Differences in Pain Perception Between Men and Women of Reproductive Age: A Laser-Evoked Potentials Study

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1 Pain Medicine 2017; 18: doi: /pm/pnw167 METHODOLOGY, MECHANISMS & TRANSLATIONAL RESEARCH SECTION Original Research Article Differences in Pain Perception Between Men and Women of Reproductive Age: A Laser-Evoked Potentials Study Chryssoula Staikou, MD, PhD, DESA,* Panagiotis Kokotis, MD, PhD, Andreas Kyrozis, MD, PhD, Demetrios Rallis, MD, George Makrydakis, MD, Dimitra Manoli, MD, Nikolaos Karandreas, MD, PhD, Elefterios Stamboulis, MD, PhD, Christos Moschovos, MD, and Argyro Fassoulaki, MD, PhD, DEAA* *Department of Anesthesiology, Aretaieio Hospital, Medical School, National and Kapodistrian University of Athens, Greece; Department of Neurology, Eginitio Hospital, Medical School, National and Kapodistrian University of Athens, Greece; Department of Neurology, Tzaneion General Hospital, Piraeus, Greece; Private Practice Correspondence to: Chryssoula Staikou, MD, PhD, DESA, Assistant Professor in Anesthesiology, Department of Anesthesiology, Aretaieio Hospital, Medical School, National and Kapodistrian University of Athens, Fleming 3, Anoixi Attikis, Greece. Tel: þ ; Fax: þ ; c_staikou@yahoo.gr. Funding sources: This work was not supported by any financial source. Disclosure and conflicts of interest: None declared. Abstract Objective. We investigated differences in pain perception between men and women of reproductive age by using Laser-Evoked Potentials (LEPs). aspect of the dorsum of the left hand. A recording montage for late LEPs was used, and the potentials of each series of stimuli were averaged to calculate mean latency and amplitude for each subject. Volunteers scored verbally pain intensity (Numerical rating scale [NRS]; 0 10). Three series of 10 numbers were averaged for calculation of mean NRS score. Methods. LEP peak-to-peak amplitude, latency, and NRS scoring were compared between genders, and correlations between LEP amplitude/latency and NRS scores were assessed. Results. Data from 44 subjects were analyzed. LEP amplitudes differed significantly (P < 0.001) between men ( mv) and women ( mv), while no difference was found for latency ( versus ms, P ) or NRS score ( versus , P ), respectively. Menstrual cycle phase did not influence LEP parameters (P for amplitude and P for latency) or NRS score (P ). No significant correlation was found between latency or amplitude and NRS score (P and P , respectively). Conclusions. Our results demonstrate a significant gender-related difference in LEP amplitudes with lower mean values in men, while no difference was found in LEP latencies or in subjective pain ratings. Further research is required to clarify the clinical significance of the above experimental findings. Key Words. Laser-Evoked Potentials; Genders; Pain; Reproductive Age Introduction Design, Setting, Subjects. Forty-four right-handed healthy volunteers (19 males/25 females), aged years were studied. A CO 2 laser generated three series of 10 thermal pulses (4.5 W) on the radial Gender-related differences in pain perception and responses to analgesics have been investigated with mixed results in both experimental and clinical settings [1 4]. Most of the studies suggest that women are more VC 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please journals.permissions@oup.com 316

2 Gender-Related Differences in Laser-Evoked Potentials sensitive to noxious stimuli than men, experiencing pain more often, and of higher intensity and longer duration [4 6]. Clinical studies on acute pain (i.e., postoperative) show that the increased sensitivity characterizes mainly women of reproductive age, but this difference is not observed in elderly patients [7,8]. Different methodologies and study designs may account for these inconsistent results [2]. Even experimental investigations have no standardized protocols in terms of subjects characteristics, types of stimuli (electrical, pressure, heat, mechanical or chemical), and pain measurement methods [9]. In humans, biological, psychosocial, and cultural factors may affect central pain processing disproportionately in the two genders [3,4,6]. Pain modulation may also play a role; according to a systematic review including subjects of reproductive age without chronic pain, women have less efficient diffuse noxious inhibitory controls compared with men [9]. Gonadal hormones may affect the peripheral and central nociceptive pathways, and consequently the processing of nociceptive stimuli, as well as sensitivity, threshold, and tolerance to pain [5,6]. Furthermore, the function of endogenous analgesic systems differs between men and women; the mu- and kappa-receptors exhibit diverse modes of activation and their response to nociceptive stimuli vary in the two genders [6]. Finally, brain imaging has revealed sex-related differences concerning the spatial distribution and the magnitude of acute pain responses [6]. Reliable assessment of pain perception is quite difficult as pain is a complex experience with sensory and emotional dimensions. In this regard, tools and methods that can measure objective dimensions of pain responses are valuable. Few studies have assessed brain activity evoked by painful stimuli. Most of them have not detected any significant sex-related difference [10 12]. The aim of the present study was to compare pain perception as well as electrophysiological responses between the two genders in healthy young volunteers by the use of CO 2 Laser-Evoked Potential (LEP) recordings. The LEPs represent a sensitive and reliable neurophysiological method for the functional assessment of nociceptive pathways [13 15]. Based on the observed higher sensitivity of young women to acute pain (i.e., postoperatively) compared with similarly aged men [7], we considered that LEPs could be useful in the objective assessment of this gender difference in an experimental setting. Our hypothesis was that LEP amplitudes may be higher in women than in men, thus reflecting the increased sensitivity to noxious stimuli of women of reproductive age. Methods The study was approved by the Institutional Review Board (M-134/ , ). Forty-four right-handed healthy volunteers (19 male, 25 female) years old were enrolled in this open-label study between September 2012 and April All subjects gave a written informed consent to participate. A detailed history was obtained from volunteers regarding medical conditions, psychiatric disorders, current medications, and menstrual cycle in females. Menstrual cycle assessment (length and phase) was based on women s history. Each participant was scored for depressive symptoms according to the Hamilton Psychiatric Rating Scale for Depression [16]. Exclusion criteria were drug or alcohol abuse, body mass index higher than 30 kg m 2, chronic/systemic disease or pain syndromes, psychiatric disorders or depression according to Hamilton scale, abnormal thyroid function testing, pregnancy, menstrual cycle abnormalities, sleep disorders, chronic consumption of analgesics, and use of contraceptive pills. The subjects were instructed to abstain from food, caffeine, methylxanthine, and nicotine for at least 7 hours before the study. They were also asked to refrain from alcohol and avoid any medication for 48 hours. All experiments were performed between 8:00 10:00 AM. The order of volunteer enrollment male or female was random by the use of sealed envelopes containing odd or even numbers for males and females, respectively. During testing, the subjects remained in a semi-seated, comfortable position in a quiet, luminous, and temperature-controlled room. All participants were instructed to stay awake, with eyes closed and muscles relaxed, avoiding any movement. ACO 2 laser with 10.6 mm wavelength and 2.5 mm laser beam area (Neurolas Electronic Engineering, Calenzano, Firenze, Italy) was used in the study. The CO 2 laser wavelength is ideally compatible with the thermophysical characteristics of the skin [13]. The LEPs were recorded during the application of brief thermal pulses to the cutaneous distribution of the radial nerve. The laser-induced thermal stimuli selectively activate free nerve endings of small-myelinated fibers (Ad type) in the skin and produce brain potentials [11,13]. Each pulse elicits a short sharp pain followed by a warm, dull ache in the region. A stimulus starting from 1.5 W and increasing at 1.5 W increments was applied to all subjects in order to define the lowest intensity pulse that was perceived from each subject. The pulses used during the study were equal to the lowest power felt by the subject multiplied by three. The test stimulus of 1.5 W was felt by all subjects, thus a power of 4.5 W was used in all experiments. Three series of 10 laser stimuli were applied on the radial aspect of the dorsum of the left hand. Each stimulus had a duration of 10 ms, with random interstimulus intervals of s in order to reduce habituation [17]. There was a 10-minute interval after each series. Every single pulse was targeted to a different spot in a 9 cm 2 area in order to avoid nociceptor fatigue and its effects on the amplitude [17]. A recording montage for late LEPs was used: the recording surface electrodes were attached to the midline of the skull at positions Fz, Cz, and Pz, with reference electrodes at the ear lobes (A1, A2) [17]. The electrode 317

3 Staikou et al. impedance was maintained below 5 KX. For the electroencephalographic signals, high- and low-pass filters were set at 0.3 and 70 Hz, respectively. LEPs were acquired and processed by the Evoked Potential Measuring System (Model MEB-5504K, Nihon Kohden Corporation, Tokyo, Japan). The recorded potentials obtained from each one of the three series of stimuli were averaged into one potential. The average of these three potentials was used to estimate the mean latency and amplitude for each subject. Latency was measured as the time elapsed between stimulus and N2 peak. Amplitude was measured as N2 P2 peak-to-peak difference, where N2 and P2 are the main negative (N2 wave) and positive (P2 wave) components. Three seconds after the applied stimulus, the volunteers scored verbally the intensity of perceived pain according to a Numerical Rating Scale ([NRS]; 0 10), with 0 corresponding to no pain and 10 to worst excruciating pain. Pain ratings were given after each single stimulus, in order to assure that the subjects kept the same level of attention throughout the procedure [17]. Ten numbers for each of the 3 series were collected and averaged. The mean of the 3 averaged scores was used as the mean NRS score for each volunteer. The primary end point of the study was the difference in LEP peak-to-peak amplitude and latency between the genders. Secondary end-points were differences in the subjective rating of pain (NRS, 0 10) by male and female subjects and also correlations between LEP amplitude or latency and NRS scores. In female subjects, any possible effects of menstrual cycle phase on LEP parameters and subjective pain intensity were also assessed. The LEP and NRS data were analyzed in a blinded fashion; the recordings from men and women were characterized as group-1 or group-2 data, respectively, and thus the investigator analyzing individual data sets was not aware of the gender. No monetary compensation was provided to the volunteers for their participation in this study. Statistics Statistical analysis of acquired data was performed by the use of Statistica 7 software StatSoft, Inc./Dell Table 1 Characteristics of the studied subjects Statistica, Tulsa, USA. Data did not significantly deviate from normal distribution according to Kolmogorov- Smirnov and Lilliefors test. Student s t-test was used to evaluate the difference between the two groups (men versus women) regarding the mean values of age, height, weight, amplitude, latency, and NRS score. Student s t-test was also used for intragroup comparisons of LEP amplitude, latency, and NRS score between women in different menstrual cycle phases. Pearson s linear regression correlation was used to estimate the correlation between continuous parameters such as mean amplitude or latency and NRS score. For all comparisons, P values < 0.05 were considered as statistically significant. Results Data from 44 volunteers, 19 men and 25 women, were analyzed. Subjects characteristics are presented in Table 1; no significant difference was found between men and women regarding age. Results for values and comparisons between the genders regarding mean amplitude and latency of the LEPs and also the mean NRS scores are shown in Table 2. We found that women had significantly higher values of mean amplitude in the recorded LEPs than men ( versus mv, P < 0.001, respectively). No significant difference was revealed for mean latency or NRS scores between the genders. Intra-group comparisons between women in follicular (n ¼ 11) versus those in luteal phase (n ¼ 14) of menstrual cycle showed no differences in mean LEP amplitudes ( versus mv, P ¼ 0.596), or latencies ( versus ms, P ¼ 0.697) or NRS scores ( versus , P ¼ 0.948, respectively). Finally, no significant correlation was found between mean latency or amplitude and mean NRS score, using linear regression model (P ¼ and P ¼ 0.902, respectively). Discussion Our results show that stimuli of constant intensity produced higher LEP amplitudes in women than men, while the latencies and subjective pain ratings did not Variable Total sample (n ¼ 44) Men (n ¼ 19) Women (n ¼ 25) P values Age (years) Height (cm) * * <0.001 Weight (kg) * * <0.001 Values are presented as mean 6 Standard Deviation (SD). Comparisons were made by the use of Student s t-test. *P < 0.05 for comparisons between men and women. 318

4 Gender-Related Differences in Laser-Evoked Potentials Table 2 Measurements and comparisons between men and women regarding laser-evoked potential (LEP) amplitude, LEP latency, and Numerical Rating Scale (NRS) scores Variable Total sample (n ¼ 44) Men (n ¼ 19) Women (n ¼ 25) P values Amplitude (lv) * * <0.001 Latency (ms) NRS score Values are expressed as mean 6 Standard Deviation (SD). Comparisons were made by the use of Student s t-test. *P < 0.05 for comparisons between men and women. differ between the genders. Finally, no significant correlation was found between mean LEP amplitudes or latencies and mean pain scores. Our findings can be most directly compared with other studies on sex-related differences in pain perception by the use of LEPs. To our knowledge, there is only one such study [11]. Truini et al. found no significant gender difference in LEP parameters from 70 male and female volunteers, but the mean age of volunteers in that study, 47 years, was significantly higher than in our study and, therefore, many women were post-menopausal, a factor that may have influenced the findings [11]. To our knowledge, our results provide the first demonstration of a gender difference in LEPs. Our findings can also be compared with studies on sexrelated differences in pain perception employing contact heat-evoked potentials (CHEPs) [12,18]. Chen et al. recorded CHEPs after application of stimuli at five different limb sites of male and female volunteers aged 18 to 44 years [12]. The authors reported no difference in the forearm amplitude and latency between the genders (10 women and 10 men). In another study investigating the effects of aging on CHEPs in volunteers of years old, the authors found that P1 and N1 P1 amplitudes for the lower limb were significantly higher in women than in men, while amplitudes for upper limb were non-significantly higher in women [18]. It is possible that CHEPs may be less sensitive than LEPs in revealing an electrophysiological gender difference. Concerning the effect of age, it has been demonstrated that age significantly decreases both LEP and CHEP amplitudes [11,18]. The two groups in our study were accurately matched for age, and only women of reproductive age, without hormonal abnormalities were included. We also performed an intragroup comparison that showed that the menstrual cycle phase did not affect the mean LEP amplitudes in the female volunteers. Obviously, the number of women compared (11 vs 14) was rather small to draw safe conclusions about the impact of menstrual phase on the responses to LEPs. However, our finding is also supported by previous studies; Turcio et al. have recently reported that in healthy women, different phases of menstrual cycle do not influence electrical activity and pressure pain threshold in temporal and masseter muscles [19]. Concerning the effect of laser stimulus intensity, relatively few LEP studies have investigated the human responses to pain [20,21]. Early research by Carmon et al. showed that LEP amplitudes exhibit a strong correlation with the intensity of noxious stimuli [20]. Similar findings were reported more recently by Ohara et al. who applied laser stimuli of different intensity and recorded LEPs directly from cortical areas in awake subjects by the use of subdural electrodes [21]. The authors found that LEP amplitudes were strongly related to the laser energy levels used for stimulation [21]. On the other hand, evoked potential studies with application of graded energy showed that latencies were not related to stimulus intensity [21,22]. In our study the LEP amplitudes, but not latencies, differed significantly between the genders even though the same stimulus intensity was applied to all subjects. Notably, the LEP amplitudes exhibited a high variability especially in women, suggesting less consistency in responses within the female population. A high variability in LEP amplitudes has also been previously reported [11] and some factors implicated in the process of nociception and LEP recordings (i.e., psychology, hormones, attentional focus) might play a role [6, 17]. Among other factors that may affect LEP amplitudes, subjective pain perception could play a role [20,21], although we found no correlation between LEP amplitudes and NRS scores. Similar results were reported by Chen et al., who found that perceived pain intensity (also scored by the subjects according to an NRS) did not correlate with the recorded CHEP amplitudes [12]. In early research by Carmon et al., intra-subject associations had shown that LEP amplitudes exhibit a stronger correlation with the subjective pain rating rather than with the intensity of noxious stimuli [20]. Similar findings were also reported in other evoked potential studies using tooth pulp stimulation [22] or thermal stimuli [23] suggesting that subjective pain perception may be the major factor influencing the recorded amplitudes. Other investigators reported different results showing that LEP amplitudes may change despite constant pain ratings [24], and thus, a dissociation between LEP amplitudes and subjective pain perception has been suggested [17]. The latter findings support and are consistent with our results. 319

5 Staikou et al. We found no difference between the genders regarding the verbal NRS scores, while the menstrual cycle phase did not influence the perceived pain intensity. Subjective pain rating has been found to correlate with stimulus intensity [20,21], which in the present study remained constant. Also, in a recent study Girard-Tremblay et al. reported that the verbal NRS pain scores and pain unpleasantness after application of painful and non-painful stimuli did not differ between men and women [10]. In this experiment the authors applied transcutaneous electrical stimulation of the sural nerve and assessed the respective cerebral responses via somatosensoryevoked brain potentials with source localization. Interestingly, although the NRS scores were comparable, the pain-evoked brain responses differed between the sexes; increased pain unpleasantness was associated with reduced prefrontal cortex activity in men, but increased perigenual anterior cingulate cortex activity in women [10]. The verbal NRS scale has been used in several experimental studies for the measurement of subjective pain [10,20 22]. We chose the verbal scale in order to avoid significant disturbance and movements of the subjects during drawing on the visual analog scale (VAS, 0 10 cm). The NRS is an acceptable tool for pain assessment; its values correspond to those of VAS [25], which has been validated for measurements not only in chronic, but also in experimental pain [26]. Nevertheless, it has been argued that in experimental pain studies, subjects are probably rating the intensity of stimulation rather than pain perception, and thus pain rating scales ranging from no pain to unbearable pain may not be reliable in providing objective information [27].The above may partly explain the absence of difference in NRS scores between the genders in our study. We applied laser-induced nociceptive superficial stimuli and recorded the brain potentials. The LEPs are very reliable laboratory tools in assessing nociceptive paths [14]. Although the laser-generated stimuli selectively activate cutaneous Ad- and C-nociceptors, the brain potentials are only related to Ad stimulation [14]. Thus, LEPs are considered more sensitive and suitable for the evaluation of nociceptive paths than somatosensory evoked potentials [14]. As in our study, only the late LEP components are usually assessed in the clinical and experimental setting, because the early components are characterized by small amplitudes that limit their usefulness [17]. The late components reflect the brain activity during pain perception [22], and their amplitude and latency can be compared between different groups to reveal differences in the neural processing of noxious stimuli. During LEP recordings, nociceptor fatigue should be avoided and the attention of subject should be kept constant [14], as we did in our experiment. Regarding any possible effects of somatometric parameters on LEP components, previous research has only demonstrated a correlation between LEP latency and body height [11]; thus, we consider that the differences in LEP amplitudes we found were not affected by body size differences between men and women. A limitation of our study is the lack of testing for other types of evoked potentials on the same subjects in order to assess whether the observed gender difference in amplitudes may be specific to pain potentials, and particularly to LEPs, or, alternatively, extend to other sensory modalities. Such multimodal studies, which entail technical complexities, would help elucidate the mechanisms responsible for observed gender differences. If, for example, gender differences in amplitude were observed only for laser stimuli but not for innocuous stimuli, mechanisms specific to pain perception would be implicated. In conclusion, we found that LEP amplitudes are higher in women than in men of reproductive age, suggesting gender-related differences in pain-evoked brain activity. LEP amplitude does not seem to reflect pain intensity on an individual basis and cannot by itself account for gender differences in pain perception. Nevertheless, the observed significant gender difference in LEP amplitude suggests that complex electrophysiological gender differences in pain processing do exist. More elaborate signal analysis methods are clearly required to further explore correlations of LEP characteristics with pain perception. Further investigation is also required to clarify whether gender differences follow different patterns between noxious and innocuous stimuli. Such investigations have possible implications for the development of more individualized and targeted analgesic treatments. References 1 Fillingim RB, King CD, Ribeiro-Dasilva MC, et al. Sex, gender, and pain: A review of recent clinical and experimental findings. J Pain 2009;10: Fillingim RB, Gear RW. Sex differences in opioid analgesia: Clinical and experimental findings. Eur J Pain 2004;8: Bartley EJ, Fillingim RB. Sex differences in pain: A brief review of clinical and experimental findings. Br J Anaesth 2013;111: Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differences in pain perception and treatment. Pain Med 2009;10: Fillingim RB, Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 2000;24: Wiesenfeld-Hallin Z. Sex differences in pain perception. Gend Med 2005;2:

6 Gender-Related Differences in Laser-Evoked Potentials 7 Aubrun F, Salvi N, Coriat P, Riou B. Sex- and agerelated differences in morphine requirements for postoperative pain relief. Anesthesiology 2005;103: Theodoraki K, Staikou C, Fassoulaki A. Postoperative pain after major abdominal surgery: Is it gender related? An observational prospective study. Pain Pract 2014;14: Popescu A, LeResche L, Truelove EL, Drangsholt MT. Gender differences in pain modulation by diffuse noxious inhibitory controls: A systematic review. Pain 2010;150: Girard-Tremblay L, Auclair V, Daigle K, et al. Sex differences in the neural representation of pain unpleasantness. J Pain 2014;15: Truini A, Galeotti F, Romaniello A, et al. Laser-evoked potentials: Normative values. Clin Neurophysiol 2005; 116: Chen IA, Hung SW, Chen YH, et al. Contact heat evoked potentials in normal subjects. Acta Neurol Taiwan 2006;15: Truini A, Romaniello A, Galeotti F, Iannetti GD, Cruccu G. Laser evoked potentials for assessing sensory neuropathy in human patients. Neurosci Lett 2004;361: Valeriani M, de Tommaso M, Restuccia D, et al. Reduced habituation to experimental pain in migraine patients: A CO(2) laser evoked potential study. Pain 2003;105: Bromm B, Chen AC. Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation. Electroencephalogr Clin Neurophysiol 1995;95: Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23: Treede RD, Lorenz J, Baumg artner U. Clinical usefulness of laser-evoked potentials. Neurophysiol Clin 2003;33: Chao CC, Hsieh ST, Chiu MJ, Tseng MT, Chang YC. Effects of aging on contact heat-evoked potentials: The physiological assessment of thermal perception. Muscle Nerve 2007;36: Turcio KHL, Garcia AR, Zuim PRJ, et al. Electrical activities and pressure pain threshold in oral contraceptives users and nonusers. Pain Stud Treat 2014; 2: Carmon A, Friedman Y, Coger R, Kenton B. Single trial analysis of evoked potentials to noxious thermal stimulation in man. Pain 1980;8: Ohara S, Crone NE, Weiss N, Treede RD, Lenz FA. Amplitudes of laser evoked potential recorded from primary somatosensory, parasylvian and medial frontal cortex are graded with stimulus intensity. Pain 2004;110: Chen AC, Chapman CR, Harkins SW. Brain evoked potentials are functional correlates of induced pain in man. Pain 1979;6: Granovsky Y, Granot M, Nir RR, Yarnitsky D. Objective correlate of subjective pain perception by contact heat-evoked potentials. J Pain 2008; 9: Chapman CR, Colpitts YH, Mayeno JK, Gagliardi GJ. Rate of stimulus repetition changes evoked potential amplitude: Dental and auditory modalities compared. Exp Brain Res 1981;43: Hjermstad MJ, Fayers PM, Haugen DF, et al. European Palliative Care Research Collaborative (EPCRC). Studies comparing numerical rating scales, verbal rating scales, and visual analogue scales for assessment of pain intensity in adults: A systematic literature review. J Pain Symptom Manage 2011;41: Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 1983;17: Kemp J, Despres O, Dufour A. Unreliability of the visual analog scale in experimental pain assessment: A sensitivity and evoked potentials study. Pain Physician 2012;15:E