Personality, Defences, Central Sensitization, and Trauma in Women With Chronic Migraine, Fibromyalgia, and Vulvodynia

Chronic pain (CP), defined as pain lasting more than 3 months, is a substantial healthcare challenge. Prevalence rates of CP are between 11% and 40% (Dahlhamer et al., 2018; Fayaz et al., 2016). CP prevalence increases with age, is greater among females, and among people with lower socioeconomic status (Tsang et al., 2008; Pergolizzi et al., 2013). CP affects relationships and self-esteem, and is associated with higher divorce and suicide rates, and an increased risk of substance abuse (Tang et al., 2016; Fitzcharles et al., 2021), psychopathology (Katz et al., 2015) and risk of medication overuse (Westergaard et al., 2015). The causes of CP are still poorly understood. Recently, the International Association for the Study of Pain (IASP, 2017) has proposed that three subtypes of CP may be differentiated based on unique causal mechanisms: nociceptive, neuropathic, and nociplastic.

Nociplastic Pain (NP) is a new descriptor of CP and includes conditions that arise from altered nociception despite no clear evidence of actual or threatened tissue damage. NP should be viewed as an overarching term that can be applied to a diverse range of clinical conditions that share common neurophysiological mechanisms, involving various organ systems (Galli, 2023). Among nociplastic chronic syndromes have been included chronic migraine, fibromyalgia, and vulvodynia (Bergeron et al., 2020; Fitzcharles et al., 2021). NP is usually accompanied by other central nervous system-associated symptoms with a close link with clinical psychological factors: general symptoms (e.g., fatigue and cognitive problems), temperamental characteristics (e.g., hypersensitivity to environmental stimuli) and psychological symptoms (e.g., anxiety/depression) (Fitzcharles et al., 2021). Many emotional states, such as depression and anxiety, and emotional processes, such as emotional awareness and regulation, may influence the presence and severity of NP (Aaron et al., 2020; Lumley et al., 2021), opening to the importance of a psychological assessment for diagnosis and psychological interventions. The concept of NP opens a new framework for understanding the co-occurrence of different chronic disorders and the role of related psychological factors. Comorbid chronic disorders may be the expression of shared pathophysiological mechanisms, with etiological and psychological features differentiating them by "pure" forms of the same disease. The comorbid association of migraine, fibromyalgia, and vulvodynia, and the well-known link with clinical psychological factors (e.g., early traumatic events, anxiety and depression, alexithymia, dissociation, etc.) is quite established (Bergeron et al., 2020; Fitzcharles et al., 2021). However, these chronic pain disorders have been usually studied as separate diseases. On the one hand, this research project wants to observe the common basis of these chronic pain disorders, which can be traced back to central sensitization mechanisms, the influence of early adverse events, and other psychological factors, and on the other hand it wants to observe the psychosocial peculiarities of each assessed condition (fibromyalgia, migraine, and vulvodynia) for tailored treatment purposes.

CHRONIC MIGRAINE (CM) Migraine affects ~15% of the general population globally and is typically characterized by recurring, often highly disabling attacks of severe headache, nausea, vomiting, super- sensitivity to light and sound, and other variable physical, mental, and psychological signs and symptoms, lasting for 4-72 h (Ferrari et al., 2022). Migraine is listed by The Global Burden of Disease Study as the third most disabling disease worldwide (Vos et al., 2012). Most patients have episodic migraine, although some patients develop CM (the presence of ≥15 headache days per month). The 1- year prevalence of migraine is 8-15% worldwide, but is highly dependent on age, sex, and migraine subtype (Ferrari et al., 2015). Migraine is 40-60% determined by genetic factors and for the remainder by non- genetic risk- modulating and trigger factors. Although a progressive increase of the attack frequency can occur spontaneously, it is often aggravated and/or induced by overuse of acute headache medications and/or caffeine. Risk factors for migraine progression toward CM include high headache frequency, high headache-related disability, obesity, allodynia, anxiety, and depression (Ferrari et al., 2022). Comorbid migraine and anxiety/depression are common in the general population, but the mechanism(s) supporting the comorbidity are still unknown. Overall, there seems to be a bidirectional relationship between migraine and depression, and a shared pathophysiological mechanism has been recently outlined (Karsan \& Goadsby, 2021). Indeed, in cohort studies, the risk of incident migraine in persons with existing major depression was threefold higher than in persons without depression, and incident major depression in persons with pre- existing migraine was more than fivefold higher than in persons without migraine history (Modgill et al., 2011). Comorbid anxiety/depression increases the risk of migraine chronification (Guidetti et al., 1998; Tietjen et al., 2007). However, there is no evidence that treating depression or anxiety mitigates migraine (Ferrari et al., 2022). Other psychological factors have been linked to migraine over time, as the case of alexithymia (Galli et al., 2017, Bottiroli et al., 2018), traumatic events (Bottiroli et al., 2019; Stensland et al., 2013), early episodes of maltreatment (Tietjen et al., 2016), personality characteristics (Bottiroli et al., 2016; 2021; Galli et al., 2019).

FIBROMYALGIA (FM) FM is a chronic syndrome characterized by widespread musculoskeletal pain associated with fatigue, nonrestorative sleep, and cognitive deficits (Wolfe et al., 2016) with high incidence among women (Branco et al., 2010). The prevalence of CP comorbidities among FM patients was also high ranging from 39% to 76% (with headache and irritable bowel syndrome that were the most prevalent). Although a central sensitization phenomenon seems to play a central role in FM (Arnold et al., 2016), the etiopathology of FM remains unknown (Thieme et al., 2017). For these reasons, researchers have proposed a biopsychosocial model of interacting variables that can activate and exacerbate FM symptoms (Sommer et al., 2012). FM patients experience excessive levels of psychological distress: 20-80% experience anxiety and 13-64% experience depression (Galvez-Sánchez et al., 2019). A recent systematic review on comorbidities in FM (Kleykamp et al., 2021) found that the most prevalent comorbidity across all studies reviewed was depression/major depressive disorder with over half of the patients included having this diagnosis in their lifetime. Another interesting personality construct involved in FM is 'distressed' personality (van Middendorp et al., 2016). Moreover, nearly one-third of FM patients had current or lifetime bipolar disorder, panic disorder, or post-traumatic stress disorder. Specifically, among environmental factors, stressful life events have been considered (Nakamura et al., 2014). Trauma and major life stress are unlikely to cause FM per se. In genetically susceptible persons, it is likely that early trauma and prolonged stress in adulthood will influence brain modulatory circuitry of both pain and emotions (Crofford, 2007; Schweinhardt et al., 2008) that could explain the increased pain responses and symptoms of patients with FM. Traumatic events have been shown to influence pain severity as well (Bote et al., 2013). Several theoretical models have suggested that some personality characteristics lead to a worse response to stressors and adjustment to diseases in people with CP, such as FM (Naylor et al., 2017; Galvez-Sánchez et al., 2019). A minority of studies have focused on the detection of personality disorders associated with FM (Attademo \& Bernardini, 2018). In general, previous studies found a high prevalence of avoidance (41.4%), obsessive-compulsive (33.1%) and borderline personality disorder (5.2-27.4%) in FM (Thieme et al., 2004; Uguz et al., 2010; Gumà-Uriel et al., 2016). In recent years, many studies on FM have reported a high prevalence of alexithymia (15-20%) (Di Tella et al., 2017; Marchi et al., 2019; Atzeni et al., 2019).

VULVODYNIA Vulvodynia is a condition that occurs in 8-10% of women of all ages (Arnold et al., 2007; Harlow et al., 2014) and is characterized by localized pain in the vulva, either spontaneous or upon touch, and can occur during sexual and/or non-sexual situations (Bergeron et al., 2020). Vulvodynia has a negative effect on the quality of life of women and their partners and imposes a profound personal and social economic burden. The diagnosis is established through a careful history and pelvic examination, including the cotton swab test, based on persistent vulvar pain lasting more than 3 months without an identifiable cause and with several potential associated factors. These include musculoskeletal and neurological factors, comorbid pain syndromes (such as fibromyalgia, chronic migraine, and irritable bowel syndrome) and psychosocial factors (Reed et al., 2012; Wesselmann et al., 2014; Bergeron et al., 2020). Current literature suggests that the onset and maintenance of vulvodynia likely involves a complex interplay of peripheral and central pain mechanisms, pelvic floor muscle and autonomic dysfunction, anxiety, depression, and adverse childhood events, as well as cognitive-affective, behavioral, and interpersonal factors (Bergeron et al., 2020). Vulvodynia has traditionally been conceptualized in a dualistic manner, arising from either physical factors or psychological and sexual difficulties, although research contrary to this concept and other hypotheses suggest that these two perspectives should be combined. Therefore, future studies should move in this direction, seeking to identify specific pathophysiological mechanisms within the framework of a biopsychosocial model. Indeed, a more recent theorization has focused on an integrated model that considers the interdependence of biopsychosocial factors in vulvodynia and associated disorders, in which medical and psychosocial mechanisms are considered to contribute to the onset, chronicization and exacerbation of pain and associated difficulties (Bergeron et al., 2011). The neurophysiology of vulvodynia is multifaceted. It is characterized by both peripheral and central sensory abnormalities (Wesselmann et al., 2014; Pukall et al., 2016). Furthermore, increased sensitivity to different sensory modalities at extragenital sites has been demonstrated in women with vulvodynia (Giesecke et al., 2004; Foster et al., 2005; Sutton et al., 2015), suggesting central sensitization. This central sensitization could explain the observation of overlapping chronic pain conditions in women with vulvodynia, which need further investigation to be better understood.

PSYCHOLOGICAL FACTORS ASSOCIATED TO NP As the investigators have already pointed out separately for the three pathological conditions (chronic migraine, fibromyalgia, and vulvodynia), there is evidence that factors such as personality traits, defense mechanisms, central sensitization, and childhood traumatic experiences may contribute significantly to the genesis of these disorders through a process of central sensitization of pain pathways. Central sensitization (CS) is defined as increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input according to the IASP - International Association for the Study of Pain (Arendt-Nielsen et al., 2018). A sensitized nervous system has been considered one of the most important mechanisms involved in NP (Cohen, 2022). CS plays a role in fibromyalgia, in which alteration of central nociceptive processing occurs and pain can be worsened by psychological factors (Sluka \& Clauw, 2016). In migraine, CS may contribute to acute allodynia and headache chronification (De Tommaso \& Sciruicchio, 2016). Furthermore, in migraine CS may play a role in trigeminal nerve activation and cortical spreading depression (De Tommaso \& Sciruicchio, 2016). It has been suggested that migraine may be considered as a brain state of altered excitability and a disorder of sensory processing (Goadsby et al., 2017), encompassing additional symptoms as fatigue and mood disorders (Karsan \& Goadsby, 2021). Structural and functional MRI studies in women with provoked vulvar or distant/extra- genital pain have supported a role of central sensitization and dysregulation of endogenous pain modulatory systems in the central nervous system in the pathophysiology of vulvodynia (Bergeron et al., 2020).

In the process of central sensitization, psychological factors such as traumatic events in childhood, the development of specific personality expressions (traits), and the use of different forms of defense mechanisms also play a role. No study to our knowledge has yet tried to identify specific clusters of psychological factors (personality traits, defense mechanisms, central sensitization, and childhood traumatic experiences) capable of characterizing or differentiating between the different pathologies expressed by a NP.

In addition to this, the study of psychosocial factors associated with the experience of such pathologies or possible emerging clusters such as depression, anxiety, somatization, quality of life, alexithymia, social support, sexual satisfaction, and functioning. This will make it possible to identify specifically for each condition the areas of greatest interest that can be investigated and treated in clinical intervention tailored to the person.

Aims To highlight possible psychosocial clusters of variables that are specific to the onset and maintenance for each condition (FM, CM, and VU). Specifically, the observation of possible clusters will be made based on variables such as personality traits, defense mechanisms, central sensitization, and childhood traumatic experiences. The hypothesis is that specific psychological factors (clusters of high number of early traumatic events, high levels of central sensitization, and specific traits and defense mechanisms) characterize FM, CM, and VU groups compared to controls.