The role of biological sex in neurophysiological associations of patients with chronic osteoarthritis pain: a prospective cross-sectional study
O papel do sexo biológico nas associações neurofisiológicas de pacientes com dor crônica de osteoartrite: um estudo prospectivo transversal
Kevin Pacheco-Barrios, Marcel Simis, Paulo S. de Melo, Ingrid Rebello-Sanchez, Karen Vasquez-Avila, Sara Pinto Barbosa, Paola Gonzalez-Mego, Linamara Battistella, Marta Imamura, Felipe Fregni
Abstract
Background
This study aims to explore the role of sex as a confounder and effect modifier in the associations of clinical outcomes, pain-related outcomes, and neurophysiological measurements in chronic knee OA pain subjects.
Methods
Sociodemographic, clinical, and neurophysiological data were extracted from 113 knee OA subjects with chronic pain. We performed exploratory multivariate regression models assessing the association of physiological outcomes (Quantitative Sensory Testing [QST], Electroencephalography [EEG], and Transcranial Magnetic Stimulation [TMS]) and clinical characteristics (pain, anxiety, and motor function). In each independent model we tested the role of biological sex as confounder and effect modifier (adding the interaction term).
Results
Females reported higher pain intensity, lower quality of life, diminished pain thresholds, and less EEG alpha power compared to males. Sex negatively confounded the association between pain interference and pain intensity with pain threshold confounding (ranged between -19% to -125%). Moreover, sex acted as an effect modifier, predominantly influencing the relationship between pain interference and frontocentral alpha-delta power in EEG. Similarly, sex modified the association between pain interference and pain threshold. In females EEG and PPT variables explained less variability of pain interference compared to males.
Conclusão
Our study suggests that sex is a confounder and effect modifier mainly in the relationship between neurophysiological variables and pain-related outcomes in a chronic OA pain population. Females may have weaker associations between pain intensity and mechanistic outcomes (EEG and QST). Thus, the use of these biomarkers in females requires further optimization. We therefore reinforce the need for accounting for biological sex in the analysis, not only as a confounder, but as an effect modifier in further randomized trials and observational studies in the field of pain.
Keywords
Resumo
Introdução
Este estudo tem como objetivo explorar o papel do sexo biológico como variável de confusão e modificador de efeito nas associações entre desfechos clínicos, desfechos relacionados à dor e medidas neurofisiológicas em pacientes com dor crônica de osteoartrite (OA) no joelho.
Métodos
Foram coletados dados sociodemográficos, clínicos e neurofisiológicos de 113 pacientes com OA no joelho e dor crônica. Modelos de regressão multivariada exploratória foram utilizados para avaliar a associação entre desfechos fisiológicos (Testes Quantitativos de Sensibilidade [QST], Eletroencefalografia [EEG] e Estimulação Magnética Transcraniana [TMS]) e características clínicas (dor, ansiedade e função motora). Em cada modelo independente, testou-se o papel do sexo biológico como variável de confusão e modificador de efeito (adicionando termo de interação).
Resultados
As mulheres relataram maior intensidade da dor, menor qualidade de vida, limiares de dor diminuídos e menor potência alfa no EEG em comparação aos homens. O sexo teve efeito negativo de confusão na associação entre interferência da dor e intensidade da dor, com variação entre -19% a -125%. Além disso, o sexo atuou como modificador de efeito, influenciando principalmente a relação entre interferência da dor e potência alfa-delta frontocentral no EEG. De forma similar, o sexo modificou a associação entre interferência da dor e limiar de dor. Em mulheres, variáveis do EEG e limiar de pressão dolorosa (PPT) explicaram menos variabilidade da interferência da dor comparado aos homens.
Conclusão
Nosso estudo sugere que o sexo é variável de confusão e modificador de efeito principalmente na relação entre variáveis neurofisiológicas e desfechos relacionados à dor em população com dor crônica de OA. Mulheres podem apresentar associações mais fracas entre intensidade da dor e desfechos mecanísticos (EEG e QST). Assim, o uso desses biomarcadores em mulheres necessita de maior otimização. Reforçamos a necessidade de considerar o sexo biológico nas análises, não apenas como variável de confusão, mas também como modificador de efeito em futuros ensaios randomizados e estudos observacionais na área da dor.
Palavras-chave
References
1. Raz L, Miller VM. Considerations of sex and gender differences in preclinical and clinical trials. Handb Exp Pharmacol. 2012 (214):127−47.
2. Clayton JA. Applying the new SABV (sex as a biological variable) policy to research and clinical care. Physiol Behav. 2018;187:2 −5.
3. Fillingim RB, King CD, Ribeiro-Dasilva MC, et al. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10:447−85.
4. Unruh AM. Gender variations in clinical pain experience. Pain. 1996;65:123−67.
5. Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13:859−66.
6. Rollman GB, Lautenbacher S. Sex differences in musculoskeletal pain. Clin J Pain. 2001;17:20−4.
7. Schmidt CO, Raspe H, Pfingsten M, et al. Back pain in the German adult population: prevalence, severity, and sociodemographic correlates in a multiregional survey. Spine. 2007;32: 2005−11.
8. Laitner MH, Erickson LC, Ortman E. Understanding the Impact of Sex and Gender in Osteoarthritis: Assessing Research Gaps and Unmet Needs. J Womens Health (Larchmt). 2021;30:634−41.
9. Bartley EJ, King CD, Sibille KT, et al. Enhanced pain sensitivity among individuals with symptomatic knee osteoarthritis: potential sex differences in central sensitization. Arthritis Care Res (Hoboken). 2016;68:472−80.
10. de Araujo Palmeira CC, Ashmawi HA, de Paula PI. Sex and pain perception and analgesia. Rev Bras Anestesiol. 2011;61:814−28.
11. Riley Iii JL, Robinson ME, Wise EA, et al. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain. 1998;74:181−7.
12. Iliffe S, Kharicha K, Carmaciu C, et al. The relationship between pain intensity and severity and depression in older people: exploratory study. BMC Fam Pract. 2009;10:54.
13. Mok LC, Lee IFK. Anxiety, depression and pain intensity in patients with low back pain who are admitted to acute care hospitals. J Clin Nurs. 2008;17:1471−80.
14. Cuff L, Fann J, Bombardier C, et al. Depression, pain intensity, and interference in acute spinal cord injury. Top Spinal Cord Inj Rehabil. 2014;20:32−9.
15. Thompson T, Correll CU, Gallop K, et al. Is pain perception altered in people with depression? A systematic review and meta-analysis of experimental pain research. J Pain. 2016;17: 1257−72.
16. Hirata J, Tomiyama M, Koike Y, et al. Relationship between pain intensity, pain catastrophizing, and self-efficacy in patients with frozen shoulder: a cross-sectional study. J Orthop Surg Res. 2021;16:542.
17. Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: a prospective study. Clin J Pain. 2005;21:439−45.
18. Nickel MM, May ES, Tiemann L, et al. Brain oscillations differentially encode noxious stimulus intensity and pain intensity. Neuroimage. 2017;148:141−7.
19. Jensen MP, Sherlin LH, Gertz KJ, et al. Brain EEG activity correlates of chronic pain in persons with spinal cord injury: clinical implications. Spinal Cord. 2013;51:55−8.
20. Pinheiro ESDS, Queiros FCd, Montoya P, et al. Electroencephalo- graphic patterns in chronic pain: a systematic review of the literature. PloS One. 2016;11:e0149085.
21. Parker RS, Lewis GN, Rice DA, et al. Is motor cortical excitability altered in people with chronic pain? A systematic review and meta-analysis. Brain Stimul. 2016;9:488−500.
22. Simis M, Imamura M, de Melo PS, et al. Deficit of inhibition as a marker of neuroplasticity (DEFINE study) in 10 K. Pacheco-Barrios, M. Simis, P.S. de Melo et al. rehabilitation: A longitudinal cohort study protocol. Front Neurol. 2021;12:695406.
23. Simis M, Imamura M, de Melo PS, et al. Increased motor cortex inhibition as a marker of compensation to chronic pain in knee osteoarthritis. Sci Rep. 2021;11:24011.
24. Tavares DRB, Trevisani VFM, Okazaki JEF, et al. Risk factors of pain, physical function, and health-related quality of life in elderly people with knee osteoarthritis: A cross-sectional study. Heliyon. 2020;6:e05723.
25. Iuamoto LR, Imamura M, Sameshima K, et al. Functional changes in cortical activity of patients submitted to knee osteoarthritis treatment: an exploratory pilot study. Am J Phys Med Rehabil. 2022;101:920−30.
26. Sorge RE, Totsch SK. Sex differences in pain. J Neurosci Res. 2017;95:1271−81.
27. Reidler JS, Mendonca ME, Santana MB, et al. Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects. J Pain. 2012;13:450−8.
28. Lautenbacher S, Kunz M, Burkhardt S. The effects of DNIC-type inhibition on temporal summation compared to single pulse processing: does sex matter? Pain. 2008;140:429−35.
29. Streff A, Michaux G, Anton F. Internal validity of inter-digital web pinching as a model for perceptual diffuse noxious inhibitory controls-induced hypoalgesia in healthy humans. Eur J Pain. 2011;15:45−52.
30. Streff A, Michaux G, Anton F. Internal validity of inter-digital web pinching as a model for perceptual diffuse noxious inhibitory controls-induced hypoalgesia in healthy humans. Eur J Pain. 2011;15:45−52.
31. Malcolm MP, Triggs WJ, Light KE, et al. Reliability of motor cortex transcranial magnetic stimulation in four muscle representations. Clin Neurophysiol. 2006;117:1037−46.
32. Rossini PM, Burke D, Chen R, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an IFCN Committee. Clin Neurophysiol. 2015;126:1071−107.
33. Schwenkreis P, Janssen F, Rommel O, et al. Bilateral motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand. Neurology. 2003;61:515−9.
34. Nuwer MR, Lehmann D, da Silva FL, et al. IFCN guidelines for topographic and frequency analysis of EEGs and EPs. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol. 1999;52:15−20.
35. Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134:9−21.
36. Delorme A, Sejnowski T, Makeig S. Enhanced detection of artifacts in EEG data using higher-order statistics and independent component analysis. Neuroimage. 2007;34:1443−9.
37. Jensen KB, Regenbogen C, Ohse MC, et al. Brain activations during pain: a neuroimaging meta-analysis of patients with pain and healthy controls. Pain. 2016;157:1279−86.
38. Burns LC, Ritvo SE, Ferguson MK, et al. Pain catastrophizing as a risk factor for chronic pain after total knee arthroplasty: a systematic review. J Pain Res. 2015;8:21−32.
39. Elboim-Gabyzon M, Rozen N, Laufer Y. Gender differences in pain perception and functional ability in subjects with knee osteoarthritis. ISRN Orthop. 2012;2012. 413105-413105.
40. Koechlin H, Coakley R, Schechter N, et al. The role of emotion regulation in chronic pain: A systematic literature review. J Psychosom Res. 2018;107:38−45.
41. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs. 2005;14:798−804.
42. Bellamy N, Buchanan WW, Goldsmith CH, et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833−40.
43. Ware Jr. JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30:473−83.
44. Kean J, Monahan PO, Kroenke K, et al. Comparative Responsiveness of the PROMIS Pain Interference Short Forms, Brief Pain Inventory, PEG, and SF-36 Bodily Pain Subscale. Med Care. 2016;54:414−21.
45. Botega NJ, Bio MR, Zomignani MA, et al. Mood disorders among inpatients in ambulatory and validation of the anxiety and depression scale HAD. Rev Saude Publica. 1995;29:355−63.
46. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychological Assessment. 1995;7:524.
47. Sarda Junior J, Nicholas MK, Pereira IA, et al. Validation of the Pain-Related Catastrophizing Thoughts Scale. Acta Fisiatrica. 2008;15:31−6.
48. Allaire J. RStudio: integrated development environment for R. Boston, MA. 2012;770:394.
49. Tracey I, Woolf CJ, Andrews NA. Composite pain biomarker signatures for objective assessment and effective treatment. Neuron. 2019;101:783−800.
50. Mogil JS. Sources of individual differences in pain. Annu Rev Neurosci. 2021;44:1−25.
51. Treede R-D. The role of quantitative sensory testing in the prediction of chronic pain. Pain. 2019;160:S66−9.
52. Georgopoulos V, Akin-Akinyosoye K, Zhang W, et al. Quantitative Sensory Testing (QST) and predicting outcomes for musculoskeletal pain, disability and negative affect: a systematic review and meta-analysis. Pain. 2019;160:1920.
53. Verberne WR, Snijders TJ, Liem KS, et al. Applications of’quantitative sensory testing. Nederlands Tijdschrift Voor Geneeskunde. 2013;157. A5434-A5434.
54. Fernandes C, Pidal-Miranda M, Samartin-Veiga N, et al. Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity. Pain. 2019;160:2679 −90.
55. Weissman-Fogel I, Sprecher E, Pud D. Effects of catastrophizing on pain perception and pain modulation. Exp Brain Res. 2008;186:79−85.
56. Fingleton C, Smart K, Moloney N, et al. Pain sensitization in people with knee osteoarthritis: a systematic review and metaanalysis. Osteoarthritis Cartilage. 2015;23:1043−56.
57. Santos LC, Gushken F, Gadotti GM, et al. Intracortical Inhibition in the Affected Hemisphere in Limb Amputation. Front Neurol. 2020;11:720.
58. Fauchon C, Kim JA, El-Sayed R, et al. Exploring sex differences in alpha brain activity as a potential neuromarker associated with neuropathic pain. Pain. 2022;163:1291−302.
59. Wada Y, Takizawa Y, Jiang ZY, Yamaguchi N. Gender differences in quantitative EEG at rest and during photic stimulation in normal young adults. Clin Electroencephalogr. 1994;25:81−5.
60. Korzekwa MI, Steiner M. Premenstrual syndromes. Clin Obstet Gynecol. 1997;40:564−76.
61. Keenan PA, Lindamer LA. Non-migraine headache across the menstrual cycle in women with and without premenstrual syndrome. Cephalalgia. 1992;12:356−9.
62. Østensen M, Rugelsjoen A, Wigers SH. The effect of reproductive events and alterations of sex hormone levels on the symptoms of fibromyalgia. Scand J Rheumatol. 1997;26:355−60.
63. Riley Iii JL, Robinson ME, Wise EA, et al. A meta-analytic review of pain perception across the menstrual cycle. Pain. 1999;81:225−35.
64. King S, Chambers CT, Huguet A, et al. The epidemiology of chronic pain in children and adolescents revisited: a systematic review. Pain. 2011;152:2729−38.
65. Boerner KE, Birnie KA, Caes L, et al. Sex differences in experimental pain among healthy children: a systematic review and meta-analysis. Pain. 2014;155:983−93.
66. Aloisi AM. Gonadal hormones and sex differences in pain reactivity. Clin J Pain. 2003;19:168−74.
67. Fillingim RB, Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev. 2000;24:485 −501.
68. Mechlin B. Lower socioeconomic status is associated with rating experimental pain as more intense. J Pain. 2012;13:S52.
69. Zajacova A, Rogers RG, Grodsky E, et al. The relationship between education and pain among adults aged 30−49 in the United States. J Pain. 2020;21:1270−80.
70. Mossey JM. Defining racial and ethnic disparities in pain management. Clinical Orthopaedics and Related Research. 2011;469:1859−70.
71. Reyes-Gibby CC, Aday LA, Todd KH, et al. Pain in aging community-dwelling adults in the United States: non-Hispanic whites, non-Hispanic blacks, and Hispanics. J Pain. 2007;8:75−84.
72. Pillay TK, Van Zyl HA, Blackbeard DR. The Influence of Culture on Chronic Pain: A Collective Review of Local and International Literature. Psychiatry. 2015;18:234.
73. Franconi F, Campesi I, Colombo D, et al. Sex-gender variable: Methodological recommendations for increasing scientific value of clinical studies. Cells. 2019;8:476.
74. Vasquez-Avila K, Pacheco-Barrios K, de Melo PS, et al. Addressing the critical role of gender identity and sex in the planning, analysis, and conduct of clinical trials. Princ Pract Clin Res. 2021;7:59−62.
75. Alabas OA, Tashani OA, Tabasam G, et al. Gender role affects experimental pain responses: a systematic review with metaanalysis. Eur J Pain. 2012;16:1211−23.
76. Mogil JS. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat Rev Neurosci. 2020;21: 353−65.
77. Kaulitzki S. Rethinking chronic pain. Lancet. 2017;391:1391−454.
78. Blyth FM, Macfarlane GJ, Nicholas MK. The contribution of psychosocial factors to the development of chronic pain: the key to better outcomes for patients? Pain. 2007;129:8−11.
79. Miaskowski C, Blyth F, Nicosia F, et al. A biopsychosocial model of chronic pain for older adults. Pain Med. 2020;21:1793−805.
80. Darnall BD, Carr DB, Schatman ME. Pain psychology and the biopsychosocial model of pain treatment: ethical imperatives and social responsibility. Pain Med. 2017;18:1413−5.
Submitted date:
10/03/2024
Accepted date:
12/18/2024
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email