Prediction of pain sensitivity in healthy volunteers

Pernille Ravn, Rune Frederiksen, Anders P Skovsen, Lona L Christrup, Mads U Werner, Pernille Ravn, Rune Frederiksen, Anders P Skovsen, Lona L Christrup, Mads U Werner

Abstract

Purpose: The primary objective of the present study was to evaluate predictive parameters of the acute pain score during induction of an inflammatory heat injury.

Patients and methods: Healthy volunteers (50 females/50 males) were included in the study. The predictive potential of gender, anthropometric (body surface area, body mass index), psychological (anxiety, depression, vulnerability), and psychophysical (quantitative sensory testing, conditioned pain modulation) variables in estimating the pain response to a validated heat injury (47°C, 7 minutes, area 12.5 cm(2)) were investigated. All assessments were made in duplicate sessions separated by 21 days (median).

Results: There were three main findings in this study. First, a predictive model of pain sensitivity during the heat injury, including both genders and using multiple regression technique, could account for 28% of the variance (P < 0.0001), but gender-related differences in the final model could not be demonstrated. Second, the results confirmed significant gender-related differences in perception of electrical, pressure, and cold pressor stimuli (P < 0.002). Third, positive correlations between anthropometric data and pain perception during electrical and pressure stimuli were demonstrated (P < 0.001 and P < 0.005, respectively).

Conclusion: The study demonstrated predictability of acute pain sensitivity, and although gender-related differences in pain perception were demonstrated, no gender-related differences in pain sensitivity could be shown. Interestingly, positive correlations between anthropometric data and pain perception were shown for the first time.

Keywords: experimental pain; gender differences; healthy subjects; prediction; quantitative sensory testing.

Figures

Figure 1
Figure 1
The study algorithm: gender, anthropometric, psychological, and psychophysical variables are used as potential predictors of heat injury-induced pain. Notes: The actual predictors are divided into gender-related and nongender-related predictors and used in a multiple regression model predicting pain sensitivity.
Figure 2
Figure 2
The testing sequence: (1) baseline assessments (secondary hyperalgesia, electronic pinprick algometry, thermal and electrical thresholds), (2) cold pressor test and pressure algometry, (3) conditioned pain modulation efficiency, (4) heat injury, (5–7) postburn 1–3 hour assessments (comparable to baseline assessments, without electrical stimulation). Abbreviations: CDT, cool detection threshold; EDT, electrical detection threshold; EPT, electrical pain threshold; EPTo, electrical pain tolerance; HPT, heat pain threshold; WDT, warmth detection threshold.
Figure 3
Figure 3
The conditioned pain modulation efficiency with repeated phasic heat stimuli (47°C, 4 seconds [1, 3–5]) in relation to submersion of the nondominant hand (2) in the cold pressor test (0.3°C–0.5°C, 30 seconds). Notes: During the phasic heat stimuli, the subjects rated their maximal pain on a visual analog scale (0–10).
Figure 4
Figure 4
Consolidated Standards of Reporting Trials diagram of the study illustrating patient enrollment, inclusion, the two study days, and analysis. Notes: The number of males/females for the intention-to-treat and per-protocol groups was 57/58 and 50/50, respectively.
Figure 5
Figure 5
Electrical stimulation: electrical detection threshold, electrical pain threshold, and electrical pain tolerance for females, males, and both genders combined (mean ± standard error of the mean). Notes: The Y-axis illustrates arbitrary units correlating with the electrical energy delivered (1–100). A significant gender-related difference was observed in electrical detection threshold and electrical pain tolerance (P < 0.002); *P < 0.005, ***P <0.001. Abbreviations: EDT, electrical detection threshold; EPT, electrical pain threshold; EPTo, electrical pain tolerance.
Figure 6
Figure 6
Assessment of pinprick pain thresholds with an electronic pinprick algometer in (A) the primary hyperalgesia area and (B) the secondary hyperalgesia area at baseline (preburn), 1 hour, 2 hours, and 3 hours after the burn injury. Notes: Significant differences between baseline and postburn assessments were seen (P < 0.005). No gender-related differences were observed. *P < 0.005. Abbreviations: EPPA, electronic pinprick algometer; PB1, 1 hour postburn; PB2, 2 hours postburn; PB3, 3 hours postburn.
Figure 7
Figure 7
Secondary hyperalgesia areas (cm2) assessed by monofilaments at 1 hour, 2 hours, and 3 hours after the burn injury for females, males, and both genders combined (mean ± standard error of the mean). Abbreviations: PB1, 1 hour postburn; PB2, 2 hours postburn; PB3, 3 hours postburn.
Figure 8
Figure 8
Thermal stimulation: (A) warmth detection threshold, (B) cool detection threshold, and (C) heat pain threshold at baseline (preburn) and 1, 2, and 3 hours after the burn injury for females, males, and both genders combined (mean ± standard error of the mean). Notes: Values on the Y-axis indicate the warmth and cool detection threshold assessments from thermal baseline (32°C) and the absolute temperature (°C) for heat pain threshold. The preburn values for warmth detection threshold demonstrated a statistical difference compared to 1 hour postburn only (P < 0.005) and the preburn values for heat pain threshold were significantly higher than the 1, 2, and 3 hour postburn values (P < 0.005); *P < 0.005. Abbreviations: CDT, cool detection threshold; HPT, heat pain threshold; PB1, 1 hour postburn; PB2, 2 hours postburn; PB3, 3 hours postburn; WDT, warmth detection threshold.
Figure 9
Figure 9
Pressure pain tolerance (left Y-axis) before and immediately after the cold pressor test, and the difference between the two assessments, for females, males, and both genders combined (mean ± standard error of the mean). Notes: Data from the first cold pressor test indicate the time to pain registration (cold pressor pain threshold [seconds]) and time to pain tolerance (cold pressor pain tolerance [mean ± standard deviation]) (right Y-axis). Significant gender-related differences were observed in pressure pain tolerance (P < 0.0001) and in time to pain tolerance (P < 0.001); **P < 0.001; ***P < 0.0001. Abbreviations: CPTpain, cold pressor pain threshold; CPTo, cold pressor pain tolerance; PPTo1, pressure pain tolerance before the cold pressor test; PPTo2, pressure pain tolerance immediately after the cold pressor test; ΔPTo, difference in pressure tolerance before and after the cold pressor test.
Figure 10
Figure 10
Conditioned pain modulation efficiency: pain ratings with visual analog scale (0–10) during the four phasic heat stimuli during the test for conditioned pain modulation (compare to Figure 3) for females, males, and both genders combined (mean ± standard error of the mean). Notes: The conditioned pain modulation efficiency is shown. Pain ratings before the cold pressor test were significantly higher in comparison to ratings during and after the cold pressor test (P < 0.0001); ***P < 0.0001. Abbreviations: CPM1, conditioned pain modulation rating before the cold pressor test; CPM2, conditioned pain modulation rating during the cold pressor test; CPM3–4, conditioned pain modulation rating after the cold pressor test; VAS, visual analog scale; ΔCPM, conditioned pain modulation efficiency.

References

    1. Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N, Harris JR. Individual differences in pain sensitivity: genetic and environmental contributions. Pain. 2008;136(1–2):21–29.
    1. Campbell CM, Edwards RR, Fillingim RB. Ethnic differences in respon-ses to multiple experimental pain stimuli. Pain. 2005;113(1–2):20–26.
    1. Rahim-Williams FB, Riley JL, 3rd, Herrera D, Campbell CM, Hastie BA, Fillingim RB. Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics. Pain. 2007;129(1–2):177–184.
    1. Abrishami A, Chan J, Chung F, Wong J. Preoperative pain sensitivity and its correlation with postoperative pain and analgesic consumption: a qualitative systematic review. Anesthesiology. 2011;114(2):445–457.
    1. Afari N, Mostoufi S, Noonan C, et al. C-reactive protein and pain sensitivity: findings from female twins. Ann Behav Med. 2011;42(2):277–283.
    1. Baum C, Huber C, Schneider R, Lautenbacher S. Prediction of experimental pain sensitivity by attention to pain-related stimuli in healthy individuals. Percept Mot Skills. 2011;112(3):926–946.
    1. Edwards RR, Campbell CM, Fillingim RB. Catastrophizing and experimental pain sensitivity: only in vivo reports of catastrophic cognitions correlate with pain responses. J Pain. 2005;6(5):338–339.
    1. Oosterman JM, Dijkerman HC, Kessels RP, Scherder EJ. A unique association between cognitive inhibition and pain sensitivity in healthy participants. Eur J Pain. 2010;14(10):1046–1050.
    1. Hastie BA, Riley JL, 3rd, Robinson ME, et al. Cluster analysis of multiple experimental pain modalities. Pain. 2005;116(3):227–237.
    1. Werner MU, Mjobo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology. 2010;112(6):1494–1502.
    1. Chizh BA, Priestley T, Rowbotham M, Schaffler K. Predicting therapeutic efficacy – experimental pain in human subjects. Brain Res Rev. 2009;60(1):243–254.
    1. Werner MU, Duun P, Kehlet H. Prediction of postoperative pain by preoperative nociceptive responses to heat stimulation. Anesthesiology. 2004;100(1):115–119.
    1. Schulz E, Zherdin A, Tiemann L, Plant C, Ploner M. Decoding an individual’s sensitivity to pain from the multivariate analysis of EEG data. Cereb Cortex. 2012;22(5):1118–1123.
    1. Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G, Choiniere 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(3):602–618.
    1. Naert AL, Kehlet H, Kupers R. Characterization of a novel model of tonic heat pain stimulation in healthy volunteers. Pain. 2008;138(1):163–171.
    1. Pedersen JL, Kehlet H. Secondary hyperalgesia to heat stimuli after burn injury in man. Pain. 1998;76(3):377–384.
    1. Werner MU, Duun P, Kraemer O, Lassen B, Kehlet H. Arthroscopic knee surgery does not modify hyperalgesic responses to heat injury. Anesthesiology. 2003;99(5):1152–1157.
    1. Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain. 2009;10(6):556–572.
    1. Granot M, Weissman-Fogel I, Crispel Y, et al. Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: do conditioning stimulus painfulness, gender and personality variables matter? Pain. 2008;136(1–2):142–149.
    1. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain. 2008;138(1):22–28.
    1. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010;23(5):611–615.
    1. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the hospital anxiety and depression scale. An updated literature review. J Psychosom Res. 2002;52(2):69–77.
    1. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–370.
    1. Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain. 2001;90(3):261–269.
    1. Borly L, Anderson IB, Bardram L, et al. Preoperative prediction model of outcome after cholecystectomy for symptomatic gallstones. Scand J Gastroenterol. 1999;34(11):1144–1152.
    1. Stener-Victorin E, Kowalski J, Lundeberg T. A new highly reliable instrument for the assessment of pre- and postoperative gynecological pain. Anesth Analg. 2002;95(1):151–157.
    1. Moller KA, Johansson B, Berge OG. Assessing mechanical allodynia in the rat paw with a new electronic algometer. J Neurosci Methods. 1998;84(1–2):41–47.
    1. Werner MU, Rotboll-Nielsen P, Ellehuus-Hilmersson C. Humidity affects the performance of von Frey monofilaments. Acta Anaesthesiol Scand. 2011;55(5):577–582.
    1. Pud D, Granovsky Y, Yarnitsky D. The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans. Pain. 2009;144(1–2):16–19.
    1. Altman DG. Practical Statistics for Medical Research. London: Chapman and Hall; 1996.
    1. Aasvang EK, Hansen JB, Kehlet H. Can preoperative electrical nociceptive stimulation predict acute pain after groin herniotomy? J Pain. 2008;9(10):940–944.
    1. Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ. Postcesarean section pain prediction by preoperative experimental pain assessment. Anesthesiology. 2003;98(6):1422–1426.
    1. Granot M, Weissman-Fogel I. The effect of post-surgical neuroplasticity on the stability of systemic pain perception: a psychophysical study. Eur J Pain. 2012;16(2):247–255.
    1. Pan PH, Coghill R, Houle TT, et al. Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement. Anesthesiology. 2006;104(3):417–425.
    1. Rudin A, Wolner-Hanssen P, Hellbom M, Werner MU. Prediction of post-operative pain after a laparoscopic tubal ligation procedure. Acta Anaesthesiol Scand. 2008;52(7):938–945.
    1. Rudin A, Eriksson L, Liedholm R, List T, Werner MU. Prediction of postoperative pain after mandibular third molar surgery. J Orofac Pain. 2010;24(2):189–196.
    1. Strulov L, Zimmer EZ, Granot M, Tamir A, Jakobi P, Lowenstein L. Pain catastrophizing, response to experimental heat stimuli, and post-cesarean section pain. J Pain. 2007;8(3):273–279.
    1. Nir RR, Granovsky Y, Yarnitsky D, Sprecher E, Granot M. A psychophysical study of endogenous analgesia: the role of the conditioning pain in the induction and magnitude of conditioned pain modulation. Eur J Pain. 2011;15(5):491–497.
    1. Popescu A, LeResche L, Truelove EL, Drangsholt MT. Gender differences in pain modulation by diffuse noxious inhibitory controls: a systematic review. Pain. 2010;150(2):309–318.
    1. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL., 3rd Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10(5):447–485.
    1. Taenzer P, Melzack R, Jeans ME. Influence of psychological factors on postoperative pain, mood and analgesic requirements. Pain. 1986;24(3):331–342.
    1. Dorn LD, Campo JC, Thato S, et al. Psychological comorbidity and stress reactivity in children and adolescents with recurrent abdominal pain and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003;42(1):66–75.
    1. McWilliams LA, Goodwin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain. 2004;111(1–2):77–83.
    1. Lautenbacher S, Rollman GB. Sex differences in responsiveness to painful and non-painful stimuli are dependent upon the stimulation method. Pain. 1993;53(3):255–264.
    1. Mylius V, Kunz M, Schepelmann K, Lautenbacher S. Sex differences in nociceptive withdrawal reflex and pain perception. Somatosens Mot Res. 2005;22(3):207–211.
    1. al’Absi M, France C, Harju A, France J, Wittmers L. Adrenocortical and nociceptive responses to opioid blockade in hypertension-prone men and women. Psychosom Med. 2006;68(2):292–298.
    1. Ashina S, Bendtsen L, Ashina M, Magerl W, Jensen R. Generalized hyperalgesia in patients with chronic tension-type headache. Cephalalgia. 2006;26(8):940–948.
    1. Ayesh EE, Jensen TS, Svensson P. Somatosensory function following painful repetitive electrical stimulation of the human temporomandibular joint and skin. Exp Brain Res. 2007;179(3):415–425.
    1. Leong GW, Lauschke J, Rutowski SB, Waite PM. Age, gender, and side differences of cutaneous electrical perceptual threshold testing in an able-bodied population. J Spinal Cord Med. 2010;33(3):249–255.
    1. Nyklicek I, Vingerhoets AJ, Van Heck GL. Hypertension and pain sensitivity: effects of gender and cardiovascular reactivity. Biol Psychol. 1999;50(2):127–142.
    1. Buhagiar L, Cassar OA, Brincat MP, et al. Predictors of post-caesarean section pain and analgesic consumption. J Anaesthesiol Clin Pharmacol. 2011;27(2):185–191.
    1. Nielsen PR, Norgaard L, Rasmussen LS, Kehlet H. Prediction of post-operative pain by an electrical pain stimulus. Acta Anaesthesiol Scand. 2007;51(5):582–586.
    1. Riley JL, 3rd, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a metaanalysis. Pain. 1998;74(2–3):181–187.
    1. Maffiuletti NA, Herrero AJ, Jubeau M, Impellizzeri FM, Bizzini M. Differences in electrical stimulation thresholds between men and women. Ann Neurol. 2008;63(4):507–512.
    1. Bakkers M, Merkies IS, Lauria G, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology. 2009;73(14):1142–1148.
    1. Goransson LG, Mellgren SI, Lindal S, Omdal R. The effect of age and gender on epidermal nerve fiber density. Neurology. 2004;62(5):774–777.
    1. Mowlavi A, Cooney D, Febus L, Khosraviani A, Wilhelmi BJ, Akers G. Increased cutaneous nerve fibers in female specimens. Plast Reconstr Surg. 2005;116(5):1407–1410.
    1. Nolano M, Provitera V, Crisci C, et al. Quantification of myelinated endings and mechanoreceptors in human digital skin. Ann Neurol. 2003;54(2):197–205.
    1. Provitera V, Nolano M, Pagano A, Caporaso G, Stancanelli A, Santoro L. Myelinated nerve endings in human skin. Muscle Nerve. 2007;35(6):767–775.
    1. Selim MM, Wendelschafer-Crabb G, Hodges JS, et al. Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements. Pain. 2010;151(3):575–581.
    1. Verbraecken J, Van de Heyning P, De Backer W, Van Gaal L. Body surface area in normal-weight, overweight, and obese adults. A comparison study. Metabolism. 2006;55(4):515–524.
    1. Hashmi JA, Davis KD. Women experience greater heat pain adaptation and habituation than men. Pain. 2009;145(3):350–357.
    1. Neziri AY, Scaramozzino P, Andersen OK, Dickenson AH, Arendt-Nielsen L, Curatolo M. Reference values of mechanical and thermal pain tests in a pain-free population. Eur J Pain. 2011;15(4):376–383.
    1. Fillingim RB, Maixner W, Kincaid S, Silva S. Sex differences in temporal summation but not sensory-discriminative processing of thermal pain. Pain. 1998;75(1):121–127.
    1. Jensen MT, Petersen KL. Gender differences in pain and secondary hyperalgesia after heat/capsaicin sensitization in healthy volunteers. J Pain. 2006;7(3):211–217.
    1. Jones A, Zachariae R, Arendt-Nielsen L. Dispositional anxiety and the experience of pain: gender-specific effects. Eur J Pain. 2003;7(5):387–395.
    1. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse noxious inhibitory controls (DNIC): association with clinical variables. Pain. 2003;106(3):427–437.
    1. Tousignant-Laflamme Y, Page S, Goffaux P, Marchand S. An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res. 2008;1230:73–79.
    1. Yarnitsky D, Arendt-Nielsen L, Bouhassira D, et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain. 2010;14(4):339.
    1. Geber C, Klein T, Azad S, et al. Test-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): a multi-centre study. Pain. 2011;152(3):548–556.
    1. Siao P, Cros DP. Quantitative sensory testing. Phys Med Rehabil Clin N Am. 2003;14(2):261–286.
    1. Bland JM, Altman DG. Measuring agreement in method comparison studies. Stat Methods Med Res. 1999;8(2):135–160.
    1. Pedersen JL, Kehlet H. Hyperalgesia in a human model of acute inflammatory pain: a methodological study. Pain. 1998;74(2–3):139–151.
    1. Werner MU, Lassen B, Pedersen JL, Kehlet H. Local cooling does not prevent hyperalgesia following burn injury in humans. Pain. 2002;98(3):297–303.
    1. Riley JL, 3rd, Robinson ME, Wise EA, Price DD. A meta-analytic review of pain perception across the menstrual cycle. Pain. 1999;81(3):225–235.
    1. Sherman JJ, LeResche L. Does experimental pain response vary across the menstrual cycle? A methodological review. Am J Physiol Regul Integr Comp Physiol. 2006;291(2):R245–R256.
    1. Klatzkin RR, Mechlin B, Girdler SS. Menstrual cycle phase does not influence gender differences in experimental pain sensitivity. Eur J Pain. 2010;14(1):77–82.
    1. Stening KD, Berg G, Hammar M, et al. Influence of estrogen levels on thermal perception, pain thresholds, and pain tolerance: studies on women undergoing in vitro fertilization. J Pain. 2012;13(5):459–466.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere