Kati Thieme, PhD
Institute of Medical Psychology, Philipps – University Marburg, Germany
The interaction of pain and fear as an etiological factor has been observed in patients with chronic pain, in psychosocial [1-5], psychophysiological [6, 7], psychophysical , endocrine [9, 10], genetic [11, 12] and central responses [13, 14], however inconsistent results suggest a heterogeneity in stress responses of chronic pain. Biopsychological mechanisms such as classical  and operant learning [16, 17] of different stress responses will be discussed.
The theoretical base of the stress influence on diseases was proposed by Lacey & Lacey “The principle of relative [stress] response specificity [is] formulated as follows: For a given set of autonomic functions (hence the term relative), subjects tend to respond with idiosyncratic pattern of autonomic activation in which maximal activation is shown by the same physiological function, whatever the stress.” (, p 50).
Our study with 120 female fibromyalgia patients examined the relationship of psychophysiological response patterns with psychological characteristics and comorbid mental disorders . Surface electromyographic data, systolic and diastolic blood pressure (BP), heart rate (HR), and skin conductance levels were recorded continuously during baseline, stress, and relaxation tasks. Cluster analysis revealed 4 subgroups of patients who differed on pain intensity, cognitive, affective, and behavioural responses to pain and stress (Table 1):
FM patients with hyperreactive BP (I) and increased electrodermal stress response (III) displayed the highest number of pain behaviours as expression of fear, in contrast to patients with hyporeactive BP (II). The results suggest that the stress response in patients with high BP and high sudomotor response may be related to operant learning that reinforces pain behaviour expression. Several studies show that baroreceptor response operantly modified by phasic BP changes [19, 20]. It is assumed that a long-term stress associated with adrenergic dysregulation  increases both systolic and diastolic BP and a reduction of BP and pressure variability in the carotid sinus. Since baroreceptors are activated only by changes of pressure intensities, reduced BP variability leads to a diminished baroreflex sensitivity that provokes a reduced regulatory activity of the dorsal medial nucleus tractus solitarii (dmNTS) reflex arcs (Fig. 1) that regulate pain, blood pressure and fear [21, 22]. The diminished solitary pathway and the disruption of emotion and emotional modulation of pain and nociception may contribute to chronic pain .
These findings contrast with those from patients with a hypotensive stress response that show reduced sympathetically mediated profiles at rest and in response to stress. This pattern is consistent with a relative enhancement in baroreceptor buffering capacity, which mediates a reduction in pain perception and diminished psychological and functional distress . Patients with hypotensive stress responses display an overlap of thermoregulation and pain modification with lower body temperatures, lower metabolic rates, and lower circulating cortisol/corticosterone in response to stress .
The identification of the mechanisms that contribute to these group differences will further our understanding of the mechanisms involved in the development and maintenance of chronic pain and suggest differential treatment strategies [16, 24-26].
Asmundson GJ, Katz J: Understanding the co‐occurrence of anxiety disorders and chronic pain: state‐of‐the‐art. Depression and anxiety 2009, 26(10):888-901.
Demyttenaere K, Bruffaerts R, Lee S, Posada-Villa J, Kovess V, Angermeyer MC, Levinson D, de Girolamo G, Nakane H, Mneimneh Z et al: Mental disorders among persons with chronic back or neck pain: results from the World Mental Health Surveys. Pain 2007, 129(3):332-342.
Edwards RR, Dworkin RH, Sullivan MD, Turk DC, Wasan AD: The Role of Psychosocial Processes in the Development and Maintenance of Chronic Pain. J Pain 2016, 17(9 Suppl):T70-92.
Lee H, Hubscher M, Moseley GL, Kamper SJ, Traeger AC, Mansell G, McAuley JH: How does pain lead to disability? A systematic review and meta-analysis of mediation studies in people with back and neck pain. Pain 2015, 156(6):988-997.
Turk DC, Okifuji A, Sinclair JD, Starz TW: Pain, disability, and physical functioning in subgroups of patients with fibromyalgia. J Rheumatol 1996, 23(7):1255-1262.
Thieme K, Turk DC: Heterogeneity of psychophysiological stress responses in fibromyalgia syndrome patients. Arthritis Res Ther 2006, 8(1):R9.
Thieme K, Turk DC, Gracely RH, Maixner W, Flor H: The relationship among psychological and psychophysiological characteristics of fibromyalgia patients. J Pain 2015, 16(2):186-196.
Rhudy JL, Meagher MW: Fear and anxiety: divergent effects on human pain thresholds. Pain 2000, 84(1):65-75.
Fischer S, Doerr JM, Strahler J, Mewes R, Thieme K, Nater UM: Stress exacerbates pain in the everyday lives of women with fibromyalgia syndrome--The role of cortisol and alpha-amylase. Psychoneuroendocrinology 2016, 63:68-77.
Light KC, Bragdon EE, Grewen KM, Brownley KA, Girdler SS, Maixner W: Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain 2009, 10(5):542-552.
Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D et al: Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005, 14(1):135-143.
Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W: Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain 2007, 128(3):199-208.
Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JN, Tracey I: Exacerbation of pain by anxiety is associated with activity in a hippocampal network. The Journal of neuroscience : the official journal of the Society for Neuroscience 2001, 21(24):9896-9903.
Rhudy JL, DelVentura JL, Terry EL, Bartley EJ, Olech E, Palit S, Kerr KL: Emotional modulation of pain and spinal nociception in fibromyalgia. Pain 2013, 154(7):1045-1056.
Vlaeyen JW, Linton SJ: Fear-avoidance model of chronic musculoskeletal pain: 12 years on. Pain 2012, 153(6):1144-1147.
Flor H, Turk DC: Chronic Pain: An Integrated Biobehavioral Approach. , 1 edn: Wolters Kluwer Health; 2015.
Fordyce WE: Behavioral concepts in chronic pain and illness. Mosby, St Louis 1976.
Lacey JI, Lacey BC: Verification and Extension of the Principle of Autonomic Response-Stereotypy. The American journal of psychology 1958, 71(1):50-73.
de la Coba P, Bruehl S, Duschek S, Reyes Del Paso GA: Blood pressure-related pain modulation in fibromyalgia: Differentiating between static versus dynamic pain indicators. International journal of psychophysiology : official journal of the International Organization of Psychophysiology 2018, 134:79-85.
Dworkin BR, Elbert T, Rau H, Birbaumer N, Pauli P, Droste C, Brunia CH: Central effects of baroreceptor activation in humans: attenuation of skeletal reflexes and pain perception. Proc Natl Acad Sci U S A 1994, 91(14):6329-6333.
Sandkuhler J: Learning and memory in pain pathways. Pain 2000, 88(2):113-118.
Tang X, Dworkin BR: The dmNTS is not the source of increased blood pressure variability in baroreflex denervated rats. Auton Neurosci 2009, 148(1-2):21-27.
Larson AA, Pardo JV, Pasley JD: Review of overlap between thermoregulation and pain modulation in fibromyalgia. The Clinical journal of pain 2014, 30(6):544-555.
Racine M, Jensen MP, Harth M, Morley-Forster P, Nielson WR: Operant Learning Versus Energy Conservation Activity Pacing Treatments in a Sample of Patients With Fibromyalgia Syndrome: A Pilot Randomized Controlled Trial. J Pain 2018.
Thieme K, Meller T, Evermann U, Malinowski R, Mathys M, Gracely RH, Maixner W, Turk DC: Efficacy of Systolic Extinction Training (SET) in Fibromyalgia Patients with elevated Blood Pressure Response to Stress - A Tailored RCT Study. Arthritis Care Res (Hoboken) 2018.
Diers M, Yilmaz P, Rance M, Thieme K, Gracely RH, Rolko C, Schley MT, Kiessling U, Wang H, Flor H: Treatment-related changes in brain activation in patients with fibromyalgia syndrome. Exp Brain Res 2012, 218(4):619-628.
Figure 1: NTS reflex arcs
Figure 1: NTS reflex arcs