1. Introduction
Pain responses of women and men may differ. For example, women seem to be at greater risk for chronic pain than men.6,14,71 Furthermore, women typically report more frequent, concurrent, and severe pain, for longer durations than do men.35,46,72 Women have also exhibited increased sensitivity and reactivity to experimental pain,6,71 albeit not consistently across studies.65 At the same time, women exhibit greater pain inhibition capabilities than do men (manifested in greater adaptation to noxious stimuli),26,41 a trait somewhat counterintuitive with the aforementioned. Emotional responses of women and men may also differ. For example, many affective disorders and stress-related conditions are more common among women than among men.2,12,73 Furthermore, men exhibit stronger cortisol and autonomic activation during acute distress than do women45,51,58; however, the emotional response to the stressor is often stronger in women than in men.47,75,81
Experimental studies show that pain perception and modulation often correspond with participants' emotional status,20,37,38 reflecting pain–stress interactions. This interaction is also manifested in the comorbidity of chronic pain and distress, which reinforce one another, significantly affecting well-being4,31,44 and in mutual limbic, prefrontal, and brain stem activation during either experimental stress or pain.19,27 Particularly, the medial prefrontal cortex and the periaqueductal gray, as well as their connectivity, have been implicated in the development of both chronic pain and distress, suggesting overall reciprocal pain–stress modulation.82,87 Of interest, depression and anxiety that are comorbid with chronic pain are more frequent among women than among men,80 and chronic pain conditions deemed as stress related, such as fibromyalgia and tension-type headaches, are also more frequent among women.18,49,52 Furthermore, there have been reports in animal studies of sexual dimorphism in fear- and stress-induced analgesia.59,65,85 Thus, sex may interpose within pain–stress interactions. Understanding the possible trilateral interaction of sex, pain, and stress is important to understand the apparent increased the vulnerability of women to pain and to mental conditions and to promote individualized patient care.
That said, many of the experimental studies assessing pain responses following acute stress manipulation have either included only men38,43 or male animals3,54,55 or included both sexes but did not compare between them.16,23,29,60,63 Only a few studies have directly examined sex effects in pain–stress interactions. In 2 studies, only women exhibited increase in pain threshold or pain tolerance following stress manipulation, namely, stress-induced analgesia (SIA).11,39 However, in another study women and men had similar SIA magnitude.1 In one study, women and men had a similar reduction in conditioned pain modulation (CPM), suggesting the opposite phenomenon of stress-induced hyperalgesia (SIH).67 Because of the dearth of information and the inconsistent results, it is yet unclear whether there are sex-specific pain responses under stress.
It is important that the induction of a stress response requires systematic validation, using cognitive and biological indices,50 a procedure that is scarcely used in studies. Furthermore, the sample size in these studies was relatively small considering the high individual variability in pain and stress responses. Thus, reexamining the trilateral interaction of sex, pain, and stress in a systematic manner and with larger samples is called for. Therefore, this study's aim was to examine the changes in pain sensitivity and pain modulation following acute, validated, stress manipulation among women and men and to search for sex-specific pain–stress interactions. Because of the test–retest nature of the study, the pain indices' reliability and reproducibility were also calculated.
2. Methods
2.1. Participants
Participants were 148 healthy women (n = 82) and men (n = 66). The participants were recruited by advertisements posted around the university campus. Inclusion criteria were (1) between the ages of 20 and 65 years and (2) good health based on participants' report. Exclusion criteria were (1) chronic diseases such as diabetes, (2) acute or chronic pain, (3) pregnancy, (4) present or previous pathology on the forearms or hands (testing site), (5) bruises or any other skin lesions on the forearms or hands, (6) mental illnesses (eg, anxiety disorders, depression, bipolar disorder), and (7) any language barriers. Participants who were interested in participating were first screened for eligibility by way of a phone interview according to the aforementioned criteria. Candidates were then invited to the laboratory and were interviewed again to ascertain their eligibility status. Informed consent was obtained from all the participants after they received a detailed explanation of the study's aims and protocols. The experiment was approved by the Institutional Review Board of the Sheba Medical Center and the Institutional Review Board of the Tel Aviv University.
2.2. Procedure
The study included 2 parts. The first part was a preliminary study that was conducted for the purpose of assessing the reliability and reproducibility of the pain indices. This part was conducted among 13 participants who did not participate in the second, main part of the study. As the second part necessitated measuring the pain indices twice (before and immediately after the application of the stress manipulation), it was pertinent to evaluate their natural variations over time and calculate their standard error of measurement (SEm) before part 2. Any changes in the pain indices following the manipulation in part 2, which were above the SEm, could thus be appreciated as being real. We have reported the results of the preliminary test–retest study elsewhere.37
The second, main part of the study included the measurement of pain and stress indices before and immediately after the application of a stress manipulation (n = 133 participants) or a sham-stress manipulation (n = 15 participants). The inclusion of the control group who underwent the sham manipulation was necessary to verify the specific effectiveness of the stress manipulation in producing stress because it consisted of similar components of the real manipulation without the elements of stress. The allocation to the real or sham manipulation was random until the point at which the sham group reached the designated sample of 15 participants and, from that point on, the rest of the participants underwent the real manipulation. Each subject was invited to a single testing session that lasted approximately 2 hours. The participants were instructed to avoid intense physical exercise 24 hours prior to the testing day and to refrain from food and caffeine one hour before testing. Given that cortisol levels normally fluctuate throughout the day, all participants were tested around 12 to 1 pm. Testing took place in a quiet room. Temperature in the room was maintained at 22°C ± 2°C. The subject sat in a comfortable armchair. After signing informed consent, the subject received training in the psychophysical and endocrine measurements. After a short break, the subject was connected to the monitor sensors that remained active thereafter for the entire experiment.
Figure 1 describes the experimental protocol. For both the real and sham manipulations, there were 3 main phases from which data were obtained, as follows: (A) baseline measurements (prestress). After attaching the subject to the recording electrodes of the autonomic function, the subject was asked to rest quietly for 10 minutes (from which time baseline autonomic variables were extracted) immediately after which the first saliva sample for cortisol was taken, and the first perceived stress and state anxiety scores were obtained. After completion of baseline data collection, the testing of pain indices commenced. Testing included the measurement of heat–pain threshold and heat–pain tolerance, performance of a stimulus–response function for heat and pain, and measurement of temporal summation of pain (TSP) and pain adaptation. The stimulus–response function always preceded the 2 latter tests because it was used to extract the stimulation intensities for these tests. Otherwise, the tests were performed in random order. (B) Real/sham stress manipulation and second measurements. In this phase, it was explained to the participants how to operate the software of the Montreal Imaging Stress Task (MIST), which was the real manipulation, or the software of the sham manipulation, and received the preparatory explanations. Afterward, the subject started the tasks in one of the 2 types of software, a process that lasted about 20 minutes, as described below. Immediately upon completion of the tasks, the second saliva sample was taken, and the second perceived stress and state anxiety scores were obtained. This part was immediately followed by measurements of the pain indices as in phase A. The same order of testing was maintained within participants before and after the manipulation to avoid additional influencing factors. (C) Recovery. Upon completion of the pain measurements, the participants received an explanation of the true purpose and nature of the manipulation, and they were assured that their performance was satisfactory. They were informed that the experiment was over and were asked to relax and rest. Approximately 20 minutes after this reassurance, the third saliva sample was taken, the third perceived stress and state anxiety scores were obtained, and autonomic variables were sampled, to evaluate whether the stress response had subsided, namely, to ensure that the stress indices had returned to baseline and that the participants were being released from the laboratory with no residual stress. Furthermore, as physiological stress is known to persist after stress exposure,50 we were interested to learn whether we would find sex differences in the recovery phase.
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Figure 1.: The study protocol. GSR, galvanic skin response; HR, heart rate; HRV, heart rate variability.
2.3. Equipment
2.3.1. The thermal stimulator
Heat stimuli were delivered using 2 Peltier-based computerized thermal stimulators (TSA II, Medoc Ltd, Ramat-Ishay, Israel), with 3 × 3 cm contact probes. According to the principles of the Peltier element, a passage of current through the Peltier element produces temperature changes at rates determined by an active feedback system. As soon as the target temperature is attained, probe temperature actively reverts to a preset adaptation temperature by passage of an inverse current. The adaptation (baseline) temperature was set to 35°C. The probes were attached to the testing site by means of a Velcro band.
2.3.2. The PMD-100 system
The physiological signals were recorded, sampled, and stored using a personal computer with the PMD-100 system (Medasense Biometrics Ltd, Ramat Gan, Israel) through a finger probe. A one-lead electrocardiogram (ECG) signal was sampled with a frequency of 500 Hz, and a reflectance-mode Photo-plethysmogram (PPG) signal from the right-hand index finger was sampled with the same frequency. Skin conductance (measured in micro-Siemens, µS) was measured using 2 electrodes positioned on the volar pads of the distal phalanx in the middle and ring fingers of the right hand and was sampled with a frequency of 31.25 Hz. The recorded signals were synchronized and processed offline using Matlab R2010 scientific software (The Mathworks, Inc, MA).
2.4. The real and sham manipulations
The MIST was used to induce acute psychosocial stress. The MIST was chosen because it is a reliable and validated tool for inducing stress perception and physiological responses.25 In addition, the MIST can be used in a functional magnetic resonance imaging environment25,70 and thus has potential in future studies assessing brain function under stress. We have reported the MIST procedure elsewhere.38 In short, the computer program displayed a mental arithmetic task, a rotary dial for submission of a response, a text field that provides feedback to the subject (“correct,” “incorrect,” or “timeout”), and 2 default performance indicators, one for the individual subject's performance and one for average performance of all participants. Before the task, participants were informed that the average number of correct answers ranges between 80% and 90% and that their performance should fall into this range to be used in the study. However, the time-limited tasks were constantly adjusted to enforce only about 20% to 45% correct answers. Participants were also told that the investigators were following their performance on a second monitor. The task ran for 8 minutes, after which participants were informed by the investigator about their poor performance and were asked to perform another task while improving their performance. After completion of the second task (an additional 8 minutes), the participants again received negative feedback about their performance, and the task was terminated.
The sham manipulation consisted of a PowerPoint presentation with an interface that looked like the screen of the MIST; however, the mental arithmetic tasks were relatively simple, and the time limit was long enough to enable participants to successfully complete the task. As with the MIST, the software ran for 8 minutes, followed by a short break during which the examiner asked the participants about their experience and then started the second run of an additional 8 minutes. After completion of the second run, the sham task was terminated.
2.5. Measurements of the stress response
Stress is defined as a cognitive perception of uncontrollability and/or unpredictability, which is expressed in a physiological and behavioral response aimed to cope with threatening circumstances.50 As such, it is important to perform a comprehensive evaluation of the stress systems, including the hypothalamic–pituitary adrenal (HPA) axis and the sympathetic adrenomedullary (SAM) system, as well as the individual's subjective perception.
2.5.1. Perceived stress
Perceived stress was evaluated using a visual analogue scale (VAS). The VAS consists of a 10-cm line with 2 anchor points at its extremes, set as 0 = no stress and 10 = most intense stress imaginable.38
2.5.2. State anxiety
Anxiety was evaluated with the short form of the State-Trait Anxiety Inventory (STAI).76 This questionnaire contains 10 items, and participants are asked to rate the degree to which they experienced each symptom of anxiety at that moment, on a 4-point Likert-type scale: 1 (not at all) to 4 (very much so). This measure of state anxiety has been used extensively in previous research and has consistently demonstrated good psychometric properties, especially under conditions of stress.62
2.5.3. Sympathetic adrenomedullary variables
The sympathetic system responds to stress by secreting noradrenaline, thereby increasing sympathetic tone and resulting in changes in heart rate variability, blood pressure, respiration, skin conductance, and the like.33 The sympathetic response was thus investigated by recording the changes in heart rate (HR), the high-frequency band of heart rate variability (HRV), and galvanic skin response (GSR), using the PMD-100 system. Heart rate, HRV, and GSR were recorded continuously throughout the entire experiment at a rate of 500 Hz, and the values were extracted offline for 3 time points, as described in Figure 1. For each of these time points, we sampled 2 minutes (end of baselines rest, end of MIST, and end of recovery rest after the reassurance) and averaged the data for each index.
2.5.4. Salivary cortisol
The HPA axis is strongly activated by psychosocial stress and secretes the stress hormone cortisol.28 Saliva samples of cortisol were collected with Salivettes (Sarstedt, Rommels-dorft, Germany) at the same time points, as described for the sympathetic indicators. Participants were asked to place a Salivette (cotton roll) in their mouths, chew on it for a minute until it became saturated, and place it in storage container. The samples were then stored at −20°C until assayed. Cortisol levels were assayed using a commercial ELISA kit (Assay Design, Ann Arbor, MI). Measurements were performed in duplicate, according to the kit's instructions with the reagents provided. Cortisol levels were calculated using MatLab-7, according to standard parametric calibration curves based on the data from the kit.56
2.6. Measurements of the pain indices
2.6.1. Heat–pain threshold and heat–pain tolerance
Heat–pain threshold and heat–pain tolerance were measured with the method of limits, as described in our previous study.36 In short, the thermal stimulator was placed on the ventral aspect of the participants' nondominant forearm. For each separate threshold measurement, participants received 4 successive ramps of gradually increasing temperature, starting from a baseline temperature of 35°C, at a rate of 2°C/s (interstimulus interval of 30 seconds). For heat–pain threshold, the participants were asked to press a computer mouse button with their free hand when a pain sensation was first perceived. For heat–pain tolerance, the participants were asked to press the button when they could no longer withstand the pain. Pressing the button resulted in an automatic recording of the threshold temperature and reset the probe temperature to baseline value. Heat–pain threshold and heat–pain tolerance were computed separately by averaging the readings of 4 successive stimuli in each measurement.36
2.6.2. Stimulus–response functions
Individual stimulus–response functions were created for each subject to extract the stimulation intensities necessary to test TSP and pain adaptation. Participants received a series of thermal stimuli on the forearm and were asked to rate their perceived pain following each stimulus on a 0 to 10 visual analogue scale (VAS) with end points set as 0 = “no pain sensation” and 10 = “the most intense pain sensation imaginable” (range 0-10 units). The stimulus intensities, presented in an ascending manner, rose from a baseline temperature of 35°C (rate of rise, 2°C/s) to a destination temperature ranging between 38°C to the intensity eliciting 7 on the VAS, at which it remained for one second and then returned to baseline. An interstimulus interval of 45 seconds was maintained. The temperatures eliciting a value of 3 to 4 and 5 to 6 on the VAS were extracted from each individual function to be used for subsequent testing.38
2.6.3. Temporal summation of pain
Temporal summation of pain is a phenomenon in which perceived pain gradually increases in response to repetitive or constant, moderately noxious stimulus of fixed intensity, and it refers to the ability of nociceptive neurons to increase their output when stimulated at a high rate.21,77 To test TSP, participants received a continuous noxious heat stimulus on the forearm at an intensity equivalent to 5 to 6 on the VAS (individually adjusted), for a duration of 30 seconds. This initial stimulation intensity was chosen based on a previous study in which TSP occurred when stimulation intensity exceeded a rating of 5 on the VAS.88 The testing of TSP using tonic stimulation has also been reported elsewhere.32,40 The participants were asked to rate the amount of perceived pain (using VAS) every 15 seconds (at times 0, 15, and 30 seconds). The participants were not informed of the time that had elapsed from the beginning of stimulation. The magnitude of TSP was calculated by subtracting the last VAS rating from the first.88
2.6.4. Pain adaptation
Pain adaptation is a phenomenon in which perceived pain gradually decreases in response to a constant, mildly noxious stimulus of fixed intensity, and it refers to segmental inhibition of neurons from which the nociceptive input has emerged.8,21 To test for pain adaptation, participants received a continuous noxious heat stimulus on the forearm at an intensity equivalent to about 4 on the VAS (individually adjusted), for a duration of 60 seconds. This initial stimulation intensity was chosen based on a previous study in which pain adaptation did not occur when stimulation intensity exceeded a rating of 5 on the VAS.88 The participants were asked to rate the amount of perceived pain (using VAS) every 10 seconds (at times 0, 10, 20, 30, 40, 50, and 60 seconds). The participants were not informed of the time that had elapsed from the beginning of stimulation. The magnitude of pain adaptation was calculated by subtracting the first VAS rating from the last.88
2.7. Data analysis
The sample size was estimated a priori for 2 main outcome measures: pain tolerance threshold and pain adaptation. Previous data collected in the laboratory with a similar measurement protocol enabled us to calculate the sample size based on means and standard deviations of healthy women and men, with α = 0.05, and a statistical power of 80% (effect size ranged between 0.88 and 0.93). The calculation yielded a sample size of 18 and 22 participants, respectively, per group. However, considering the number of factors in the study and the test–retest manner, the sample size was tripled.
Data were analyzed using IBM SPSS statistic software version 27. All data underwent Kolmogorov–Smirnov analysis for normality of distribution. Continuous variables were described as means ± SD. Analyses of variance and corrected post hoc tests (Fisher least significant difference) were used to evaluate the main effect of sex (woman or man) and condition (baseline, stress, or recovery), as well as their interaction, on the stress indices (perceived stress, perceived anxiety, HR, HRV, GSR, and cortisol) and on the pain indices (heat–pain threshold, heat–pain tolerance, TSP, and pain adaptation). Effect sizes of post hoc comparisons were evaluated with Cohen d. Differences in the outcome measures between prestress and during stress conditions (delta) were calculated by subtracting the former from the latter. Linear regression analyses were used to predict the change in the sensory measures (dependent variables) by the independent variables: sociodemographic data (age, education) and the stress indices. P values <0.05 were considered significant.
3. Results
3.1. Characterization of the study groups
The women and men did not differ in their age (30.9 ± 10 and 28.3 ± 10, respectively, P = 0.11) or years of education (14.6 ± 1.6 and 15.1 ± 2, P = 0.46), and most of the participants in each of these subgroups were not married.
3.2. Validation of the stress response and sex effects on the stress indices
Table 1 presents the changes in the stress indices within each group during the 3 phases (conditions) of the study; baseline, stress (post-MIST), and recovery as well as post hoc comparisons between the conditions. The MIST induced a significant stress response among both men and women, which manifested in the subjective indices (perceived stress and perceived anxiety) and in the objective indices (cortisol and autonomic variables) except for a borderline effect on cortisol among women. Post hoc comparisons revealed that among both men and women, perceived stress and anxiety significantly increased following the MIST and then significantly decreased back to baseline levels or lower during recovery. Similarly, among both men and women, HR increased, HRV decreased, and GSR increased following the MIST and then returned to baseline values except for GSR, which remained somewhat higher than baseline during recovery in men. In contrast, only in men, cortisol significantly increased following the MIST and almost doubled its level, whereas in women, the cortisol level did not significantly change (a borderline increase from baseline to recovery was observed, P = 0.055).
Table 1 -
Changes in the stress indices throughout the entire protocol within each sex.
|
Baseline |
During stress |
Recovery |
ANOVA |
| F |
P
|
| Men |
|
|
|
|
|
| Perceived stress (0-10) |
1.27 (1.7) |
4.18 (2.9)a
|
0.99 (1.3)b
|
53.81 |
<0.0001 |
| State anxiety (10-40) |
12.72 (3.3) |
19.20 (6.5)a
|
13.17 (3.5)b
|
57.41 |
<0.0001 |
| Cortisol (pg/mL) |
671.54 (419.1) |
1159.08 (1007.1)a
|
692.36 (652.2)b
|
4.94 |
<0.05 |
| HR (bpm) |
68.27 (11.4) |
76.92 (12.2)a
|
68.16 (10.5)b
|
46.82 |
<0.0001 |
| HRV (Hz) |
36.84 (14.8) |
31.16 (15.8)a
|
34.61 (16.3)b
|
6.66 |
<0.001 |
| GSR (mho) |
4.08 (2.8) |
9.42 (4.5)a
|
8.16 (5.0)c
|
30.51 |
<0.0001 |
| Women |
|
|
|
|
|
| Perceived stress (0-10) |
1.20 (1.5) |
5.26 (2.9)a
|
0.18 (1.5)b,c
|
128.88 |
<0.0001 |
| State anxiety (10-40) |
12.95 (2.9) |
22.16 (6.9)a
|
12.61 (2.8)b
|
121.82 |
<0.0001 |
| Cortisol (pg/mL) |
587.51 (366.9) |
718.15 (517.5) |
889.17 (489.2) |
2.97 |
0.064 |
| HR (bpm) |
75.67 (10.4) |
82.51 (10.9)a
|
73.75 (9.8)b
|
27.01 |
<0.0001 |
| HRV (Hz) |
35.87 (10.28) |
26.70 (13.1)a
|
31.65 (15.6)b
|
7.41 |
<0.001 |
| GSR (mho) |
5.19 (6.8) |
7.86 (8.9)a
|
6.36 (8.3) |
4.92 |
<0.05 |
Values are mean ± SD. F and P values are of the analyses of variance. Upper script letters signify corrected post hoc paired comparisons: a = between baseline and stress measurements, b = between stress and recovery measurements, c = between baseline and recovery measurements. For all the comparisons the superscripts a and b signify P < 0.001 except for cortisol in men and GSR in women, in which the superscript a signifies P < 0.01.
ANOVA, analysis of variance; bpm, beats per minute; GSR, galvanic skin response; HR, heart rate; HRV, heart rate variability; Hz, hertz; mho, micro-Mho; npm, number per second.
Table 2 presents the two-factor repeated-measure analysis of variances (ANOVAs) testing the effect of sex and of condition as well as their interaction on all the stress indices. A significant main effect of condition was found for all the stress indices as reflected in Table 1; however, a significant main effect of sex was found only for HR. The HR of women was higher than that of men in all the 3 experimental conditions: baseline (t = −2.8, P < 0.01, Cohen d = −0.67), stress (t = −2.1, P < 0.05, Cohen d = −0.48), and recovery (t = −2.3, P < 0.05, Cohen d = −0.52).
Table 2 -
Fvalues and significance of condition and sex main effects on the stress indices and the sex × condition interactions.
|
Condition |
Sex |
Condition × sex |
| Perceived stress (0-10) |
170.6*** |
1.05 |
4.89** |
| State anxiety (10-40) |
172.4*** |
2.12 |
7.21** |
| Cortisol (pg/mL) |
3.99* |
0.42 |
4.10* |
| HR (bpm) |
69.88*** |
6.55* |
0.83 |
| HRV (Hz) |
14.86** |
0.77 |
0.82 |
| GSR (mho) |
24.56*** |
0.18 |
3.86* |
bpm, beats per minute; GSR, galvanic skin response; HR, heart rate; HRV, heart rate variability; Hz, hertz; mho, 1 siemens; npm, number per second.
Numbers are F values of the 2-factor analysis of variance. The asterisks represent the significance of the ANOVA factors: *P < 0.05, ** P < 0.01, *** P < 0.001.
A significant condition × sex interaction was found for the 2 subjective stress indices and 2 objective stress indices (Fig. 2). Thus, although men and women had similar perceived stress and anxiety levels at baseline and recovery, women exhibited a greater increase in these variables during stress compared with men: perceived stress: t = −2.1, P < 0.05, Cohen d = −0.37 (Fig. 2A) and anxiety: t = −2.5, P < 0.01, Cohen d = −0.87 (Fig. 2B). Regarding the objective stress indicators, cortisol levels among women showed a moderate gradual increase during the experiment that almost reached significance during the recovery phase compared with baseline (t = −2.3, P = 0.055). In contrast, cortisol levels of men significantly increased from baseline to stress (t = −2.1, P < 0.05, Cohen d = −0.45) and decreased back to baseline levels during recovery (Fig. 2C). In GSR, although the levels increased from baseline to stress among both men (t = −6.9, P < 0.0001, Cohen d = −1.2) and women (t = −3.2, P < 0.01, Cohen d = −0.76), the GSR level returned to baseline levels during recovery only among women but remained significantly higher than baseline among men (t = −5.8, P < 0.0001, Cohen d = −1.0) (Fig. 2D).
Figure 2.: Stress responses. Significant sex × condition (baseline stress, recovery) interactions were observed in perceived stress (A), perceived anxiety (B), salivary cortisol (C), and galvanic skin response (D). Although both sexes exhibited an increase in perceived stress and anxiety during stress compared with baseline (***1, P < 0.001), women exhibited greatere increase than men (*2, P < 0.05 and **2, P < 0.01, respectively). Cortisol increased during stress compared with baseline only among men (*1, P < 0.05) and was greater than that of women (*2, P < 0.05), whereas cortisol in women gradually increased throughout the study and showed a tendency toward higher values in recovery compared with baseline (^3, P = 0.055). Galvanic skin response levels increased from baseline to stress among both men (*1, P < 0.0001) and women (*1, P < 0.01) and returned to baseline levels during recovery only among women but remained significantly higher than baseline among men (*3, P < 0.0001). Values denote mean ± SE. VAS, visual analogue scale.
With respect to the sham stress manipulation, the Supplementary Table (available as supplemental digital content at https://links.lww.com/PAIN/B690) presents the values of all the stress indices in the 3 phases (conditions): baseline, sham stress, and recovery. With the exception of 2 indices, none exhibited a significant effect of condition as indicated by the ANOVAs. The indices that were affected by condition were perceived stress, F(2,28) = 4.07, P < 0.05 and HR: F(2,28) = 8.85, P < 0.01. Perceived stress gradually decreased across the 3 conditions, from 2.0 ± 1.1 to 1.15 ± 1.1 to 0.78 ± 1.7, respectively. Similarly, HR decreased across the 3 conditions, from 76.83 ± 13.0 to 71.58 ± 11.4 to 70.6 ± 9.5, respectively. Thus, the sham stress manipulation did not induce a stress response.
3.3. Effects of sex on pain responses during stress
3.3.1. Pain threshold and pain tolerance thresholds
The two-factor ANOVA revealed no significant effects of condition (baseline/stress) or of sex on pain threshold and no significant condition × sex interaction. Pain threshold of women and men was similar at baseline (42.52 ±3.1 and 43.27 ± 2.9°C, respectively, t = 1.4, P = 0.16) and during stress (42.80 ± 2.9 and 43.04 ± 3.2°C, respectively, t = 0.41, P = 0.68). The sham stress manipulation did not induce any changes in pain threshold (please see Supplementary Table, available as supplemental digital content at https://links.lww.com/PAIN/B690).
Regarding pain tolerance, ANOVA revealed no significant effects of condition (baseline/stress), F(1,131) = 3.56, P = 0.06; rather, it revealed a trend showing a slight reduction in pain tolerance from baseline to stress condition. However, the effect of sex was significant, F(1,131) = 4.46, P < 0.05. Pain tolerance of women was significantly lower than that of men regardless of condition (baseline: t = −2.03, P < 0.05, Cohen d = 0.52; stress: t = −2.08, P < 0.05, Cohen d = 0.53). The condition × sex interaction was not significant, F(1,131) = 0.07, P = 0.93, suggesting that both sexes responded similarly to stress (Fig. 3). The sham stress manipulation did not induce any changes in pain tolerance (please see Supplementary Table, available as supplemental digital content at https://links.lww.com/PAIN/B690).
Figure 3.: Heat–pain tolerance. Heat–pain tolerance threshold of men was significantly higher than that of women during both baseline and stress conditions (*P < 0.05, between the groups). Values denote mean ± SE of temperature.
3.3.2. Temporal summation of pain
Figure 4 presents the magnitude of TSP among women and men during baseline and during stress. Analysis of variance revealed no significant effect of condition on the magnitude of TSP, F(1,131) = 1.64, P = 0.19. However, the effect of sex was significant, F(1,131) = 7.49, P < 0.01. The condition × sex interaction effect was also significant, F(1,131)= 13.91, P < 0.0001. The magnitude of TSP at baseline was similar for both sexes (t = 0.82, P = 0.41); however, the TSP of men increased from baseline to stress (from 0.87 to 1.53 VAS units, t = −2.27, P < 0.05, Cohen d = −0.42) but that of women decreased from baseline to stress (from 0.43 to −0.90 VAS units, t = 3.11, P < 0.01, Cohen d = 0.53) and essentially showed pain reduction and not pain facilitation. These changes were beyond the SEm of TSP of pain adaptation, suggesting a real difference. Consequently, the magnitude of TSP of women and men during stress was significantly different (t = 3.98, P < 0.0001, Cohen d = 1.01). The sham stress manipulation did not induce any changes in TSP (please see Supplementary Table, available as supplemental digital content at https://links.lww.com/PAIN/B690).
Figure 4.: Temporal summation of pain. The magnitude of temporal summation of pain (TSP) at baseline was similar for both sexes; however, TSP of men increased from baseline to stress condition (*1, P < 0.05), and TSP of women decreased from baseline to stress (**1, P < 0.01). Consequently, the TSP magnitude of women and men during stress was significantly different (***2, P < 0.0001). Values denote mean ± SE of visual analogue scale ratings (0-10).
3.3.3. Pain adaptation
Figure 5 presents the magnitude of pain adaptation among women and men during baseline and during stress. Analysis of variance revealed a significant effect of condition on pain adaptation, F(1,98) = 7.75, P = 0.01, and a significant condition × sex interaction, F(1,98) = 5.12, P < 0.05, but no significant effect on sex, F(1,98) = 0.66, P = 0.42. The magnitude of pain adaptation at baseline was similar for both sexes; however, pain adaptation of men did not change from baseline to stress (t = 0.44, P = 0.66) but that of women significantly increased (improved) during stress (from −1.64 to −3.64 VAS units, t = 2.79, P < 0.01, Cohen d = 0.68). This change was beyond the SEm of pain adaptation, suggesting a real difference. The sham stress manipulation did not induce any changes in pain adaptation (please see Supplementary Table, available as supplemental digital content at https://links.lww.com/PAIN/B690).
Figure 5.: Pain adaptation. The magnitude of pain adaptation at baseline was similar for both sexes; however, pain adaptation of men did not change from baseline to stress, whereas pain adaptation of women significantly increased during stress compared with baseline (**1, P < 0.01). Consequently, the pain adaptation magnitude of women and men during stress was significantly different (***2, P < 0.001). Values denote mean ± SE of visual analogue scale ratings (0-10). VAS, visual analogue scale.
3.4. Regression analyses predicting the change in temporal summation of pain and pain adaptation during stress
Table 3 presents the results of the significant regression models. The models were significant only for women. Thus, out of all the stress indices and demographic data, only the change in stress level (delta stress) predicted the change in TSP among women: TSP decreased by 0.27 units for every increase in the units of perceived stress following the MIST. Also, for pain adaptation, out of all the stress indices and demographic data, only the change in anxiety level (delta anxiety) predicted the change in pain adaptation among women: Pain adaptation improved by 0.53 units for every increase in the units of perceived anxiety following the MIST.
Table 3 -
Linear regressions for the prediction of the change in temporal summation of pain and in pain adaptation among women.
|
Significance |
B |
95% CI of B |
R
|
| Prediction of TSP |
|
|
|
|
| Delta stress |
0.036 |
−0.271 |
−0.520 -0.022 |
0.61 |
| Prediction of pain adaptation |
|
|
|
|
| Delta anxiety |
0.015 |
0.533 |
0.141 0.924 |
0.84 |
B, unstandardized beta; CI, confidence interval; TSP, temporal summation of pain.
4. Discussion
The study examined the trilateral interaction of sex, pain, and stress. Women and men varied in their stress and pain responses during distress: Women exhibited reduced TSP and an increase in pain adaptation, suggesting “stress-induced antinociception,” whereas men exhibited an increase in TSP, suggesting “stress-induced pronociception.” To our knowledge, this study is the first to report such findings.
4.1. Sex effects on acute stress responses
The physiological stress response was evaluated with cortisol (HPA axis) and with autonomic indices (SAM system). However, these responses are nonspecific. For example, in male rats, the magnitude of HPA-axis and SAM response was similar for both rewarding (social victory and sexual behavior) and aversive (social defeat) stimuli.10,23 Furthermore, HPA-axis and SAM responses increase following situations, such as physical exercise and excitement, which are not necessarily threatening.57,60 Such findings have resulted in defining stress as a “cognitive perception of uncontrollability and unpredictability,”50 thus emphasizing the importance of assessing individual appraisal in addition to the physiological changes, as done in this study.
Overall, men and women had comparable levels of baseline stress indices except for a higher HR in women, which was maintained throughout the protocol. The stress manipulation induced a significant stress response among both men and women, yet differential in nature. Women exhibited a greater increase in perceived stress and anxiety, whereas men exhibited a greater increase in cortisol and GSR. The greater perceived stress and anxiety among women is consistent with previous studies in which following psychosocial stressors, women exhibited a greater decrease in happiness,47 greater psychological impact,75 and a greater increase in anxiety64 and distress13,42,81 compared with men. The stronger HPA-axis and GSR responses in men are also consistent with previous studies45,51 (for review see Refs. 57, 89).
Considering that subjective stress indices are more specific/representative than biological stress indices, one may conclude that the women in this study exhibited stronger stress responses or perceived the MIST as more threatening than did men. Although sex is related to the anatomy and physiology of individuals, gender refers to individuals' identity; sex and gender may overlap and therefore the observed sex disparity in emotional distress may have been affected by gender role expectations: Traditional female gender roles encourage women to share their feelings/experiences more freely than men, whereas traditional male gender roles encourage stoicism and emotional control.15,24 Thus, although both sexes exhibited increases in the various stress indices, women may have felt more open to share their negative emotions following the manipulation, and men may have toned down their reports.74 In addition, the nature of the MIST may have influenced the differential stress response: It has been reported that men have significant cortisol increases after confronting an achievement challenge (mathematical and verbal tasks), whereas women show significant cortisol responses to social rejection challenges.79 The achievement challenge posed by the MIST may have thus induced a greater cortisol increase in men. Another explanation may be the overall blunted HPA-axis activity in women compared with men78 and the sex-specific neural engagements during acute psychosocial stress found in imaging studies.30 In short, the MIST induced a genuine stress response among both sexes, albeit with some variations.
4.2. Sex effects in the pain–stress interactions
Following the stress manipulation, women responded with an enhancement of pain inhibition capacity indicated by the increased pain adaptation and decreased TSP, whereas men responded with an enhancement of pain excitability, indicated by the increased TSP. Few studies have evaluated sex effects in the stress–pain interaction, and none have used pain adaptation and TSP in addition to pain threshold and tolerance, as was done in this study. Three studies reported similar pain responses among women and men following stress manipulations as follows: no change in pain threshold and TSP among 23 men and women18; similar increase in pain threshold among 40 men and women, namely, stress-induced analgesia5; and similar decrease in conditioned pain modulation among 20 men and women, namely, stress-induced antinociception.67 Another study reported stress-induced elevation in pain tolerance among smokers and nonsmokers with a sex interaction but did not specify whether this interaction was related to baseline or poststress values.1 Nevertheless, 2 studies reported that following stress manipulation, only women exhibited an increase in pain tolerance among 77 participants11 and an increase in pain threshold and pain tolerance, as well as a decrease in pain unpleasantness among 74 participants.39 The stress-induced hypoalgesia among women in these studies corresponds with the stress-induced pain inhibition of the women in this study.
The present study has several advantages over previous studies. First, the sample size of this study was 2-5-fold that of previous studies to minimize within- and between-sex variability in pain and stress measurements.65 Second, we used thermal computerized stimuli for pain measurements because these are deemed more precise than manually applied pressure (used in several studies). Third, we used 2 control procedures: the test–retest repeatability analysis, which enabled us to verify that the changes in the pain outcomes following the MIST were beyond their natural variations/SEm, and the sham stress manipulation, which enabled us to confirm that the observed effects were indeed the result of stress. Such dual confirmation of results is reported here for the first time and supports the conclusions. Noteworthy, although most studies used an arithmetic task as a stress manipulation, not all of them included the social component of public speaking1,11,39 or negative feedback18 as reported in this study, the lack of which probably resulted in varying levels of stress and hence in inconsistent results. Moreover, only al'Absi et al.1 validated the stress response by means of 3 aspects—perceived stress, HPA axis, and SAM activity—as in this study, whereas other studies chose fewer indices for validation.
The observed improvement in pain inhibition under stress among women seems somewhat counterintuitive to reports on increased vulnerability of women to chronic pain and to stress-related mental and pain disorders.7,68,84 However, although chronic stress interferes with adaptive behavior and function, acute stress promotes optimal function. Thus, women may be inherently more vulnerable than men to chronic stressors, perhaps because of their apparent blunted HPA-axis response,78 which was identified as a risk factor for comorbidity.83 Yet, at the same time, women may be more capable to cope with acute stress: an ability which may serve a protective evolutionary purpose. Thus, more efficient pain inhibition in the face of threat may strengthen the coping abilities of women and hence the survival of the offspring, whereas pain enhancement in the face of threat in men may promote their survival by increasing their attention to injury.
Animal studies related to sexual dimorphism in the expression of fear- or stress-induced analgesia are relatively scarce and inconsistent, probably because of variability in the animal strains and stress induction methods.65 For example, in one study, only male rats exhibited fear-conditioned analgesia,59 in another study, female rats exhibited more robust stress-induced analgesia,85 and in another study, the magnitude of stress-induced analgesia was similar for male and female mice.66 Yet, when medial prefrontal cortex (mPFC) activity was evaluated during stress, female rats had a more passive coping style and greater mPFC activity than did male rats.22 As the PFC is involved in descending pain modulation,9,61 the observed stress-induced antinociception capacity among women in this study may be explained by enhanced stress-induced PFC activity. Although translation of such data from rodents to humans has yet to be tested, this finding may correspond with sex-related connectivity patterns in human participants,86 suggesting that brain circuitry in healthy women provides for greater engagement of the descending modulation system mediating pain adaptation.
The stress-induced antinociceptive response of women may also have stemmed from their stronger emotional response to the manipulation. Although men exhibited a greater increase in HPA-axis and SAM responses following the stress manipulation, increase in perceived stress and anxiety among women was stronger and predicted the improvement in pain adaptation and the decrease in TSP. Previous studies have concluded that strong stressors more often induce analgesia than hyperalgesia.34 In animal models as well, pain sensitivity has varied with respect to the severity of the social threat: Mild social threat produced hyperalgesia, and more severe social threat produced analgesia.17,34,53 Given that stress is a cognitive perception,50 and the individual's appraisal may better reflect the magnitude of distress than the physiological responses, the sex-specific effect of the MIST on appraisal may underlie the opposite effects seen in the pain behavior of men and women.
4.3. Limitations and summary
One limitation may be that we have no information on the menstrual cycle of women. However, studies are inconsistent regarding the effect of menstrual cycle phase on experimental pain responses.6,35 Moreover, sex differences in acute stress responses occurred even when women were in the follicular phase, when progesterone levels are most similar to that of men.78 Another limitation may be the lack of conditioned pain modulation test, which could have added additional information on pain modulation.
The study showed that women exhibited greater emotional responses to the stress manipulation, and men exhibited a greater physiological response. Furthermore, sex-specific pain responses under stress were observed, in that women exhibited an enhancement in pain inhibition capacity, whereas men exhibited an enhancement in pain excitability. Sex-specific responses are important to consider in the management of either pain disorders or affective disorders so that individual-based care can be improved.48,69 Specifically, the seemingly advantageous stress-induced pain inhibition of women in acute conditions, which may serve an evolutionary need, may diminish upon recurrent or chronic stress conditions. Further research is required to understand how to regain or harness this acute trait in pain management.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be found online at https://links.lww.com/PAIN/B690.
Supplemental audio content
An audio abstract associated with this article can be found at https://links.lww.com/PAIN/B787.
Acknowledgments
The study was partly supported by a grant from the Israeli Pain Association.
References
[1]. al'Absi M, Nakajima M, Grabowski J. Stress response dysregulation and stress-induced analgesia in nicotine dependent men and women. Biol Psychol 2013;93:1–8.
[2]. Altemus M, Sarvaiya N, Neill Epperson C. Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol 2014;35:320–30.
[3]. Andre J, Zeau B, Pohl M, Cesselin F, Benoliel J-J, Becker C. Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: behavioral and biochemical studies. J Neurosci 2005;25:7896–904.
[4]. Asmundson GJG, Katz J. Understanding the co-occurrence of anxiety disorders and chronic pain: state-of-the-art. Depress Anxiety 2009;26:888–901.
[5]. Bandura A, Cioffi D, Taylor CB, Brouillard ME. Perceived self-efficacy in coping with cognitive stressors and opioid activation. J Personal Soc Psychol 1988;55:479–88.
[6]. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth 2013;111:52–8.
[7]. Bartley EJ, Fillingim RB. Sex differences in pain and stress. Neuroscience of pain, stress, and emotion: psychological and clinical implications. M. al'Absi, M.A. Flaten, eds. Academic Press, 2016. p. 77–95. doi: 10.1016/B978-0-12-800538-5.00004-2.
[8]. Bingel U, Schoell E, Herken W, Büchel C, May A. Habituation to painful stimulation involves the antinociceptive system. PAIN 2007;131:21–30.
[9]. Bogdanov VB, Viganò A, Noirhomme Q, Bogdanova OV, Guy N, Laureys S, Renshaw PF, Dallel R, Phillips C, Schoenen J. Cerebral responses and role of the prefrontal cortex in conditioned pain modulation: an fMRI study in healthy subjects. Behav Brain Res 2015;281:187–98.
[10]. Bonilla-Jaime H, Vázquez-Palacios G, Arteaga-Silva M, Retana-Marquez S. Hormonal responses to different sexually related conditions in male rats. Horm Behav 2006;49:376–82.
[11]. Bragdon EE, Light KC, Girdler SS, Maixner W. Blood pressure, gender, and parental hypertension are factors in baseline and poststress pain sensitivity in normotensive adults. Int J Behav Med 1997;4:17–38.
[12]. Brivio E, Lopez JP, Chen A. Sex differences: transcriptional signatures of stress exposure in male and female brains. Genes Brain Behav 2020;19:e12643.
[13]. Brugnera A, Zarbo C, Tarvainen MP, Marchettini P, Adorni R, Compare A. Heart rate variability during acute psychosocial stress: a randomized cross-over trial of verbal and non-verbal laboratory stressors. Int J Psychophysiol 2018;127:17–25.
[14]. Bueno CH, Pereira DD, Pattussi MP, Grossi PK, Grossi ML. Gender differences in temporomandibular disorders in adult populational studies: a systematic review and meta-analysis. J Oral Rehabil 2018;45:720–9.
[15]. Burleson BR, Holmstrom AJ, Gilstrap CM. “Guys can't say that to guys”: four experiments assessing the normative motivation account for deficiencies in the emotional support provided by men. Commun Monogr 2005;72:468–501.
[16]. Caceres C, Burns JW. Cardiovascular reactivity to psychological stress may enhance subsequent pain sensitivity. PAIN 1997;69:237–44.
[17]. Callahan BL, Gil ASC, Levesque A, Mogil JS. Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state. J Pain 2008;9:174–84.
[18]. Cathcart S, Winefield AH, Lushington K, Rolan P. Noxious inhibition of temporal summation is impaired in chronic tension-type headache. Headache 2010;50:403–12.
[19]. Chapman CR, Tuckett RP, Song CW. Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions. J Pain 2008;9:122–45.
[20]. Choi JC, Chung MI, Lee YD. Modulation of pain sensation by stress-related testosterone and cortisol. Anaesthesia 2012;67:1146–51.
[21]. Coghill RC, Mayer DJ, Price DD. Wide dynamic range but not nociceptive-specific neurons encode multidimensional features of prolonged repetitive heat pain. J Neurophysiol 1993;69:703–16.
[22]. Colom-Lapetina J, Begley SL, Johnson ME, Bean KJ, Kuwamoto WN, Shansky RM. Strain-dependent sex differences in a long-term forced swim paradigm. Behav Neurosci 2017;131:428–36.
[23]. Coppieters I, Cagnie B, Nijs J, Van Oosterwijck J, Danneels L, De Pauw R, Meeus M. Effects of stress and relaxation on central pain modulation in chronic whiplash and fibromyalgia patients compared to healthy controls. Pain Physician 2016;19:119–30.
[24]. Croft A, Atkinson C, Sandstrom G, Orbell S, Aknin L. Loosening the GRIP (gender roles inhibiting prosociality) to promote gender equality. Personal Soc Psychol Rev 2021;25:66–92.
[25]. Dedovic K, Renwick R, Mahani NK, Engert V, Lupien SJ, Pruessner JC. The Montreal Imaging Stress Task: using functional imaging to investigate the effects of perceiving and processing psychosocial stress in the human brain. J Psychiatry Neurosci 2005;30:319–25.
[26]. Defrin R, Pope G, Davis KD. Interactions between spatial summation, 2-point discrimination and habituation of heat pain. Eur J Pain 2008;12:900–9.
[27]. Descalzi G, Mitsi V, Purushothaman I, Gaspari S, Avrampou K, Loh YHE, Shen L, Zachariou V. Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression. Sci Signal 2017;10:eaaj1549.
[28]. Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 2004;130:355–91.
[29]. Diener SJ, Wessa M, Ridder S, Lang S, Diers M, Steil R, Flor H. Enhanced stress analgesia to a cognitively demanding task in patients with posttraumatic stress disorder. J Affect Disord 2012;136:1247–51.
[30]. Dong D, Ironside M, Belleau EL, Sun X, Cheng C, Xiong G, Nickerson LD, Wang X, Yao S, Pizzagalli DA. Sex-specific neural responses to acute psychosocial stress in depression. Transl Psychiatry 2022;12:2–8.
[31]. Edwards DJ. Age, pain intensity, values-discrepancy, and mindfulness as predictors for mental health and cognitive fusion: hierarchical regressions with mediation analysis. Front Psychol 2019;10:517.
[32]. Eisenberg E, Burstein Y, Suzan E, Treister R, Aviram J. Spinal cord stimulation attenuates temporal summation in patients with neuropathic pain. PAIN 2015;156:381–5.
[33]. Engert V, Linz R, Grant JA. Embodied stress: the physiological resonance of psychosocial stress. Psychoneuroendocrinology 2019;105:138–46.
[34]. Ferdousi M, Finn DP. Stress-induced modulation of pain: role of the endogenous opioid system. Prog Brain Res 2018;239:121–77.
[35]. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL III. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10:447–85.
[36]. Geva N, Defrin R. Enhanced pain modulation among triathletes: a possible explanation for their exceptional capabilities. PAIN 2013;154:2317–23.
[37]. Geva N, Defrin R. Opposite effects of stress on pain modulation depend on the magnitude of individual stress response. J Pain 2018;19:360–71.
[38]. Geva N, Pruessner J, Defrin R. Acute psychosocial stress reduces pain modulation capabilities in healthy men. PAIN 2014;155:2418–25.
[39]. Girdler SS, Maixner W, Naftel HA, Stewart PW, Moretz RL, Light KC. Cigarette smoking, stress-induced analgesia and pain perception in men and women. PAIN 2005;114:372–85.
[40]. Granot M, Granovsky Y, Sprecher E, Nir R-R, Yarnitsky D. Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation. PAIN 2006;122:295–305.
[41]. Hashmi JA, Davis KD. Women experience greater heat pain adaptation and habituation than men. PAIN 2009;145:350–7.
[42]. Helbig S, Backhaus J. Sex differences in a real academic stressor, cognitive appraisal and the cortisol response. Physiol Behav 2017;179:67–74.
[43]. Hoegh M, Poulsen JN, Petrini L, Graven-Nielsen T. The effect of stress on repeated painful stimuli with and without painful conditioning. Pain Med 2020;21:317–25.
[44]. IsHak WW, Wen RY, Naghdechi L, Vanle B, Dang J, Knosp M, Dascal J, Marcia L, Gohar Y, Eskander L, Yadegar J, Hanna S, Sadek A, Aguilar-Hernandez L, Danovitch I, Louy C. Pain and depression: a systematic review. Harv Rev Psychiatry 2018;26:352–63.
[45]. Juster R-P, Raymond C, Desrochers AB, Bourdon O, Durand N, Wan N, Pruessner JC, Lupien SJ. Sex hormones adjust “sex-specific” reactive and diurnal cortisol profiles. Psychoneuroendocrinology 2016;63:282–90.
[46]. Keefe FJ, Lefebvre JC, Egert JR, Affleck G, Sullivan MJ, Caldwell DS. The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: the role of catastrophizing. PAIN 2000;87:325–34.
[47]. Kelly MM, Tyrka AR, Anderson GM, Price LH, Carpenter LL. Sex differences in emotional and physiological responses to the trier social stress test. J Behav Ther Exp Psychiatry 2008;39:87–98.
[48]. Keogh E, McCracken LM, Eccleston C. Do men and women differ in their response to interdisciplinary chronic pain management? PAIN 2005;114:37–46.
[49]. Kleykamp BA, Ferguson MC, McNicol E, Bixho I, Arnold LM, Edwards RR, Fillingim R, Grol-Prokopczyk H, Turk DC, Dworkin RH. The prevalence of psychiatric and chronic pain comorbidities in fibromyalgia: an ACTTION systematic review. Semin Arthritis Rheum 2021;51:166–74.
[50]. Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flügge G, Korte SM, Meerlo P, Murison R, Olivier B, Palanza P, Richter-Levin G, Sgoifo A, Steimer T, Stiedl O, van Dijk G, Wohr M, Fuchs E. Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev 2011;35:1291–301.
[51]. Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol 2005;69:113–32.
[52]. Labanski A, Langhorst J, Engler H, Elsenbruch S. Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases: a transdisciplinary challenge. Psychoneuroendocrinology 2020;111:104501.
[53]. Langford DJ, Tuttle AH, Briscoe C, Harvey-Lewis C, Baran I, Gleeson P, Fischer DB, Buonora M, Sternberg WF, Mogil JS. Varying perceived social threat modulates pain behavior in male mice. J Pain 2011;12:125–32.
[54]. Larauche M, Moussaoui N, Biraud M, Bae WK, Duboc H, Million M, Taché Y. Brain corticotropin-releasing factor signaling: involvement in acute stress-induced visceral analgesia in male rats. Neurogastroenterol Motil 2019;31:e13489.
[55]. Lee MT, Chiu Y-T, Chiu Y-C, Hor CC, Lee H-J, Guerrini R, Calo G, Chiou L-C. Neuropeptide S-initiated sequential cascade mediated by OX 1, NK 1, mGlu 5 and CB 1 receptors: a pivotal role in stress-induced analgesia. J Biomed Sci 2020;27:1–15.
[56]. Levine A, Zagoory-Sharon O, Feldman R, Lewis JG, Weller A. Measuring cortisol in human psychobiological studies. Physiol Behav 2007;90:43–53.
[57]. Liu JJW, Ein N, Peck K, Huang V, Pruessner JC, Vickers K. Sex differences in salivary cortisol reactivity to the Trier Social Stress Test (TSST): a meta-analysis. Psychoneuroendocrinology 2017;82:26–37.
[58]. Liu Q, Zhang W. Sex differences in stress reactivity to the trier social stress test in virtual reality. Psychol Res Behav Manag 2020;13:859–69.
[59]. Llorente-Berzal A, McGowan F, Gaspar JC, Rea K, Roche M, Finn DP. Sexually dimorphic expression of fear-conditioned analgesia in rats and associated alterations in the endocannabinoid system in the periaqueductal grey. Neuroscience 2022;480:117–30.
[60]. Löffler M, Schneider P, Schuh-Hofer S, Kamping S, Usai K, Treede R-D, Nees F, Flor H. Stress-induced analgesia in patients with chronic musculoskeletal pain and healthy controls. Eur J Pain 2007;11:743–55.
[61]. Makovac E, Venezia A, Hohenschurz-Schmidt D, Dipasquale O, Jackson JB, Medina S, O'Daly O, Williams SCR, McMahon SB, Howard MA. The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey. J Physiol 2021;599:5243–60.
[62]. McDowell I. Measuring health: a guide to rating scales and questionnaires. Oxford, United Kingdom: Oxford University Press, 2006.
[63]. Mertens M, Hermans L, Van Oosterwijck J, Meert L, Crombez G, Struyf F, Meeus M. The result of acute induced psychosocial stress on pain sensitivity and modulation in healthy people. Pain Physician 2020;23:E703–12.
[64]. Merz CJ, Wolf OT. Examination of cortisol and state anxiety at an academic setting with and without oral presentation. Stress 2015;18:138–42.
[65]. Mogil JS. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat Rev Neurosci 2020;21:353–65.
[66]. Mogil JS, Sternberg WF, Kest B, Marek P, Liebeskind JC. Sex differences in the antagonism of swim stress-induced analgesia: effects of gonadectomy and estrogen replacement. PAIN 1993;53:17–25.
[67]. Nilsen KB, Christiansen SE, Holmen LB, Sand T. The effect of a mental stressor on conditioned pain modulation in healthy subjects. Scand J Pain 2012;3:142–8.
[68]. Palacios-Ceña D, Albaladejo-Vicente R, Hernández-Barrera V, Lima-Florencio L, Fernández-de-Las-Peñas C, Jimenez-Garcia R, López-de-Andrés A, de Miguel-Diez J, Perez-Farinos N. Female gender is associated with a higher prevalence of chronic neck pain, chronic low back pain, and migraine: results of the Spanish National Health Survey, 2017. Pain Med 2021;22:382–95.
[69]. Pisanu C, Franconi F, Gessa GL, Mameli S, Pisanu GM, Campesi I, Leggio L, Agabio R. Sex differences in the response to opioids for pain relief: a systematic review and meta-analysis. Pharmacol Res 2019;148:104447.
[70]. Pruessner JC, Dedovic K, Khalili-Mahani N, Engert V, Pruessner M, Buss C, Renwick R, Dagher A, Meaney MJ, Lupien S. Deactivation of the limbic system during acute psychosocial stress: evidence from positron emission tomography and functional magnetic resonance imaging studies. Biol Psychiatry 2008;63:234–40.
[71]. Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G, Choinière M. A systematic literature review of 10 years of research on sex/gender and experimental pain perception–part 1: are there really differences between women and men? PAIN 2012;153:602–18.
[72]. Rosseland LA, Stubhaug A. Gender is a confounding factor in pain trials: women report more pain than men after arthroscopic surgery. PAIN 2004;112:248–53.
[73]. Rubinow DR, Schmidt PJ. Sex differences and the neurobiology of affective disorders. Neuropsychopharmacology 2019;44:111–28.
[74]. Samulowitz A, Gremyr I, Eriksson E, Hensing G. “Brave men” and “emotional women”: a theory-guided literature review on gender bias in health care and gendered norms towards patients with chronic pain. Pain Res Manag 2018;2018:6358624.
[75]. Santl J, Shiban Y, Plab A, Wüst S, Kudielka BM, Mühlberger A. Gender differences in stress responses during a virtual reality trier social stress test. Int J Virtual Reality 2019;19:2–15.
[76]. Spielberger CD. Manual for the State-Trait Anxiety Inventory STAI (form Y) (“Self-Evaluation Questionnaire”). CA: Consulting Psychologists Press, 1983.
[77]. Staud R, Vierck CJ, Robinson ME, Price DD. Effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects. J Pain 2005;6:323–32.
[78]. Stephens MAC, Mahon PB, McCaul ME, Wand GS. Hypothalamic–pituitary–adrenal axis response to acute psychosocial stress: effects of biological sex and circulating sex hormones. Psychoneuroendocrinology 2016;66:47–55.
[79]. Stroud LR, Salovey P, Epel ES. Sex differences in stress responses: social rejection versus achievement stress. Biol Psychiatry 2002;52:318–27.
[80]. Stubbs B, Vancampfort D, Veronese N, Thompson T, Fornaro M, Schofield P, Solmi M, Mugisha J, Carvalho AF, Koyanagi A. Depression and pain: primary data and meta-analysis among 237 952 people across 47 low-and middle-income countries. Psychol Med 2017;47:2906–17.
[81]. Taylor MK, Larson GE, Hiller Lauby MD, Padilla GA, Wilson IE, Schmied EA, Highfill-McRoy RM, Morgan CA. Sex differences in cardiovascular and subjective stress reactions: prospective evidence in a realistic military setting. Stress 2014;17:70–8.
[82]. Terpou BA, Harricharan S, McKinnon MC, Frewen P, Jetly R, Lanius RA. The effects of trauma on brain and body: a unifying role for the midbrain periaqueductal gray. J Neurosci Res 2019;97:1110–40.
[83]. Turner AI, Smyth N, Hall SJ, Torres SJ, Hussein M, Jayasinghe SU, Ball K, Clow AJ. Psychological stress reactivity and future health and disease outcomes: a systematic review of prospective evidence. Psychoneuroendocrinology 2020;114:104599.
[84]. Umeda M, Kim Y. Gender differences in the prevalence of chronic pain and leisure time physical activity among US adults: a NHANES study. Int J Environ Res Public Health 2019;16:988.
[85]. Vendruscolo LF, Pamplona FA, Takahashi RN. Strain and sex differences in the expression of nociceptive behavior and stress-induced analgesia in rats. of nociceptive behavior and stress-induced analgesia in rats. Brain Res 2004;1030:277–83.
[86]. Wang G, Erpelding N, Davis KD. Sex differences in connectivity of the subgenual anterior cingulate cortex. cingulate cortex. PAIN 2014;155:755–63.
[87]. Webb EK, Huggins AA, Belleau EL, Taubitz LE, Hanson JL, deRoon-Cassini TA, Larson CLCL. Acute posttrauma resting-state functional connectivity of periaqueductal gray prospectively predicts posttraumatic stress disorder symptoms. Biol Psychiatry Cogn Neurosci Neuroimaging 2020;5:891–900.
[88]. Weissman-Fogel I, Dror A, Defrin R. Temporal and spatial aspects of experimental tonic pain: understanding pain adaptation and intensification. Eur J Pain 2015;19:408–18.
[89]. Zänkert S, Bellingrath S, Wüst S, Kudielka BM. HPA axis responses to psychological challenge linking stress and disease: what do we know on sources of intra-and interindividual variability? Psychoneuroendocrinology 2019;105:86–97.
