Clinical features of headache patients with fibromyalgia comorbidity

In this study, which is the extension of the previous one in a smaller headache series [7], we found a lower frequency of FM representation in the selected patients. Other studies on this topic were specially dedicated to chronic or episodic migraine without aura (MWA), with a reported frequency, respectively, of 35 and 22% in the selected populations [5, 6]. A recent multicentre study on 1,413 patients [28], reported 10% of migraine patients presenting with FM comorbidity, but the features of migraine were not specified. The frequency of 17.8% that we actually found in the migraine group was almost the same as the previous report [7], with a minimum in purely MA and a maximum in chronic migraine. The apparent discordance of FM prevalence across studies may be due to variability in applying FM diagnostic criteria, or the uncertainness of a story of widespread pain reported from patients who came to visit for another reason. The FM diagnostic criteria are not devoid of problems, and the ACR has proposed to enlarge the symptoms useful for diagnosis [29], applying clinical criteria based on fatigue, cognitive symptoms, and the extent of somatic symptoms, without considering the number of positive tender points. These new criteria would be easily applied in headache centre and facilitate the detection of FM comorbidity. Interestingly, FM comorbidity was absent in patients presenting exclusively with MA attacks. This is a new data, given that in the study by Ifergane et al. [6] and Tietjen et al. [28], the presence of aura was reported without specifying the contemporary occurrence of MWA attacks. In the present study, patients with both MA and MWA diagnosis had the same FM frequency as those without aura, while it seemed that it was the exclusive presence of MA attacks to preserve from FM comorbidity. These data need to be confirmed in larger series, and may be supported by a pathophysiological explanation, as also supposed below. No studies are available on FM prevalence in the other forms of primary headache. Even in tension-type headache, where growing evidences indicate common pathophysiological basis with FM, only single cases of comorbidity are reported [30‐34]. In our study, according to the previous one [7], tension-type headache showed the major FM representation among primary headaches, with 35.1% prevalence. In FM populations, both migraine and tension-type headache are considered among the main causes of comorbidity [4]. The present results indicate a 25% frequency of FM in migraine and tension-type headache groups, not largely dissimilar from our preliminary study [7], in accord with which the chronic forms share the highest FM representation. This may also partly explain the preponderance of patients associating tension-type headache and generalized pain, given that in the tension-type group, most of the patients were chronic. It was the low representation of FM patients in the other primary headache groups (TACs and other forms) that reduced the FM frequency found in the total headache sample. For hemicrania continua, the retrospective evaluation used to prescribe indomethacine for confirming diagnosis after the observational period, may have induced an underestimation of FM comorbidity, with respect to the other considered headache types. Also, taking into consideration the low number of patients included in groups three and four of primary headaches, no definitive conclusion about FM comorbidity could be made, rather an impression of a low FM representation even in types with high headache frequency was found. In this sense, the frequency of headache should be the main but not the exclusive factor favouring FM, as specified below.

The phenotype expression of headache patients complaining with FM comorbidity included higher headache frequency, anxiety, pericranial tenderness, reduced physical performances, and sleep disturbances. Allodynia, which expresses the severity of central sensitization occurring during headache episodes [38], was not significantly increased in our FM series, suggesting that central sensitization should persist outside acute headache and generate myofascial pain to favour FM comorbidity. As expected, women prevailed in the FM group, as FM is six times more common in women, while headache and specially migraine is three times more common. The cycle phase would also influence pericranial and somatic tender points sensitivity [39], though in the present study this aspect was not taken into consideration. This is a confirmation of discriminating features of FM previously detected in a smaller headache series [7] with the inclusion of physical component of quality of life. Chronic migraine and chronic tension-type headache subtypes shared this headache profile in a significant way with respect to the other forms, confirming headache frequency as the primary factor for FM comorbidity. Pericranial tenderness is considered as a consequence of chronic headache [36, 37], as a sign of permanent sensitization at cervical and trigeminal second-order nociceptive neurons, subtended by a pathogenic process similar to that causing pain at tender points [32]. Reduced habituation to pain, common to migraine and FM [10], may facilitate central sensitization and myofascial pain persistence in the presence of other favouring conditions such as anxiety and sleep disturbances. A self-outstanding circuit of increased headache frequency, development of pericranial myofascial pain, persisting central sensitization with somatic diffusion of pain, may explain FM comorbidity in both chronic tension-type headache and chronic migraine, where the persistence of pericranial tenderness contributes to the transformation from episodic into chronic form [40]. Sleep disturbance is a well-recognized factor in FM syndrome [35], and our results confirm that in headache patients it favours generalized myofascial pain. The total numbers of sleep hours were not dissimilar between FM and non-FM patients, while the quality of sleep was the discriminating factor for FM in our headache series, in accord with our previous reports [7]. Clinical and preclinical data concur that sleep disruption causes hyperalgesia, and despite widely distributed and overlapping neural networks, regulate states of sleep and pain; and the brain mechanisms through which sleep and pain interact, remain poorly understood [41, 42]. There is an intriguing hypothesis that sleep deprivation decreases the analgesic effect of distraction in healthy individuals [43], and in the case of migraine, it may accentuate the pattern of altered pain modulation under distracting factors [44]. There are also evidences that rapid eye movement (REM) sleep deprivation is especially linked to hyperalgesia [45]. A significant association between severe sleep disturbances and chronic headache [46, 47] and central sensitization [48] has further been reported. Poor quality of sleep promotes diffusion of myofascial pain in headache patients, but which sleep phase is more involved in the generation of widespread pain remains to be clarified. Despite FM patients exhibiting higher depression and anxiety levels, it was the latter feature that best discriminated patients with diffuse pain among our headache population. Mongini et al. [49] found that the presence of anxiety considerably increases the level of muscle tenderness in the head and, even more, in the neck, and might facilitate the evolution into chronic headache forms. In this way, anxiety may also facilitate diffuse myofascial pain and FM comorbidity in headache patients presenting with higher pericranial muscle tenderness. FM patients were also characterized by a reduced functioning in daily living, inherent to physical abilities. This may suggest that persisting pericranial and somatic myofascial pain have a consequence on motor performances and that physical inability mainly compromise quality of life in patients sharing FM comorbidity. A combination of symptoms is needed to favour FM comorbidity, headache frequency being the main, though not the only cause. In fact, other primary headache types such as cluster headache, hemicrania continua, or parossistic migraine presented with high headache frequency and low probability do match the clinical profile of FM patients. However, the low number of patients included in these types of primary headaches deserves further confirmation in a larger series. Purely MA patients presented with the lowest probability to share the FM profile, while the combination with migraine attacks not preceded by aura symptoms conditioned higher representation of features facilitating diffuse somatic pain. Tietjen et al. [28] recently found that the presence of aura did not preserve the patients from FM comorbidity who were presenting with both types of migraine. Acute central sensitization phenomena were firstly described as a development of migraine aura [50] and allodynia has been confirmed a usual symptom in this type of migraine [28]. Moreover, acutely occurring allodynia does not account for FM comorbidity, which is present when central sensitization persists outside attacks and determines pericranial tenderness. This argument needs, in our opinion, further evaluation to specify if the prevalent presence of aura characterizes a migraine phenotype with low predisposition to chronic pain.

According to the previous report [7], headache severity concurs with FM gravity, as expressed by the positive correlation between the MIDAS and the impact of FM on life functions. Although the findings reported by Marcus et al. [8] did not support headache as an aggravating factor for FM, our data confirm that when headache is present its severity is linked to an increase in expression of FM symptoms. Our cases probably represent a subpopulation among FM patients, reporting headache as the most relevant problem, though in our opinion the relevance of headache features deserves much attention in FM series, for the large frequency of this symptom [35]. Allodynia expressed during acute headache, correlated with the invalidity linked with diffuse pain. This correlation may suggest that the central sensitization phenomena occurring during headache may also worsen the sufferance linked with fibromyalgic pain. An increased activation of the nociceptive system at central level may be a generalized phenomenon explaining a more severe impairment derived from diffuse muscle-skeletal pain. In future studies, it would be interesting to evaluate if the transformation of headache into whole-body allodynia/hyperalgesia during a migraine attack, mediated by sensitization of thalamic neurons, may be an aggravating factor for FM [51].The degree of evoked pain at tender points, was correlated with pericranial tenderness, confirming that both symptoms are subtended by analogous mechanisms of muscular hyperalgesia [32]. Frequency of headache seemed to concur with augmented pain evoked at tender points, suggesting that a generalized increment of pain sensitivity may develop with the increase in headache occurrence [36]. A more robust correlation should be confirmed in larger multi-centre studies.