Altered serum levels of kynurenine metabolites in patients affected by cluster headache.

BACKGROUND: The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls. METHOD: We assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. RESULTS: LC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH. CONCLUSION: The reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.

Stigma and Chronic Pain.

Stigma is defined by the World Health Organization (WHO) as "a mark of shame, disgrace or disapproval that results in an individual being rejected, discriminated against and excluded from participating in a number of different areas of society". Extensive literature searches have documented stigma in the context of health. Among the physical health conditions that are associated with stigma, chronic pain deserves particular attention. Stigma experienced by individuals with chronic pain affects their entire life. Literature identifies multiple dimensions or types of stigma, including public stigma, structural stigma and internalized stigma. Recent literature supports the biopsychosocial model of pain, according to which biological, psychological and sociocultural variables interact in a dynamic manner to shape an individual's response to chronic pain. Chronic pain affects a higher proportion of women than men around the world. There is an inadequate education of health care professionals regarding pain assessment and their insecurity to manage patients with chronic pain. A first-line intervention strategy could be to promote pain education and to expand knowledge and assessment of chronic pain, as recently highlighted for headache disorders, paradigmatically for resistant or refractory migraine, whose diagnosis, without an adequate education to understand the possible fluctuations of the disease, may have profound psychological implications with the idea of insolvability and contribute to stigmatizing the patient.