Psychological Layers of Nociplastic Pain: Cluster Analysis of The Role of Personality Traits, Defence Mechanisms, Central Sensitization, and Childhood Traumatic Experiences in Patients With Chronic Migraine, Fibromyalgia, and Vulvodynia
Conditions: Fibromyalgia, Chronic Migraine, Headache, Vulvodynia
Sponsor: University of Roma La Sapienza

Protocollo Versione 1.0 del 26.10.2022 
PROTOCOLLO PSYCHOFIBRO  
Title 
Psychological layers of Nociplastic Pain: cluster analysis of the role of personality traits, defence 
mechanisms, central sensitization, and childhood traumatic experiences in patients with chronic migraine, 
fibromyalgia, and vulvodynia. 
 
Abstract 
Chronic pain (CP) is a substantial healthcare challenge with considerable economic costs. Recently, the 
term of Nociplastic Pain (NP) has been advanced as a third descriptor of mechanisms related to CP. NP 
describes conditions that arise from altered nociception despite no clear evidence of actual or threatened 
tissue damage. It is a new way of describing somatoform painful conditions, originating from altered 
central-nervous pathways (e.g., central sensitization) and with the important involvement of clinical 
psychological factors. Among nociplastic chronic syndromes have been included fibromyalgia (FM), chronic 
migraine (CM) and vulvodynia (VU). These chronic pain disorders have been usually studied separately, 
although the high comorbidity rates. Many studies evidenced the role of psychosocial variables in the onset 
and maintenance of the burden related to these conditions. Among them, personality traits, defense 
mechanisms, central sensitization, and childhood traumatic experiences may play a pivotal role in the onset 
of the NP. The first aim of this study is to highlight possible psychosocial clusters of variables that are 
specific for each condition (FM, CM, and VU). A second aim, to improve the tailored psychological 
treatment devoted to these conditions, is to explore the association between FM, CM, and VU with 
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. To identify specific descriptors, NP 
conditions will be compared with a control group of subjects reporting other types of CP (e.g., knee 
arthrosis, rheumatoid arthritis). The study involves the collection of data from a self-administered 
questionnaire in several Italian centers specializing in the above-mentioned clinical conditions under the 
guidance of the research team of the Department of Dynamic and Clinical Psychology and Health Studies, PI 
Professor Federica Galli. 
 
Rational 
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). A systematic review reported a 
pooled CP prevalence rate of 43.5%, with the rate of moderate-to-severe disabling pain ranging from 10% 
to 14% (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 
terminology 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 

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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 

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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 and 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., 

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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 we 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 
The first aim of this study is 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 reporting other types 
of CP (e.g., knee arthrosis, rheumatoid arthritis). 
A second aim, to give directions for tailored psychological treatments devoted to these conditions, is to 
explore the association between FM, CM, and VU with depression, anxiety, somatization, quality of life, 
alexithymia, social support, sexual satisfaction, and functioning. In line with our hypothesis that each of 

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these conditions has specific areas of psychological sensitivity, 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. 
 
Methods 
Participants 
The study involves the collection of data from a self-administered questionnaire in several Italian centers 
specializing in the above-mentioned clinical conditions under the guidance of the research team of the 
Department of Dynamic and Clinical Psychology and Health Studies, PI Professor Federica Galli.  
The four centers involved in the recruitment of the participants will be the Università di Milano IRCCS 
Sant’Ambrogio Galeazzi under the haed of Prof. Sarzi-Puttini and Dott. Valeria Giorgi, the IRCCS Mondino di 
Pavia under the head of Prof. Cristina Tassorelli and Prof. Sara Bottiroli, The Policlino San Matteo of 
Paviaunder the head of Prof. Rossella Nappi and Dott. Lara Tiranini, and the Policlinico Umberto I of 
Sapienza University of Rome under the head of Dott. Cristina Iannuccelli. 
Questionaires will be accessible online through a web survey available on the Google.forms platform. 
Participants will provide an informed consent before accessing the survey, and the questionnaire will be 
anonymous with no remuneration provided. The institutional ethics committee of the Dept. of Dynamic, 
Clinical and Health Psychology, Sapienza University of Rome, Italy (protocol code 0001979) approved the 
study on 25th November 2022 [UOR: SI000092 - Classif. VII/15]. 
Inclusion criteria: 
- age range 18-65 years 
- education > 5 years 
- diagnosis of FM according to Wolfe, 2016  
- diagnosis of CM according to Olesen, 2017 
- diagnosis of VU according to Bornstein et al., 2016 
 
Exclusion criteria 
- severe psychiatric disorders and/or cognitive impairment 
- difficulties in comprehension/expression in Italian 
- history of other chronic pain disorder(s)  
- history of other neurological disorders besides migraine  
 
MEASURES 
The study involves the administration of a protocol of self-report questionnaires consisting of two parts: 
the main (about 25 minutes for the administration) and the optional one (additional 20 minutes). This 
decision stems from the realization of the length of the protocol, to increase the collection of data in 
pursuit of the main objective of the study (cluster analysis). 

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Self-report questionnaires 
Main questionnares (all the participants are requested to complete them) 
- Highly Sensitive Person Scale (HSP-12) (Aron & Aron, 1997; Lionetti et al., 2018): this questionnaire 
investigates the theoretical framework of Sensory Processing Sensitivity, referring to a temperamental trait 
that predisposes to a broader sensory processing of information captured by a variety of indicators, rather 
than simple sensitivity to sensory stimuli. The questionnaire reports a total sensitivity score and 3 sub-
factors (Easy of Excitation (EOE), Aesthetic Sensitivity (AES) and Low Sensory Threshold (LST)). 
- Central Sensitivity Inventory (CSI) (Chiarotto et al., 2018): The Central Sensitisation Inventory was 
developed to assess the overlapping symptomatic dimensions of the central sensitivity syndrome.  This 
measure is intended as a screening tool to help identify the presence of the syndrome and to alert clinicians 
that presenting symptoms may be related to it. It consists of two parts: part A provides a 0-100 total score 
for 25 items on current health symptoms with five response options ranging from 'never' (0) to 'always' (4); 
part B investigates if patients were previously diagnosed by a physician with one or more of seven different 
conditions. 
- Traumatic Experiences Checklist (TEC) (Nijenhuis et al., 2002): the instrument investigates 29 types of 
potential trauma, including the events listed in criterion A of PTSD, as well as other potentially 
overwhelming events: loss of significant others, life-threatening illness or aggression, experience of 
warehousing, emotional neglect, emotional abuse, physical abuse, sexual harassment and sexual trauma. 
The questionnaire includes a total complex trauma score and 5 subscales investigating emotional neglect, 
emotional abuse, physical threat, sexual harassment, and sexual abuse. 
- PID-5 Short form (Thimm et al., 2016): This instrument represents the short version of the PID-5 self-
report inventory designed to assess the 25 facets of pathological personality traits and the five higher-order 
domains of DSM-5 Criterion B. It assesses 5 personality trait domains including negative affect, 
detachment, antagonism, disinhibition, and psychoticism, with each trait domain consisting of 5 items. 
- Defense Mechanism Rating Scales - DMRS-SR-30 (Di Giuseppe et al., 2020); is an instrument based on the 
identification of 30 individual defenses arranged hierarchically in 7 levels according to similarity of function 
and level of adaptability. The DMRS provides a definition of each defense mechanism, a description of its 
intrapsychic function and criteria for discriminating one defense from its neighboring defenses. Defense 
levels can be categorized as mature and immature neurotic, and the latter is further subdivided into 
depressive and non-depressive. 
- Mental Pain Questionnaire (Svicher et al., 2019): is a 10-item true-false style self-report questionnaire 
developed to assess mental pain. 
 
Optional questionnaires (the participant decides whether to complete them) 
- Brief Symptom Inventory (BSI-18) (Franke et al., 2017): an abbreviated version of Derogatis' Brief 
Symptom Inventory, contains the three six-item scales of Somatization, Depression, Anxiety and the Global 
Symptom Score (GSI). 
- SF-12 - Quality of Life Assessment (Apolone et al., 2001): The SF-12 is a generic short-form health survey 
developed in the United States from the original SF-36. It produces two summary measures for the 
assessment of self-perceived physical and mental health that are interchangeable with those of the SF-36. 

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- Toronto Alexithymia Scale (TAS-20) (Bagby et al., 1994): The Toronto Alexithymia Scale is a 20-item self-
administered questionnaire that measures difficulty in identifying and describing emotions, which is an 
important part of alexithymia. 
- Chronic Pain acceptance Questionnaire (CPAQ-8) (Fish et al., 2010): is an 8-item inventory measuring the 
acceptance of chronic pain. 
- SPQ - Social Support Questionnaire (SPQ) (van der Lugt et al., 2012): is a short measure of perceived social 
support in relation to pain. 
- Sexual Satisfaction Scale (SSS) - Short form) (Meston & Trapnell, 2005): represents a short 6-item measure 
of sexual satisfaction and discomfort. 
- Short Form McGill Questionnaire (SF-MGQ) - Adapted for genito-pelvic pain (Melzack & Raja, 2005). 
Represents a qualitative and quantitative measure of pain, adapted to the genito-pelvic area. 
- Female Sexual Function Index (FSFI) (optional) and International Index of Erectile Function (IIEF) (optional) 
(Rosen et al., 1997; 2000): represents a differentiated questionnaire for females and males on sexual 
function (desire, arousal and orgasm and satisfaction). 
 
STATYSTICAL PLANNED ANALYSES  
The required sample size was estimated a priori for the ANOVA procedure that tested the cluster model 
sensitivity having 4 groups (migraine, fibromyalgia, vulvodynia, and controls). Using the G*power program, 
p= 0.05, statistical power of 85%, and effect size of 0.35, the calculation yielded a total sample size of n = 
108 participants per group (432 as total) The four centers involved in the recruitment of the participants 
will be the Università di Milano IRCCS Sant’Ambrogio Galeazzi under the haed of Prof. Sarzi-Puttini and 
Dott. Valeria Giorgi, the IRCCS Mondino di Pavia under the head of Prof. Cristina Tassorelli and Prof. Sara 
Bottiroli, The Policlino San Matteo of Paviaunder the head of Prof. Rossella Nappi and Dott. Lara Tiranini, 
and the Policlinico Umberto I of Sapienza University of Rome under the head of Dott. Cristina Iannuccelli. 
ANOVAs and chi2 analyses will be carried out to compare groups on sociodemographic characteristics for 
descriptive reasons and to select possible covariates based on selection bias. 
A group of cluster analyses will be performed to classify the samples based on personality traits, defense 
mechanisms, central sensitization, and childhood traumatic experiences (twenty-two variables 
corresponding to total scores and thematic subscales of the related measures), aiming to identify different 
clinical phenotypes within the study samples. A statistical procedure of Two-Step Cluster Analysis will be 
preferred due to its ability to ensure that one variable does not dominate the cluster solution. 
Furthermore, it enables the user to identify the importance of each item in the cluster solution. The model 
fit will be assessed by Schwarz’s Bayesian Information Criterion and evaluated by the average silhouette 
coefficient, an internal validity index representing cluster cohesion and separation quality, ranging between 
0 and 1; the closer to 1, the better the model. 
Crosstab analyses will be performed to test the association and their strength, and MANOVAs to detect 
differences in the classification variables based on cluster groups, and Pearson’s correlation to explore 
associations among clusters and other psychological domains. The statistical analyses will be performed 
using IBM SPSS v. 27.0 and AMOS v.22 (SPSS Inc., Chicago, IL, USA). 
 
 
 

Protocollo Versione 1.0 del 26.10.2022 
 
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