found between the pain ratings of the CS and the CPM response. This was observed for both the CPM water (r = 0.171, P = 0.341) and for the CPM contact (r = 0.091, P = 0.615), thus, the possibility that greater pain reports of the CS induced greater CPM responses may be ruled out. Associations between Psychological Factors and Pain Psychophysical Measures The scores of the HA, RD, and NS are presented in Table 2. As can be observed, there were no gender
Table 1. The Pain Ratings, TS, and CPM Values of the 2 Paradigms
“test stimulus”_alone “test stimulus”_water “test stimulus”_contact
1st Pain Rating
5th Pain Rating
10th Pain Rating
45.9 19.4 52.6 20.3 53.0 20.1
61.1 14.9 60.0 22.8 63.3 19.9
72.4 18.3 64.6 24.4 70.0 18.9
TS Value 26.5 21.3 12.0 16.6 17.0 19.6
CPM Response 14.6 22.1 9.6 22.6
Personality Traits and Endogenous Analgesia 5
Table 2. Comparison of Psychological Factors between Men and Women Men (n = 14)
All HA NS RD Anxiety state sPCS
11.0 14.2 19.5 29.1 21.8
5.6 4.1 3.5 7.8 9.9
11.6 14.6 19.0 29.4 20.2
5.6 4.7 3.0 8.5 8.4
Women (n = 14)
P Value
0.557 0.652 0.489 0.869 0.407
10.4 13.9 19.9 28.8 23.5
5.8 3.5 3.9 7.4 11.3
A
HA, harm avoidance; NS, novelty seeking; RD, reward dependent; sPCS, situational pain catastrophizing scale.
Table 3. Correlations between Psychological Factors and the Conditioned Pain Modulation Response HA CPM water CPM contact
0.418* 0.374*
NS 0.157 0.123
RD 0.161 >0.001
Anxiety State
sPCS
0.170 0.239
0.339 0.230
B
HA, harm avoidance; NS, novelty seeking; RD, reward dependent; sPCS, situational pain catastrophizing scale; CPM, conditioned pain modulation. *P ≤ 0.05.
differences in the personality trait scores. Among all the assessed measures, only the HA dimension of the TPQ traits was associated with the CPM responses. This association was observed for both CPM paradigms (see Table 3). Higher levels of HA were associated with lessefficient CPM responses obtained for both the CPM water (r = 0.418, P = 0.027, Figure 1A) and the CPM contact (r = 0.374, P = 0.050, Figure 1B) paradigms. The levels of sPCS and state anxiety were not associated with CPM magnitude. Temporal summation value was not correlated with any of the Tridimensional Personality Questionnaire traits, indicating that the effect of HA was specific to CPM.
DISCUSSION Despite the growing number of publications indicating that pain modulation responses are affected by a variety of pain-related psychological variables, no study has yet focused on the possible role of the personality traits, as assessed by the TPQ, on the pain modulation capacity. The main finding of the present study was that higher scores of HA trait were associated with less-efficient inhibitory pain modulation responses induced by 2 CPM paradigms. This may suggest that greater predisposition to react intensely to signals of aversive stimuli and learning to avoid punishment, innovation and frustrating nonreward, may be related to lower endogenous analgesia. Accordingly, it may be assumed that pronociceptive pain modulation profile35 as expressed by the
Figure 1. Positive correlations between harm avoidance and (A) conditioned pain modulation (CPM) water (r = 0.418, P = 0.027) as well as with (B) CPM contact (r = 0.374, P = 0.050).
less-efficient CPM response, characterized the individuals with higher HA. The results of the current study give a better understanding of the factors that can affect the CPM efficiency. CPM was found to be less efficient among chronic pain patients10,12,17,35 and to predict the development of chronic and acute pain following a surgery.6,7 Thus, according to our findings, it can be suggested that individuals with high HA levels may be prone to develop chronic pain and therefore may need to be treated differently to prevent chronic pain development. Brain imaging studies provide evidence for the possible effect of HA on the processing of nociceptive input. It has been reported in fMRI studies that higher HA levels were associated with greater brain activation during expectations and processing of noxious stimulus. This was observed in brain areas involved in pain modulation such as medial prefrontal cortex, premotor cortex, anterior and posterior cingulate cortex, thalamus, and amygdala.25 In addition, in healthy subjects, HA was negatively correlated with gray matter volume
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in frontal, occipital, and parietal structures.36 The previously mentioned brain regions such as the thalamus, anterior and posterior cingulate cortex, and prefrontal cortex, all of which have been found to be related to the HA trait, are also known to be involved in pain modulation, particularly CPM.37,38 Thus, we can conceptualize that the same brain areas which are involved in both inhibitory pain response and aversive stimulus avoidance may explain our findings. Another possible explanation for such relations may be attributed to the fact that serotonin plays a significant role in both CPM and HA. Variation in the serotonin transporter (5-HTT) gene explained interindividual differences in pain modulation, such that subjects with low 5-HTT expression exhibited less-efficient CPM response,4,39 although another study failed to find this effect.40 Yarnitsky et al. (2012) reported that pretreatment CPM efficiency predicted treatment success with duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in patients with diabetic neuropathy. Moreover, the extent of pain alleviation in these patients was linked to the extent of CPM modification following treatment that modified the serotonin levels.8 According to Cloninger’s suggestion that higher HA is related to higher synaptic levels of serotonin,19 it was expected that higher HA scores will characterize individuals with more efficient CPM responses. However, our findings revealed an opposite direction of associations in which higher HA was correlated with less-efficient CPM responses. Previous studies indeed reported that high activity in the serotonergic system characterized individuals with high HA,41–44 however, others did not find these relationships.45–47 Furthermore, one study reported findings in the opposite direction: low basal levels of central serotonin were related to higher HA scores.48 Additionally, use of tricyclic antidepressants (TCA) or selective serotonin reuptake inhibitors (SSRI) was followed by reduction in HA scores in studies of patients with depression and generalized anxiety disorders.49,50 This suggests that the pattern of relationships between serotonin and HA is more complex and may be mediated by an interaction between serotonin and dopamine51 or norepinephrine.52 Therefore, our observation that higher HA was associated with less-efficient CPM may be explained by an involvement of other neurotransmitters that intervene between serotonin and HA or CPM. Our findings may also illuminate the role of the CS on CPM response. We applied 2 types of thermal tonic noxious stimuli for the CS delivered at the same intensity
and duration. Although both represent the same pain modality, the water immersion evokes higher pain reports, which may be attributed to the different quality of pain experience activated by water and/or to the larger area of stimulation compared with the contact heat. As a positive correlation between the 2 CPM responses was observed, it can be assumed that if the CS is painful, then its particular characteristics have minor effect on the CPM magnitude. This notion is further supported by the lack of correlation between the pain ratings reported for the CS and the CPM response magnitude in both paradigms. This is in line with previous studies that demonstrated no association between CPM responses and pain intensity of the CS.32,53 It has been assumed that CPM response is influenced by psychological factors such as anxiety and pain catastrophizing. While some studies found associations between CPM responses and these factors9-11, the majority of the studies found no associations.12–18 Similarly, this study found no associations between the 2 CPM responses and the levels of state anxiety and situational pain catastrophizing. The sPCS is a relatively new measure which has been examined in only a few studies in relation to the CPM response. Although one study which controlled for gender found a significant relationship between sPCS and the CPM response,54 the other study found no significant correlation,6 similar to our result. Still, there are other psychological factors that were not included in this study and may affect the CPM response. The major limitation of our study is the relative small number of subjects that were tested. Still, this study is the first to suggest that HA and CPM responses are related. Nevertheless, there is a need to further explore the association between the TPQ traits and the CPM response in larger samples and other populations, especially for HA.
CONCLUSIONS The lower capacity of pain inhibition which characterized individuals with greater tendency to avoid aversive experience can be explained by mutual mechanisms involving modulation processes invoked by nociceptive input and behavioral features of pain perception. These findings illuminate the key role of pain-related psychological factors in determining the characteristics of pain modulation profile. Therefore, an assessment of CPM should encompass the evaluation of these psychological factors, mainly via tools that represent biopsychosocial facets of pain.
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