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Adult Attention Deficit Hyperactivity Disorder in Patients with Fibromyalgia Syndrome: Assessment and Disabilities

In the broader list of cognitive concerns, neuropsychological testing has shown that attentional impairment may have a specific burden in Fibromyalgia Syndrome (FMS).
Preliminary observations have reported a subset of FMS patient screened for attention disorders fulfilling the actual diagnosis of ADHD, a neurodevelopmental disorder characterized by
developmentally inadequate levels of inattention, hyperactivity and impulsivity that might persist in adulthood. Yet, no study to date has systematically examined the history and the specific
contribution of ADHD to FMS in terms of clinical impact and related specific disabilities.
In this study, 106 individuals with a FMS diagnosis based on the 2010 criteria of the American College of Rheumatology have been assessed for (a) the presence of ADHD; (b) the burden of
disability caused by ADHD versus FMS; (c) the presence of other psychiatric disorders. Results indicated that ADHD was present in 24.5% of FMS individuals, it was associated with higher FMS symptoms severity and a greater functional impairment, particularly in the work/school domain.
Moreover, patients with both FMS and ADHD had higher frequency of substance use disorders than those with FMS only (38.5% versus 3.8%) and mainly opioids. Overall, results suggest that ADHD can increase burden adding specific disability in work and social activities, and it is associated with
a trend for the excessive use of opioid painkillers. Detection of neurodevelopmental and actual symptoms of ADHD is highly recommended especially in patient prone to increase the dose of antipain medication.

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Adult Attention Deficit Hyperactivity Disorder in Patients with Fibromyalgia Syndrome: Assessment and Disabilities

  1. 1. Journal Pre-proof Adult Attention Deficit Hyperactivity Disorder in Patients with Fibromyalgia Syndrome: Assessment and Disabilities Pallanti Stefano, Porta Francesco, Salerno Luana PII: S0022-3956(20)31030-X DOI: https://doi.org/10.1016/j.jpsychires.2020.10.027 Reference: PIAT 4104 To appear in: Journal of Psychiatric Research Received Date: 18 June 2020 Revised Date: 18 October 2020 Accepted Date: 21 October 2020 Please cite this article as: Stefano P, Francesco P, Luana S, Adult Attention Deficit Hyperactivity Disorder in Patients with Fibromyalgia Syndrome: Assessment and Disabilities Journal of Psychiatric Research, https://doi.org/10.1016/j.jpsychires.2020.10.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Ltd. All rights reserved.
  2. 2. Adult Attention Deficit Hyperactivity Disorder in Patients with Fibromyalgia Syndrome: Assessment and Disabilities Pallanti Stefanoa,b Porta Francescoa,c Salerno Luanaa a INS, Istituto di Neuroscienze, Florence (Italy) b Albert Einstein College of Medicine (New York), Department of Psychiatry and Behavioral Sciences c MedCare, Pistoia (Italy) JournalPre-proof
  3. 3. Abstract In the broader list of cognitive concerns, neuropsychological testing has shown that attentional impairment may have a specific burden in Fibromyalgia Syndrome (FMS). Preliminary observations have reported a subset of FMS patient screened for attention disorders fulfilling the actual diagnosis of ADHD, a neurodevelopmental disorder characterized by developmentally inadequate levels of inattention, hyperactivity and impulsivity that might persist in adulthood. Yet, no study to date has systematically examined the history and the specific contribution of ADHD to FMS in terms of clinical impact and related specific disabilities. In this study, 106 individuals with a FMS diagnosis based on the 2010 criteria of the American College of Rheumatology have been assessed for (a) the presence of ADHD; (b) the burden of disability caused by ADHD versus FMS; (c) the presence of other psychiatric disorders. Results indicated that ADHD was present in 24.5% of FMS individuals, it was associated with higher FMS symptoms severity and a greater functional impairment, particularly in the work/school domain. Moreover, patients with both FMS and ADHD had higher frequency of substance use disorders than those with FMS only (38.5% versus 3.8%) and mainly opioids. Overall, results suggest that ADHD can increase burden adding specific disability in work and social activities, and it is associated with a trend for the excessive use of opioid painkillers. Detection of neurodevelopmental and actual symptoms of ADHD is highly recommended especially in patient prone to increase the dose of anti- pain medication. Words count: 239 Keywords FMS ADHD Burden of Disability Opiate Misuse JournalPre-proof
  4. 4. Adult Attention Deficit Hyperactivity Disorder in Patients with Fibromyalgia Syndrome: Assessment and Disabilities Pallanti Stefanoa,b Porta Francescoa,c Salerno Luanaa a INS, Istituto di Neuroscienze, Florence (Italy) b Albert Einstein College of Medicine (New York), Department of Psychiatry and Behavioral Sciences c MedCare, Pistoia (Italy) Corresponding author: Salerno Luana, salerno.luana@gmail.com Highlights • 24.5% of individuals with FMS also have ADHD • Impairment due to ADHD brings increased total functional and even specific disability • ADHD is associated with increased use of opiate and sedative drugs Abstract In the broader list of cognitive concerns, neuropsychological testing has shown that attentional impairment may have a specific burden in Fibromyalgia Syndrome (FMS). Preliminary observations have reported a subset of FMS patient screened for attention disorders fulfilling the actual diagnosis of ADHD, a neurodevelopmental disorder characterized by developmentally inadequate levels of inattention, hyperactivity and impulsivity that might persist in adulthood. Yet, no study to date has systematically examined the history and the specific contribution of ADHD to FMS in terms of clinical impact and related specific disabilities. In this study, 106 individuals with a FMS diagnosis based on the 2010 criteria of the American College of Rheumatology have been assessed for (a) the presence of ADHD; (b) the burden of disability caused by ADHD versus FMS; (c) the presence of other psychiatric disorders. Results indicated that ADHD was present in 24.5% of FMS individuals, it was associated with higher FMS symptoms severity and a greater functional impairment, particularly in the work/school domain. Moreover, patients with both FMS and ADHD had higher frequency of substance use disorders than those with FMS only (38.5% versus 3.8%) and mainly opioids. Overall, results suggest that ADHD can increase burden adding specific disability in work and social activities, and it is associated with a trend for the excessive use of opioid painkillers. Detection of neurodevelopmental and actual symptoms of ADHD is highly recommended especially in patient prone to increase the dose of anti- pain medication. Words count: 239 Keywords FMS ADHD Burden of Disability Opiate Misuse JournalPre-proof
  5. 5. 1. Introduction In the diagnostic process of the fibromyalgia syndrome (FMS) the detection of some cognitive symptoms is part of the diagnostic assessment. However, despite a substantial proportion of patients with FMS complains of a cognitive dysfunction such forgetfulness, inattention as well as declines in cognitive function, working memory, and mental alertness-symptoms that have been termed "fibrofog", those studies aiming to characterize the neuropsychological functioning of adults with FMS reported some interesting but not conclusive results (Walteros et al 2011; Walitt et al 2011; Park et al 2001; Grace et al 1999; Lee et al 2010; Landro et al 1997; Kim et al 2012; Walitt et 2008; Suhr 2003; Miro et a 2011; Kratz et al 2019). Attention Deficit /Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inadequate levels of inattention, hyperactivity and impulsivity affecting the 2.8% of adult population (Fayyad et al 2017), and there is growing evidence suggesting a high frequency of symptoms of ADHD in people with FMS. Indeed, Reyero and colleagues (2011) found childhood ADHD in 32.3% of women with FMS compared to the 2.52% of healthy controls, according to the scores obtained at the WURS, whereas Derksen and colleagues (2015) found that 25% of their patients with FMS fulfilled the DSM-5 Criteria for adult ADHD at the time of the (unspecified) interview performed by a trained psychiatrist. More recently, Yilmaz & Tamam (2018) reported that 29.5% of their female patients with FMS fulfilled the DSM criteria for the presence of ADHD compared to 7.4% of controls, based on the scores obtained on rating scales, with significantly different ratios in childhood and adolescent attention-hyperactivity disorder in these groups (33.3% versus 11.1%, respectively). Overall, up to date evidence shows that both adult and childhood ADHD are quite common in female fibromyalgia patients. However, despite these undoubtedly interesting findings, it should be considered that in the studies reported so far the diagnosis of ADHD has been made on the criteria but without a specific diagnostic interview for adult ADHD that has been highly recommended (Pettersson et al 2016), especially considering the overlapping symptomatology of the two condition. Moreover, there are not studies that have examined if the presence of comorbid ADHD in FMS may eventually lead to an additional burden of disability or not. Hence, the question is still open: are attentional problems in FMS a true comorbidity with its own related disabilities or can we consider them as just overlapping phenomena? Therefore, in this study we aimed to examine if: 1. the co-occurrence of ADHD and FMS is a real comorbidity, using the “gold standard” diagnostic interview for the retrospective and current assessment of ADHD symptoms in adults, 2. it is possible to differentiate the burden of disability associated with each disorder, 3. the presence of ADHD is associated with a different pattern of psychiatric comorbidities. 2. Material and methods 2.1 Study design and participants The study included 106 patients with FMS consecutively diagnosed by a reumatologist (FP) and a specialist in psychiatry and neurophysiology (SP) at the Istituto di Neuroscienze (INS), Florence JournalPre-proof
  6. 6. (Italy), between June 2017 and January 2020, and subsequently evaluated by other members of the multidisciplinary team, i.e. an internist, a neurologist and a psychologist (LS). For what concerns exclusion criteria, people whose education level was not sufficient to complete the clinical interview and the rating scales included in this study were excluded, as well as those with intellectual disability, schizophrenia, and other psychotic disorders. Subjects for whom a collateral informant was not available to participate in the diagnostic interview were also excluded. Based on these exclusion criteria, 8 patients have been excluded from the original sample of 114 subjects. Our local Human Ethics Committees approved the research protocol, the investigation was performed in accordance with the principles of the Declaration of Helsinki, and all patients gave their written informed consent after the nature of the study and the procedures had been explained. 2.2 Diagnosis of fibromyalgia The diagnosis of fibromyalgia was made on the basis of the 2010 criteria of the American College of Rheumatology (ACR) (Wolfe et al 2010), which requires the administration of the Widespread pain index (WPI) investigating the areas in which the patient had pain over the past weeks (score 0- 19) and the Symptom severity score (SS), which is divided into two parts. In the first one, fatigue, waking unrefreshed and cognitive symptoms are evaluated on a severity scale ranging from 0 (no problem) to 3 (severe). The second part requires physicians to evaluate the presence of a set of symptoms that the patient experienced over the past week. The score of this part depends on the number of experienced symptoms and must be added to the score of part 1 to determine the symptom severity score. The only cognitive symptoms included in this second part are numbness, thinking or memory problem. According to these criteria, a patient meets diagnostic criteria for fibromyalgia if he/she presents: 1. widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3-6 and SS scale score ≥ 9; 2. symptoms that have been present at a similar level for at least three months, and 3. a pain that cannot be explained by another disorder. In our sample, the presence of a somatic disease sufficiently explaining the symptoms has been excluded (Fitzcharles et al 2013). For a clinical evaluation of the spectrum of FMS problems affecting the last seven days, the Fibromyalgia Impact Questionnaire Revised version (FIQR, Bennett et al 2009, Salaffi et al 2013), a self-administered questionnaire composed by 21 items (all based on an 11-point numeric rating scale of 0–10) covering the three domains of function, overall impact, and FMS symptoms has been used. The FIQR total score is the sum of the three domain scores: the summed score for the 9-item function domain (range 0–90) is divided by three; the summed score for the 2-item overall impact domain (range 0–20) remains as it is; and the summed score for the 10-item symptom domain (range 0–100) is divided by two (Salaffi et al 2013). The total maximum score is 100, with higher scores indicating greater disease impact. The Fibromyalgia Assessment Status (FAS, Salaffi et al 2009) has been instead administered to quantify the patient’s fatigue, sleep disturbances and pain. The pain is evaluated on the basis of the 16 non-articular sites included in the Self-Assessment Pain Scale (SAPS) (range 0 to 10) (Salaffi et al 2009), and the FAS total score is calculated by summing the three subscores (non-articular pain, fatigue and sleep) and dividing the result by three (range 0–10). JournalPre-proof
  7. 7. 2.3 Diagnosis of ADHD The assessment of ADHD in adults requires the investigation of the presence of core symptoms of ADHD in both childhood and adulthood, and the assessment of how these symptoms interfere with the subject’s functioning in more than one domain of daily life. In consideration of the complex developmental presentation of ADHD, which can change its presentation during the lifetime, a clinical interview such as the Diagnostic Interview for ADHD in Adults (DIVA) (Kooij 2010) has been considered the “gold standard” for its detection (Pettersson et al 2016). The DIVA 2.0 (Kooij 2010) has been developed on the basis of the criteria of the DSM-IV-TR, has been validated by two studies (Petterson et al 2016; Ramos-Quiroga et al 2016), and recently adapted to the new criteria for ADHD included in DSM-5 (APA, 2013; Kooij 2019b). According to DSM-5, the number of symptoms required for a diagnosis of ADHD (from either the inattention criteria or the hyperactivity/impulsivity criteria, or both) has been lowered from 6 to 5, and the age of onset criteria requiring that symptoms should be present by age 7 years has been changed to symptoms present by age 12 years. It includes both the childhood and adulthood DSM symptoms list for ADHD, and provides examples of impairments that are commonly associated with the symptoms in 5 areas of everyday life for each age group: work and education; relationships and family life; social contacts; free time and hobby; self-confidence and self-image. The ADHD diagnosis was made if the symptoms could not be better explained by the presence of another psychiatric disorder. In our sample, the DIVA was completed with the patient in the presence of the partner and/or a family member, to allow retrospective and collateral information to be ascertained at the same time. 2.4 The diagnosis of disability associated with FMS or ADHD in patients with ADHD In those patients who met the diagnostic criteria for adult ADHD, we investigated the functional impairment associated with FMS and ADHD by using the Sheehan Disability Scale (SDS, Sheehan et al., 1996), which allows the evaluation of disability in three domains, i.e. work/school, social life/leisure activities and family life/home responsibilities. Each domain is scored from 0 (not at all) to 10 (very severely), and by summarizing the scores obtained by each domains it is possible to obtain the global SDS score, which ranges from 0 (unimpaired) to 30 (highly impaired) (Sheehan et al., 1996). 2.5 The diagnosis of psychiatric comorbidities The Clinician Version (CV) of Structured Clinical Interview for DSM-5 (SCID-5-CV) has been used to assess the presence of other psychiatric disorders. It has been released in 2014, consists of 10 modules covering 39 of the most common diagnoses of psychiatric conditions and permits to screen for additional 16 diagnoses (First et al 2015). The SCID-5-CV assesses the presence of some disorders (such as substance use disorders and obsessive-compulsive disorder) only as a current diagnosis, while others as lifetime disorders (such as bipolar disorder and major depressive disorder, among others). Since pain is the most prevalent symptom in fibromyalgia, treatments directed toward pain relief includes analgesics, nonsteroidal anti-inflammatory drugs, and opioids (Fitzcharles et al 2011). We considered the presence of an opioid use disorder in patients with FMS when they reported “aberrant drug-related behaviors” according to the Portenoy’s list (1996), and if the patient admitted to accessing opioids by aberrant means. JournalPre-proof
  8. 8. 2.6 Statistical analysis Data were analyzed using the program IBM SPSS Statistics 23. Sex and comorbid psychiatric disorders have been presented as a percentage, whereas scores obtained at rating scales have been presented as medians. Analyses used for comparing FMS subjects with or without ADHD included Mann-Whitney U test for independent samples. For what concerns the analysis of differences in Sheehan Disability Scale (SDS) scores, an exact sign test has been used since the differences between paired observations were neither normal nor symmetrical. To compare comorbidity between groups the Fisher’s exact test was used. Statistical significance was set up at p<0.05, two- tailed. 3. Results Our sample of adults with FMS was composed by 11 males and 95 females. Age, sex, and years of education of the whole group of adults with FMS and divided according to the presence or not of ADHD have been reported in Table 1. In this sample, 26 subjects with FMS had ADHD (24.5%) and they were all females. Regarding the adult clinical presentation, 18 (69.2%) patients had combined ADHD, whereas 8 (30.8%) had predominantly inattentive ADHD. For what concerns childhood ADHD, 16 (61.5%) had the combined, and 10 (38.5%) had the predominantly inattentive presentation. In both cases, none had a predominantly hyperactive-impulsive presentation of ADHD. There was a statistically significant difference in age between patients with both ADHD and FMS compared to those with FMS only (p<.0001), but not in years of education, ranging from 8 to 18 years. As shown in Table 2, subjects with both ADHD and FMS had higher FIQR and FAS scores compared to those with FMS only (p<.05). Table 1. Demographic characteristics of the sample CHARACTERISTIC FMS (n=106) FMS only (n=80) FMS +ADHD (n=26) p Age, mean (SD), years 41.70 (±8.18) 39,76 (±7.09) 47.65 (±8.56) p<.0001 Sex, No. (%) Male 11 (10.4%) 11 (13.8%) - Female 95 (89.6%) 69 (86.3%) 26 (100%) Education (years) 11.83 (±2.52) 11.59 (±2.41) 12.58 (±2.74) p =.117 JournalPre-proof
  9. 9. Figure 1. ADHD clinical presentation in childhood and adulthood Table 2. Differences in Fibromyalgia Impact Questionnaire Revised version (FIQR) and Fibromyalgia Assessment Status (FAS) scores between groups Rating Scales FMS (N=106) FMS only (n=80) FMS+ADHD (n=26) p* FIQR Median Median Median Function sub-total 15.3 15.3 18.0 p=.008 Overall impact sub-total 10.0 10,0 10.5 p=.027 Symptoms sub-total 25.0 24.0 27.75 p<.0001 Total score 50,0 49,1 56.10 p<.0001 FAS Total score 5.7 5.6 6.5 p<.0001 FIQR= Fibromyalgia Impact Questionnaire Revised FAS= Fibromyalgia Assessment Status *statistically significant based on Mann-Whitney U Test In those subjects who met criteria for adult ADHD, we investigated the distinct effect of ADHD and FMS on perceived disability, as measured by the SDS. As not all data were normally nor symmetrically distributed, we used an exact sign test. There was a statistically median increase in disability ADHD-related in SDS work/school and total scores compared to FSM. Specifically, of the 26 patients with both ADHD and FMS 25 had “positive differences”, meaning that they had greater disability in the work/school domain associated with ADHD. Indeed, medians at SDS work/school domain were 7 for disability FMS-related versus 10 for disability ADHD-related (p<.0001). Similarly, 19 patients out of 26 reported greater total disability, as measured by SDS total score, associated with ADHD. Indeed, median FMS-related SDS total score was 22 versus 24 of that ADHD-related (p=.001). For what concerns functional disability associated with FMS, 18 patients reported greater functional impairment in social life because of FMS. Indeed, median FMS- related SDS Social life domain score was 7.50 whereas median ADHD-related SDS Social life score was 6 (p=.011). Conversely, there was not a statistically significant difference between the two groups for what concerns impairment in family life, as median FMS-related SDS Family life score was 8.50 whereas ADHD-related was 8 (p=.064). JournalPre-proof
  10. 10. Table 3 shows the different pattern of lifetime comorbid disorders characterizing our sample of patients. According to Fisher’s Exact Test results, patients with FMS had a statistically significant higher rate of Anxiety disorders compared to those with both FSM and ADHD, whereas individuals with both FMS and ADHD have shown a statistically significant higher frequency of substance use disorders than those with FMS only. Specifically, only patients with ADHD presented current cannabis use and opioid use disorders, and a frequency two-fold higher of sedative, hypnotic or anxiolytic use disorder. The difference between the two groups regarding the proportion of opioid use and sedative, hypnotic or anxiolytic use disorders was statistically significant (p>.05). In those subjects with both ADHD and FMS who also had SUDs, the abused prescription drugs were tramadol (n=1), oxycodone/naloxone combination (n=2), and clonazepam (n=6). Table 3. The frequency of psychiatric diagnoses according to SCID-5-CV Primary psychiatric comorbid disorders FMS (n=106) FMS only (n=80) FMS +ADHD (n=26) p-values* Major Depressive Disorder 16 (15.1%) 13 (16.3%) 3 (11.5%) p=.076 Anxiety Disorders 33 (31.1%) 30 (37.5%) 3 (11.5%) p=.015 Bipolar Disorder 7 (6.6%) 6 (7.5%) 1 (3.8%) p=1.00 Substance Use Disorders 13 (12.3%) 3 (3.8%) 10 (38.5%) p=.000 - Cannabis Use - 1 (3.8%) p=.245 - Opioid Use - 3 (11.5%) p=.013 - Sedative, Hypnotic, or Anxiolytic Use - 3 (3.8%) 6 (23.1%) p=.006 Sleep Disorders 27 (25.5%) 21 (26.3%) 6 (23.1%) p=1.00 Eating Disorders 3 (2.8%) 2 (2.5%) 1 (3.8%) p=1.00 Obsess Compuls Disorders 5 (4.7%) 5 (6.3%) - p=.331 Gambling Disorder 2 (1.9%) - 2 (7.7%) p=0.58 SCID-5-CV: Clinician Version (CV) of Structured Clinical Interview for DSM-5 *Fisher’s Exact Test, p<.05, two-sided 4. Discussion Adult ADHD has been found in 24.5% of our sample of adults with FMS, a frequency that is more than 8 times greater than that of adult ADHD reported by epidemiological studies (Fayyad et al 2017). Such a frequency appeared in line with data reported by Derksen et al (2015), but lower than that by Yilmaz & Tamam (2018). We found a greater rate of combined presentation of ADHD in both childhood and adulthood, unlike from findings from Reyero et al. (2011), who found higher scores for the WURS items pertaining to attention deficit compared to those of hyperactivity- impulsivity in their clinical sample of women with ADHD. However, the WURS is a self- evaluation instrument, while this study is the first assessing the presence of ADHD in FMS patients using a validated DSM-criteria based clinical interview for the retrospective and current assessment of ADHD, administered in presence of collateral informants. Undoubtedly, this finding has great clinical implications, as cognitive difficulties, restlessness, and fatigue are symptoms characterizing both people with FMS and ADHD. Research showed that 70% of those with FMS complain a JournalPre-proof
  11. 11. cognitive dysfunction named “fibro-fog”, which includes concentration problems, memory difficulties and confusion (Kratz et al 2019). Therefore, FMS and ADHD are two apparently distant disorders having cognitive fog in common. However, even though those with FMS showed worse performance on standardized neuropsychological testing in comparison with controls, in the domains of attention, working memory and processing speed the between-groups differences resulted minor than a standard deviation (Kratz et al. 2019). On the other side, despite the well- known presence of some cognitive deficits in people with ADHD, neuropsychological testing has not proved useful in discriminating people with ADHD from those with other disorders (Kooij et al 2019a; Wasserman & Wasserman 2012). Indeed, approximately 11% of people affected do not have a measurable cognitive deficit (Geffen & Forster 2018). For all these reasons, only a specific full diagnostic interview can help clinicians to detect ADHD in people with FMS with an adequate accuracy. ADHD exerts a negative impact on several areas of functioning during the lifetime, and evidence shows that people affected are characterized by lower educational and occupational outcomes than those without the disorder (for a review see Kuriyan et al. 2013). Despite the amounting evidence of the co-presence of these two conditions, to date there was no study exploring the different impact on daily activities of ADHD and FMS in people with both disorders. According to our data, ADHD adversely affects daily activities/functioning with a greater intensity than FMS. This is particularly true for what concerns work/school activities, while FMS showed to exert a greater negative impact on social life compared to ADHD. For what concerns psychiatric comorbidities, it is noteworthy that, in our sample, while anxiety disorders were significantly more frequent among subjects with FMS only, those with ADHD were characterized by a higher frequency of substance use disorders, particularly sedative, hypnotic, or anxiolytic use disorder and opioid use disorder than those without ADHD. This was not unexpected, since the evidence from literature shows that adults with ADHD are twice as likely to suffer from a substance dependence than those without the disorder (Martinez-Raga et al. 2013) especially when not adequately treated (Zulauf et al. 2014). This finding may be of great value in the pharmacological management of the patient with FMS because ADHD may constitute a specific vulnerability factor for the excessive use of prescribed opioids and sedative medication. The dopaminergic system has a central role in the modulation of pain perception and in analgesia (Wood 2008; Reyero et al 2011), but it is also the target of most pharmacological agents for the treatment of ADHD. Evidence up to date indicates lower D2-receptor binding and presynaptic dopamine activity in people suffering from chronic pain (Taylor et al 2016), a disruption in dopaminergic neurotransmission in people with FMS (Wood et al 2007a,b), and a positive effect of drugs that enhance dopamine neurotransmission (Graven-Nielsen et al 2000; Holman & Myers 2005). This is line with previous research comparing 12 patients with FMS with 12 subjects suffering from pain due to other causes that found that patients with FMS who had higher past and present ADHD symptoms score experienced pain relief after taking ADHD medication (Krause et al 1998). Similar results have been reported by Young and Redmond (2007), and more recently by Katz and colleagues (2013), who found that a 30-day treatment of methylphenidate 10-60 mg daily improved concentration, mood, and energy in 48 patients with FMS. The existence of a dopaminergic dysfunction in FMS has received further support in the effectiveness of the dopamine JournalPre-proof
  12. 12. D2/D3 agonist pramipexole, in improving pain and other symptoms in people with FMS in a trial lasting 14-weeks (Holman et al 2004). The findings of this study have to be seen in light of some limitations. ADHD is a neurodevelopmental disorder with a childhood onset, and although 26 patients have met criteria for both childhood and adult ADHD according to the DIVA, none of them had received a formal diagnosis during the childhood. It may be the case that they may have received adequate external support from teacher and parents, or had supportive internal resources, such as a high IQ, in line with what it has been reported by the literature (Faraone & Biederman 2016; Franke et al 2018). Indeed, we have not found a statistically significant difference in years of education between patients with FMS only and those who received the “extra” diagnosis of ADHD. However, further studies could deepen this aspect, for example by administering an IQ test. The second issue requiring further exploration is that ADHD is known for being more prevalent in males but in our study all ADHD cases were female. This may be due to the fact the fibromyalgia is much more common in females than in males, and males were underrepresented in our study. Future research could address these limitations by using larger samples of population, in which there is a greater presence of males and gathering more information on the possible presence of supports in developmental age, able to mask the presence of the disorder and prevent its recognition. Finally, the SCID-5-CV did not identify any patient suffering from current alcohol use disorder. Although some of them reported some episodes of alcohol consumption mainly in social situations or during meals, the number of criteria required for the current diagnosis was not met, but they could have met them if the diagnostic clinical interview had investigated the lifetime presence of the disorder. This limitation might be addressed in future studies, by using diagnostic interviews investigating all the psychiatric disorders for both current and lifetime presentation. Despite these limitations, our findings support the existence of a true comorbidity between FMS and ADHD, the presence of a more severe FMS symptomatology in those patients who also have ADHD, and a higher frequency of opioids and sedative, hypnotic, or anxiolytic use disorders that has substantial clinical implications for both prevention and monitoring. Therefore, these two conditions should be addressed as appropriate, considering the preliminary evidence suggesting a positive effect of ADHD medications on pain and fatigue associated with FMS. References American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: Author. Bennett, R.M., Friend, R., Jones, K.D., Ward, R., Han, B.K., Ross, R.L., 2009. The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther. 11: R120 Derksen, M.T., Vreeling, M.J., Tchetverikov, I., 2015. High frequency of adult attention deficit hyperactivity disorder among fibromyalgia patients in the Netherlands: should a systematic collaboration between rheumatologists and psychiatrists be sought? Clin Exp Rheumatol. 33(1 Suppl 88): S141. JournalPre-proof
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  17. 17. Conflict of Interest All authors have participated in (a) conception and design, analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript. JournalPre-proof

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