Search

BackgroundMental pain has been proposed as a global person-centered outcome measure. The aim of this cross-sectional study was to test an essential requisite of such a measure, namely that mental pain incorporates independent contributions from a range of discrete but disparate outcome measures.MethodsTwo hundred migraine patients were assessed concerning migraine disability, psychosomatic syndromes, mental pain, depression, anxiety, and psychosocial dimensions. General linear models were tested to verify which measures would individually make unique contributions to overall mental pain.ResultsThe final model, accounting for 44% of variance, identified that higher mental pain was associated with more severe depressive symptoms, higher migraine disability, lower well-being, and poorer quality of life.ConclusionIn this sample, mental pain was shown to behave as expected of a global outcome measure, since multiple measures of symptomatology and quality of life showed modest but significant bivariate correlations with mental pain and some of these measures individually made unique contributions to overall mental pain.

Objective.The Diagnostic Criteria for Psychosomatic Research (DCPR) are those of psychosomatic syndromes that did not find room in the classical taxonomy. More recently, the DCPR were updated, called DCPR-revised (DCPR-R). The present study was conducted to test the criterion-related validity of the DCPR-R.Methods.Two hundred consecutive subjects were enrolled at the Headache Center of Careggi University Hospital (Italy): 100 subjects had a diagnosis of chronic migraine (CM) and 100 had a diagnosis of episodic migraine (EM). Participants received a clinical assessment, which included the DCPR-revised Semi-Structured Interview (DCPR-R SSI), the Structured Clinical Interview for DSM-5 (SCID-5), and the psychosocial index (PSI).Results.Forty-seven subjects (23.5%) had at least one DSM-5 diagnosis: major depressive disorder (8.5%; n = 17) and agoraphobia (7.5%; n = 15) were the most frequent. One hundred and ten subjects (55%) reported a DCPR-R diagnosis: allostatic overload (29%; n = 58) and type A behavior (10.5%; n = 21) were the most frequent. When the incremental validity of the DCPR system over the DSM system was tested using PSI subscales as the criterion variable, the DCPR-R increased up to 0.11–0.24 the amount of explained variance. Subjects with at least one DCPR-R diagnosis showed lower PSI well-being scores (p = .001), higher PSI stress scores (p < .001), and higher PSI psychological distress scores (p = .008) than subjects without a DCPR-R diagnosis.Conclusion. The DCPR-R showed a good criterion-related validity in migraine outpatients. Thus, they might be implemented, together with the DSM-5, in the assessment of migraine subjects.

BackgroundPain has been qualified under four categories: nociception, perception of pain, suffering, and pain behaviors. Most of the literature on migraine has devoted attention to the first two. The aim of the present cohort study was to investigate patients with migraine enrolled at a tertiary care unit to study suffering and mental pain and identify potential risk factors for migraine.MethodsAn observational cross-sectional study was carried out on patients with chronic migraine (CM) and episodic migraine (EM), and healthy subjects (HS). The three groups were matched for age and sex. A comprehensive assessment of migraine disability, pain, psychiatric disorders, psychosomatic syndromes, depressive and anxious symptoms, euthymia, psychosocial variables, mental pain, and pain-proneness (PP) was performed.ResultsThree hundred subjects were enrolled (100 CM, 100 EM, and 100 HS). Based on the multiple regression analyses, those presenting PP (social impairment: odds ratio [OR] = 3.59, 95% confidence interval [CI] = 1.14-11.29; depressive symptoms: OR = 3.82, 95% CI = 1.74-8.41) were more likely to be CM than HS. Those with higher levels of PP (social impairment: OR = 4.04, 95% CI = 1.60-10.22; depressive symptoms: OR = 2.02, 95% CI = 1.26-3.24) were more likely to be EM than HS. Those presenting higher levels of mental pain were more likely to be CM than EM (OR = 1.45, 95% CI = 1.02-2.07).ConclusionMigraine is an unpleasant sensory and emotional experience associated with psychosocial manifestations that might contribute to the level of suffering of the individuals. Mental pain resulted to be the variable that most differentiated patients with CM from EM.

Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH). Furthermore, psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previous history of migraine, and legal issues often reported by PPTH patients have complicated the understanding of this condition, hence treatment approaches for PTH remain problematic. Recent findings from structural and functional neuroimaging studies have attempted to describe the brain architecture of PPTH, suggesting the involvement of different networks compared to migraine. It also seems that calcitonin gene-related peptide (CGRP) levels are not particularly raised in PPTH, although CGRP monoclonal antibodies have obtained positive initial open-label evidence of efficacy in PPTH, and more trials assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.

In the last 15 years relevant efforts have been made to demonstrate that calcitonin gene-related peptide (CGRP) antagonism is a valuable and druggable mechanism for treatment or prevention of migraine. Galcanezumab is one of the antibodies developed and studied to prevent migraine by targeting CGRP. The scope of this review is to report data currently available on galcanezumab. According to available data, galcanezumab is safe and efficacious in preventing migraine in episodic migraine patients, also reducing disability and functional impairment due to the disorder. In September 2018, galcanezumab was approved in the USA for the prevention of migraine in adults. The placement of galcanezumab into the current therapeutic scenario will be a revolution for migraine patients, and probably in a less near future also for patients affected by other primary headaches.

Objective We propose a new outcome measure to assess the efficacy of migraine treatments translating the approach of the Global Burden of Disease studies from a societal to an individual level: Instead of calculating “years lived with disability”, we suggest estimating “time lost due to an attack”. Methods Time lost due to an attack is calculated by multiplying the duration and the degree of impaired functioning during an attack. Results Time lost due to an attack, different from other outcome measures, does not just focus on the short-term analgesic effects of treatments, but rather on the improvement of all migraine symptoms and restoration of functioning, also considering therapy-related impairment. Importantly, time lost due to an attack measures the entire time patients are not functioning normally, from onset to complete resolution. Conclusions Time lost due to an attack represents a new paradigm to assess migraine burden in single patients for a patient-centered evaluation of both acute and prophylactic treatments.

Objective To investigate headache treatment before and during pregnancy. Background Most headaches in pregnancy are primary disorders. Headaches are likely to ameliorate during pregnancy, although they may also begin or worsen. Most headache medications should be avoided during pregnancy because of potential fetal risks. However, only scarce evidence on headache drug consumption during pregnancy is available. Design ATENA was a retrospective, self-administered questionnaire-based, cohort study on women in either pregnancy or who have just delivered and reporting headache before and/or during pregnancy. Results Out of 271 women in either pregnancy or who have just delivered, 100 (37%) reported headache before and/or during pregnancy and constituted our study sample. Before pregnancy, the attitude toward the use of symptomatic drugs was characterized by both a strong focus on their safety and the willingness to avoid possible dependence from them. Compared to the year before, pregnancy led to changes in behavior and therapeutic habits as shown by a higher proportion of patients looking for information about drugs (44/100 [44%] vs. 36/100 [36%]) and a lower proportion of those treating headache attacks (88/100 [88%] vs. 52/100 [52%]) and by a lower use of nonsteroidal anti-inflammatory drugs (68/100 [68%] vs. 5/100 [5%]) and a much higher use of paracetamol (33/100 [33%] vs. 95/100 [95%]). Conclusions Pregnancy changes how women self-treat their headache, and leads to search for information regarding drug safety, mostly due to the perception of fetal risk of drugs. Healthcare providers have to be ready to face particular needs of pregnant women with headache.

Objectives A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH. Methods A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded. Results Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30–150) to 16 (5–30), p p p Conclusion LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.

Background According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months. Main body Currently, due to the high prevalence of this disorder, several preclinical studies have been conducted using different animal models of mild TBI to reproduce conditions that engender PTH. Despite representing a simplification of a complex disorder and displaying different limitations concerning the human condition, animal models are still a mainstay to study in vivo the mechanisms of PTH and have provided valuable insight into the pathophysiology and possible treatment strategies. Different models reproduce different types of trauma and have been ideated in order to ensure maximal proximity to the human condition and optimal experimental reproducibility. Conclusion At present, despite its high prevalence, PTH is not entirely understood, and the differential contribution of pathophysiological mechanisms, also observed in other conditions like migraine, has to be clarified. Although facing limitations, animal models are needed to improve understanding of PTH. The knowledge of currently available models is necessary to all researchers who want to investigate PTH and contribute to unravel its mechanisms.

Background and purpose Although migraine is the second most disabling condition worldwide, there is poor awareness of it. The objective was to assess the awareness of migraine and previous diagnostic and therapeutic consultations and treatments in a large international population of migraineurs. Methods This was a multicentre study conducted in 12 headache centres in seven countries. Each centre recruited up to 100 patients referred for a first visit and diagnosed with migraine. Subjects were given a structured clinical questionnaire-based interview about the perceptions of the type of headache they suffered from, its cause, previous diagnoses, investigations and treatments. Results In all, 1161 patients completed the study. Twenty-eight per cent of participants were aware that they suffered from migraine. Sixty-four per cent called their migraine 'headache'; less commonly they used terms such as 'cervical pain' (4%), tension headache (3%) and sinusitis (1%). Eight per cent of general practitioners and 35% of specialists (of whom 51% were neurologists and/or headache specialists) consulted for migraine formulated the correct diagnosis. Before participating in the study, 50% of patients had undergone X-ray, computed tomography and/or magnetic resonance imaging of the cervical spine and 76% underwent brain and/or cervical spine imaging for migraine. Twenty-eight per cent of patients had received symptomatic migraine-specific medications and 29% at least one migraine preventive medication. Conclusions Although migraine is a very common disease, poor awareness of it amongst patients and physicians is still an issue in several countries. This highlights the importance of the promotion of migraine awareness to reduce its burden and limit direct and indirect costs and the risk of exposure to useless investigations.

Melanoma is one of the most aggressive and less chemotherapy-responsive human cancers, representing a major public health issue worldwide. The early diagnosis still represents the best approach in order to reduce mortality, especially in advanced stages. Preclinical evidence, collected through several in vitro and in vivo models, has been accumulating about the pathophysiological involvement of β-adrenoceptors in melanoma progression. This involvement has been paralleled by the evidence that drugs blocking β-adrenoceptors (β-blockers) may have a relevant role in the treatment of melanoma and in the prevention of its progression. β-blockers are a class of drugs extensively used in clinical practice, not limited to cardiovascular therapeutics. Evidence collected through retrospective and prospective observational studies suggests that treatment with β-blockers, mainly propranolol, is able to delay melanoma progression. Although conclusive evidence is still lacking, current knowledge proposes β-blockers as an opportunity for antitumor treatment in melanoma. Clinical trials are needed in order to prove their claimed efficacy. Graphical Abstract.

Cluster headache (CH) shows a more severe clinical picture than migraine (Mig). We tested whether brain changes can explain such difference. Multimodal MRI was acquired in attack-free patients with CH (n = 12), Mig (n = 13) and in normal controls (NC, n = 13). We used FSL for MRI data analysis and nonparametric permutation testing for voxelwise analyses (p

Background Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Recommended medications for the acute treatment of migraine encompass triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. While it is true that triptans have been the first successful mechanism-driven treatment in the field, recently, new targets involved in migraine pathogenesis have emerged and new drug classes have been studied for migraine attack therapy. Areas covered: Pharmacodynamics and pharmacokinetics of the new acute treatments of migraine (i.e. ditans, gepants, and glutamate receptor antagonists), considering also marketed drugs in new formulations and administration routes. Expert opinion: Research on the administration routes of marketed drugs was performed in order to improve, in accordance with basic pharmacokinetics parameters, the speed of action of these medications. Similar to the triptans, the new acute treatments are migraine-specific medications, acting on the trigeminovascular system, albeit with different mechanisms. Although available data do not conclusively indicate the superiority of a class over the others, the pharmacodynamics explains the peculiar tolerability and safety profile of different drug classes emerging from clinical trials. Further studies are needed to investigate the possibility of combining different drug classes to optimize the clinical response and the potential role of the novel drugs in medication-overuse headache.

Background: The Mental Pain Questionnaire (MPQ) is a self-report questionnaire developed to assess mental pain. The aim of the present study was to test the clinimetric properties of the MPQ.Methods: A sample of 200 migraine outpatients were enrolled; homogeneity of MPQ was assessed by Mokken Analysis; item-level severity and item-level sensitivity were calculated via Two-Parameter Logistic model; Total Information Function was evaluated to assess reliability of MPQ; internal consistency was calculated via Cronbach's alpha and Sijtsma and Molenaar rho; sensitivity and specificity were assessed via Receiver Operating Characteristic curves.Results: The MPQ showed unidimensional factor structure; satisfactory homogeneity of the item and total score, except items 4 ("my pain is everywhere") and 6 ("I cannot understand why I feel this pain"); good discrimination, except item 7 ("I feel empty"); low information provided by items 4, 6, 7; good reliability for mild and high levels of mental pain; poor reliability for low levels of mental pain; acceptable internal consistency; acceptable sensitivity and specificity.Limitations: The sample size is barely sufficient to calculate item parameters; it is a monocentric study that enrolled outpatients from a tertiary facility; the study enrolled migraine outpatients not affected by other medical disease.Conclusions: The MPQ showed good psychometric properties. Items 4, 6, 7 should be considered with caution when migraine patients are evaluated. A score of at least 3 indicates mental pain clinically relevant, a score of at least 2 indicates distress. These data are preliminary and refer to migraine patients, results might be different in psychiatric populations.

Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.

Background Primary headache are prevalent and debilitating disorders. Acute pain cessation is one of the key points in their treatment. Many drugs have been studied but the design of the trials is not usually homogeneous. Efficacy of the trial is determined depending on the selected primary endpoint and usually other different outcomes are measured. We aim to critically appraise which were the employed outcomes through a systematic review. Methods We conducted a systematic review of literature focusing on studies on primary headache evaluating acute relief of pain, following the PRISMA guideline. The study population included patients participating in a controlled study about symptomatic treatment. The comparator could be placebo or the standard of care. The collected information was the primary outcome of the study and all secondary outcomes. We evaluated the studied drug, the year of publication and the type of journal. We performed a search and we screened all the potential papers and reviewed them considering inclusion/exclusion criteria. Results The search showed 4288 clinical trials that were screened and 794 full articles were assessed for eligibility for a final inclusion of 495 papers. The studies were published in headache specific journals (58%), general journals (21.6%) and neuroscience journals (20.4%). Migraine was the most studied headache, in 87.8% studies, followed by tension type headache in 4.7%. Regarding the most evaluated drug, triptans represented 68.6% of all studies, followed by non-steroidal anti-inflammatories (25.1%). Only 4.6% of the papers evaluated ergots and 1.6% analyzed opioids. The most frequent primary endpoint was the relief of the headache at a determinate moment, in 54.1%. Primary endpoint was evaluated at 2-h in 69.9% of the studies. Concerning other endpoints, tolerance was the most frequently addressed (83%), followed by headache relief (71.1%), improvement of other symptoms (62.5%) and presence of relapse (54%). The number of secondary endpoints increased from 4.2 (SD = 2.0) before 1991 to 6.39 after 2013 (p = 0.001). Conclusion Headache relief has been the most employed primary endpoint but headache disappearance starts to be firmly considered. The number of secondary endpoints increases over time and other outcomes such as disability, quality of life and patients’ preference are receiving attention.

The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment.

Previous observational studies have reported the protective effect of β-blockers on the progression of different types of cancers. In 2011, we published a prospective study, including patients with histologically confirmed malignant melanoma in stage II-IIIA. In total, 25% of them reported previous use of β-blockers that were administered at any time for any other diseases. After a median follow-up of 2.5 years, 34% of the patients in the untreated group showed disease progression. In contrast, only 3% of the patients in the treated group showed progression. We report the findings obtained in the same cohort after a longer period of β-blocker therapy and follow-up (8 years). We prospectively reviewed data of the patients enrolled in the original prospective study. Disease progression was assessed by evaluating the presence of lymphatic, in-transit or visceral metastases. Deaths by any cause and deaths because of melanoma were recorded. A multivariate Cox proportional hazards model was used to evaluate the effect of β-blocker use on disease-free survival and overall survival, adjusting for significant confounders. After a median follow-up of 8 years and a median duration of β-blocker use of 7.6 years, 45% of the patients in the untreated group and 30% of the patients in the treated group showed disease progression. Notably, in the untreated group 35% patients died from melanoma and only 17% patients died from melanoma in the treated group. Results of this hospital-based prospective cohort study with a median follow-up of 8 years confirmed our previous results that the use of β-blockers significantly reduced the risk of recurrence and mortality in melanoma patients.

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment. Linked Articles This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10

Migraine is the second-most disabling disease worldwide, and the second most common neurological disorder. Attacks can last many hours or days, and consist of multiple symptoms including headache, nausea, vomiting, hypersensitivity to stimuli such as light and sound, and in some cases, an aura is present. Mechanisms contributing to migraine are still poorly understood. However, transient receptor potential (TRP) channels have been repeatedly linked to the disorder, including TRPV1, TRPV4, TRPM8, and TRPA1, based on their activation by pathological stimuli related to attacks, or their modulation by drugs/natural products known to be efficacious for migraine. This review will provide a brief overview of migraine, including current therapeutics and the link to calcitonin gene-related peptide (CGRP), a neuropeptide strongly implicated in migraine pathophysiology. Discussion will then focus on recent developments in preclinical and clinical studies that implicate TRP channels in migraine pathophysiology or in the efficacy of therapeutics. Given the use of onabotulinum toxin A (BoNTA) to treat chronic migraine, and its poorly understood mechanism, this review will also cover possible contributions of TRP channels to BoNTA efficacy. Discussion will conclude with remaining questions that require future work to more fully evaluate TRP channels as novel therapeutic targets for migraine.

Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side effect of many chemotherapeuticdrugs, including platinum-based compounds (e.g., cisplatin and oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincristine), and the first-in-class proteasome inhibitor, bortezomib. Among the various sensory symptoms of CIPN, paresthesia, dysesthesia, spontaneous pain, and mechanical and thermal hypersensitivity are prominent. Inflammation, oxidative stress, loss of intraepidermal nerve fibers, modifications of mitochondria, and various ion channels alterations are part of the several mechanisms contributing to CIPN. Because attempts to mitigate chemotherapeutic- induced acute neuronal hyperexcitability and the subsequent peripheral neuropathy have yielded unsatisfactory results, a more in-depth understanding of the mechanism(s) responsible for the neurotoxic action of anticancer drugs is required. Some members of the transient receptor potential (TRP) family of channels, as the TRPV1 and TRPV4 (vanilloid), TRPA1 (ankyrin) and TRPM8 (melastatin) are expressed on the plasma membrane of primary sensory neurons (nociceptors), where they are activated by an unprecedented series of physical and chemical stimuli. There is evidence that TRPV1, TRPV4, TRPA1 and TRPM8 are prominent contributors of mechanical and thermal hypersensitivity in models of CIPN. In particular, in vitro and in vivo studies have pointed out the unique role of TRPA1 and oxidative stress in the mechanism responsible for cold and mechanical hyperalgesia in rodent models of CIPN.

The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and melanoma progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signaling can inhibit multiple cellular processes involved in melanoma progression and metastasis. These observations have suggested the possibility that drugs originally intended for the treatment of cardiovascular disease, the β-AR blockers, may provide new therapeutic opportunities for the control of tumor progression. A large number of observational studies demonstrated the protective effect of β-blockers in breast cancer but, more recently, similar findings were also reported in other cancers such as prostate cancer and melanoma. With regard to melanoma, two recently published studies demonstrated a great reduction in the risk of disease progression for each year of treatment with β-blockers. The results from these studies have suggested a potential role for targeting the β-AR pathway in melanoma patients. Questions regarding the type of β-blocker or tumor characteristics, appropriate treatment paradigms and, most importantly, efficacy must be answered in randomized clinical studies before β-blockers can be considered a therapeutic option for patients with melanoma.

Adherence to statin treatment is expected to be associated with health outcomes. Much of the available evidence is derived from studies conducted on selected populations (eg, Medicaid population), on specific cohorts of patients (eg, patients with diabetes mellitus or those who have experienced acute myocardial infarction [AMI]), or with respect to a single outcome (eg, only death or only AMI).The aim of this study was to evaluate the association between adherence to statin therapy and all-cause mortality and cardiovascular morbidity (AMI and stroke) in an unselected cohort of newly treated patients.We performed a population-based retrospective cohort study that included adult patients with a first prescription of a statin from January 1, 2004, through December 31, 2006, using data from the administrative databases of the Local Health Unit of Florence in Italy. Adherence to statin treatment was estimated as the proportion of days covered (PDC) by filled prescriptions and classified as low (PDC, 21%-40%), intermediate-low (PDC, 41%-60%), intermediate-high (PDC, 61%-80%), and high (PDC,80%). Cases with PDC ≤20% were excluded. A Cox regression model was used to investigate the association between adherence to treatment and all-cause mortality and hospitalization for AMI or stroke.The cohort consisted of 19,232 patients (9823 men and 9409 women) aged 18 to 102 years (mean [SD], 66.5 [11.4] years): 20.1% had been previously hospitalized for cardiovascular events and 17.6% had been treated with hypoglycemic drugs. Adherence to statins was low in 4427 patients (23.0%), intermediate-low in 3117 (16.2%), intermediate-high in 3784 (19.7%), and high in 7904 (41.1%). Lower-adherent patients were younger and had fewer comorbidities compared with higher-adherent patients. In our multivariable analyses, high adherence was significantly associated with decreased risk of all-cause death, AMI, or stroke. Compared with low adherence (hazard ratio [HR] = 1), the risk was lower in intermediate-low adherence (HR = 0.83; 95% confidence interval [CI], 0.71-0.98; P0.05) and much lower in intermediate-high (HR = 0.60; 95% CI, 0.51-0.70; P0.001) and high adherence (HR = 0.61; 95% CI, 0.54-0.71; P0.001).In this Italian cohort of newly treated patients, suboptimal adherence to statins occurred in a substantial proportion of patients and was associated with increased risk of adverse health outcomes.

Despite the fact that an unprecedented series of new discoveries in neurochemistry, neuroimaging, genetics and clinical pharmacology accumulated over the last 20 years has significantly increased our current knowledge, the underlying mechanism of the migraine headache remains elusive. The present review article addresses, from early evidence that emerged at the end of the nineteenth century, the role of ‘antidromic vasodilatation’ as part of the more general phenomenon, currently defined as neurogenic inflammation, in the unique type of pain reported by patients suffering from migraine headaches. The present paper describes distinctive orthodromic and antidromic properties of a subset of somatosensory neurons, the vascular- and neurobiology of peptides contained in these neurons, and the clinical–pharmacological data obtained in recent investigations using provocation tests in experimental animals and human beings. Altogether, previous and recent data underscore that antidromic vasodilatation, originating from the activation of peptidergic somatosensory neurons, cannot yet be discarded as a major contributing mechanism of the throbbing head pain and hyperalgesia of migraine.

Summary What is known and Objective: Methotrexate (MTX) is widely used in the management of paediatric cancer with a generally favourable benefit/risk profile. We report an unusual adverse drug reaction with the first course of high-dose MTX in a paediatric patient and review the literature for similar cases. Case summary: An 11-year-old boy with small-cell osteoblastic osteosarcoma in the lower limb experienced a case of life-threatening anaphylaxis during the first course of high-dose MTX. The adverse event occurred during the first course, likely due to an immune-mediated mechanism. We postulate that prior antineoplastic treatment might have contributed to the immune response to MTX. What is new and Conclusion: Given that this reaction has rarely been reported, we discuss the present case with a review of other similar cases. Further studies are needed to substantiate this ‘signal alarm’ for serious MTX-related hypersensitivity reactions.

Objective: To evaluate adherence to antihypertensive therapy (AHT) and the association between adherence to AHT, all-cause mortality, and cardiovascular (CV) morbidity in a large cohort of patients newly treated with antihypertensives in a clinical practice setting. Methods: An administrative database kept by the Local Health Unit of Florence (Italy) listing patient baseline characteristics, drug prescription, and hospital admission information was used to perform a population-based retrospective study including patients newly treated with antihypertensives, ≥18 years of age, with a first prescription between January 1, 2004 and December 31, 2006. Patients using antihypertensives for secondary prevention of CV disease, occasional spot users, and patients with early CV events, were excluded from the study cohort. Adherence to AHT was calculated and classified as poor, moderate, good, and excellent. A Cox regression model was conducted to determine the association among adherence to AHT and risk of all-cause mortality, stroke, or acute myocardial infarction. Results: A total of 31,306 patients, 15,031 men (48.0%), and 16,275 women (52.0%), with a mean age of 60.2 ± 14.5 years was included in the study. Adherence to AHT was poor in 8038 patients (25.7% of included patients), moderate in 4640 (14.8%), good in 5651 (18.1%), and excellent in 12,977 (41.5%). Compared with patients with poor adherence (hazard ratio [HR] = 1), the risk of all-cause death, stroke, or acute myocardial infarction was significantly lower in patients with good (HR = 0.69, P < 0.001) and excellent adherence (HR = 0.53, P < 0.001). Conclusions: These findings indicate that suboptimal adherence to AHT occurs in a substantial proportion of patients and is associated with poor health outcomes already in primary prevention of CV diseases. For health authorities, this preliminary evidence underlines the need for monitoring and improving medication adherence in clinical practice.

Chronic headaches represent a significant burden for the affected individuals and for the society, and a major challenge for successful care. Among the various types of chronic headaches, those that are associated with medication overuse (medication-overuse headache, MOH) are of particular importance because of the large proportion of patients who complain of this condition and their poor outcome. Most patients with MOH had migraine as primary headache. Practically, almost all drugs used for the symptomatic relief of migraine, including triptans and analgesics can cause MOH. Although the pathophysiology of MOH is unknown, recent studies hypothesize that plastic changes in specific pain areas of the central nervous system are main contributors to establishing MOH. Not infrequently, drug overuse is associated with habituation and failure of previously effective medications. Finally, treatment of MOH is poorly evidence based and mostly relies on clinical experience and belief.

Calcitonin gene related peptide (CGRP) has been proposed to contribute to pain transmission and inflammation and for these reasons to the mechanism of migraine. CGRP is, in fact, expressed in and released from a subset of polymodal primary sensory neurons of the trigeminal ganglion. Release of CGRP in the dorsal spinal cord has been associated to nociceptive transmission, and release from perivascular nerve endings causes neurogenic vasodilatation. CGRP levels increase in the cranial circulation during migraine attacks, and GRP injection in migraineurs results in migraine-like attacks. Most importantly, two chemically unrelated CGRP-receptor antagonists, the parenteral agent, olcegepant, and the orally available telcagepant demonstrated efficacy in the treatment of migraine attacks, thus supporting CGRP as an important mediator in migraine.

OnabotulinumtoxinA (OnabotA) was approved for treatment of chronic migraine (CM) following the PREEMPT trials[1, 2], and was licensed in Italy in February 2013. Thus, in December 2013 we began to offer OnabotA to patients with CM who did not respond to other preventive therapy (mostly topiramate, beta blockers, amitriptyline and calcium channel antagonists). Demographic and migraine characteristics of patients were recorded, and changes in monthly migraine days and headache intensity (the latter variable was evaluated only after the first session of treatment), as well as, the number of symptomatic medications intake, were assessed. From December 2013, 40 patients (9 males, 31 females) were treated with at least four therapeutic sessions. Their mean age (± SD) at treatment onset was 51.3±12.6 years (range: 27-80). All the patients fulfilled the ICHD-III criteria for CM[3] and 28 (70%) were receiving other preventive therapy. In 34 of these patients (85%) overuse of symptomatic medications was observed at the onset of treatment. After obtaining an informed consent, we administered OnabotA according to the PREEMPT protocol (155 UI for a total of 31 injections divided across 7 head/neck muscles), performing no additional injections in the first session (from the second session we also adopted “follow the pain” protocol), and we gave the patients a paper diary to register the headache evolution. After one year of treatment we analyzed the data related to the 40 patients, observing positive results in all the variables considered. In particular, following 1-year treatment there was a reduction from 25.1±6.1 to 19.8±9.1 in the mean (± SD) number of monthly migraine days (reduction of 21%, p < 0.0001). The intake of symptomatic medications was reduced of about 12%, but the difference was not statistically significant. Most (78%) of the patients (n = 23) who had accurately registered the data reported that the greatest clinical benefit of OnabotA was the reduction in the headache intensity. Finally, no severe adverse event was observed, and mild pain in the injection site was the most reported experience. No patient discontinued the treatment because of side effects. We can conclude that the use of OnabotA according to the PREEMPT paradigm is an effective and well-tolerated treatment in patients with chronic migraine in a real-life setting. Written informed consent to publication was obtained from the patient(s).

Calcitonin gene-related peptide (CGRP) seems to play a major role in migraine mechanism. Overwhelming data report the efficacy of small molecule CGRP receptor antagonists in the treatment of migraine attacks. If some CGRP receptor (CGRP-R) antagonists could theoretically cross the blood brain barrier (BBB) one of them, olcagepant, due to its peptoid nature could not. However, the clinical development of such otherwise well tolerated compounds has been spoiled by their hepatic liability that has been considered an off-target effect. In the last few years the identification of monoclonal antibodies (Ab) for CGRP or the CGRP-R has provided an alternative strategy to maintain a good efficacy profile and circumvent the severe liver toxicity of classical small molecules CGRP-R antagonists. Indeed, data from phase-II trials are showing that the therapeutic gain between active treatment with the various anti-CGRP Abs and placebo varies from about 20% to 40% and adverse reactions are limited to irritation at the site of injection and few other minor effects. Anti-CGRP mAbs predictably may cross the BBB at a minimum extent, thus making unlikely the hypothesis that they act at sites of action within the central nervous system. This observation is associated with the prevalent localization of the complex multimeric assembly of CGRP-R in the vascular smooth muscle where they mediate the inflammatory neurogenic vasodilatation. Thus, the most parsimonious hypothesis proposes that blockade of the CGRP/CGRP-R receptor system within the cranial neurovascular system produces the desirable analgesic effect in migraine pain. If the mechanism and the genetic background that by promoting cranial neurogenic vasodilatation generate migraine pain remain a mystery, some insights on the triggers that may activate this pathogenic pathway are now better understood. A series of agents known to provoke migraine attacks have been identified as activators of certain transient receptor potential (TRP) channels expressed by a subpopulation of peptidergic nociceptors. In particular, the subtypes ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are activated by migraine provoking agents. Nitric oxide, umbellulone and acrolein gate TRPA1 and alcohol TRPV1. All stimuli by channel targeting generate CGRP release from perivascular terminals of cranial sensory neurons, thus producing the neurogenic effect blunted by CGRP-R antagonists and by anti CGRP mAbs. More importantly, antimigraine medicines, such as metamizole (dipyrone), propyphenazone and parthenolide exert their analgesic effect by antagonizing TRPA1.

Results Since May 3, 2012 up to January 8, 2015, we enrolled 24 patients (18 females, 6 males; average age, 48 years) who were considered eligible to be treated with methadone. Nine patients dropped out because of adverse drug reactions (n=4, mean time of drop-out 7 days) or treatment ineffectiveness (n=5, mean time of drop-out 6 months). Six patients completed the 12-month treatment. After 1-year follow-up they still reported daily headache, however, they showed an impressive decrease of analgesic and/or antimigraine drug consumption (from 147.7 medications per month ± SD 124 to 8.5 medications per month ± SD 6.1) and a significant decrease of visual analogic scale (VAS) pain intensity (from 5.8 ± SD 2.6 to 2.8 ± SD 2.1). These patients were treated with daily methadone doses ranging from 5 mg to 60 mg; methadone dosages were safe and well tolerated. Conclusions In patients affected by daily refractory headache and medication-overuse headache, who are exposed to the risk of serious side effects due to prolonged analgesic and/or antimigraine treatment, prophylaxis with low-dose methadone therapy seems to represent an effective therapeutic option. Written informed consent to publication was obtained from the patient(s).

Background: De novo onset or aggravation of migraine has been observed after atrial septal defect closure (ASDC), whereas antiplatelet drugs, such as clopidogrel, used to prevent post-ASDC thromboembolic events, have been associated with migraine amelioration. Case: We report the case of a woman who, after ASDC, experienced de novo severe migraine with aura. Whereas use of acetylsalicylic acid or clopidogrel had no effect, ticlopidine use was associated with migraine amelioration. Migraine relapsed after two ticlopidine dechallenges, and disappeared after drug rechallenges. Conclusion: A ticlopidine trial could be proposed to patients with migraine which occurs or worsens immediately after ASDC and does not improve with clopidogrel.

Objective To verify preliminary studies on patients with melanoma exposed to β-blockers that suggested a reduced risk of disease recurrence and death. Patients and Methods Data were obtained from all consecutive patients diagnosed as having melanoma between January 1, 1993, and December 31, 2009, at the Department of Dermatology of the University of Florence, Azienda Sanitaria di Firenze. Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease. We also excluded participants with evidence of visceral, lymph nodal, and in-transit metastasis at the time of the diagnosis. Results Of 741 consecutive patients with melanoma, 79 (11%) were prescribed β-blockers (for hypertension in most cases) for 1 or more years (treated) and 662 (89%) were not (untreated). The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years ( P =.005). For each year of β-blocker use, the risk of death was reduced by 38%. The presence of hypertension, the use of antihypertensive agents for 1 or more years, or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma. Conclusion The results confirm and strengthen previous findings that β-blocker use is associated with a reduced risk of melanoma recurrence and death. The results also indicate the strong need for a randomized clinical trial to conclusively assess whether β-blockers afford protection against melanoma recurrence and death.

Preclinical evidence shows that β-adrenoceptor antagonists (β-blockers) inhibit tumor and metastasis progression in animal models of melanoma. We hypothesized that the use of β-blockers for concomitant diseases is associated with a reduced risk of progression of thick (Breslow thickness >1 mm) malignant melanoma. Two patient subgroups were identified from the medical records of 121 consecutive patients with a thick melanoma. Of these, 30 patients had been prescribed β-blockers for 1 year or more (treated subgroup), whereas the other 91 were untreated. After a median follow-up time of 2.5 years, tumor progression was observed in 3.3% of the treated subgroup and in 34.1% of the untreated subgroup. The Cox model on progression indicated a 36% (95% confidence interval, 11%-54%) (P = .002) risk reduction for each year of β-blocker use. No deaths were observed in the treated group, whereas in the untreated group 24 patients died. To our knowledge, the present study suggests for the first time that exposure to β-blockers for 1 year or more is associated with a reduced risk of progression of thick malignant melanoma, indicating the need for larger epidemiological studies and randomized clinical trials.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected.

Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2(2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24(27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value by multivariate analysis (P = .01). The present study indicates that pathologists should be aware of the peculiar morphologic changes of cutaneous graft-versus-host disease following reduced-intensity conditioning and further recommends histopathology in the diagnostic workup of graft-versus-host disease in patients undergoing reduced-intensity conditioning regimen. (C) 2011 Elsevier Inc. All rights reserved.

Umbellularia californica, a shrub or tree indigenous to southwestern Oregon and northern California, is commonly known as headache tree, probably because it is reported that its scent can cause headache. Here, we report the case of a 69-year-old Italian gardener, affected during his young adult age by cluster headache, who, 10 years from his last cluster episode, developed shorter-lasting cluster-like headache attacks after and at any time he was exposed to U. californica scent. The present case indicates that, even though endogenous mechanisms causing the cluster headache were no longer present, susceptibility to exogenous triggers remains active in this patient, and suggests that identification of the constituent(s) of U. californica responsible for triggering cluster headache-like attacks may help in the understanding of the hitherto elusive mechanism of cluster headache.

Cluster headache (CH) consists of attacks of severe, unilateral orbital/supraorbital/temporal pain, lasting for 15–180 min, occurring once or more times a day, and associated with ipsilateral conjunctival injection, lacrimation and other symptoms. Cataract is clouding of the lens of the eye causing a progressive and painless loss of vision. We describe the cases of two men (not relative, but with the same last name, which originates from north-eastern Italy) that in young adult age, after years of suffering from chronic CH, developed cataract on the same side of the pain attacks. Patient 1 was diagnosed as having cataract 18 years after the onset of episodic (and subsequently chronic) CH. Patient 2 began suffering from chronic CH at the age of 44 years and after 8 years he developed cataract. This is the first report of cataract in patient suffering of CH and occurring in the eye affected by the pain attack.

Over the last 100 years, the discovery of new analgesics has been a complex and difficult task. However, remarkable progress in the identification of novel molecular targets relevant for pain medicines has been reported. Here we will focus on the neuropeptide calcitonin generelated peptide (CGRP) and its receptors (CGRP-R) because of their role in migraine mechanism and migraine therapy. Recent preclinical and clinical data on the localisation, regulation and plasma levels of CGRP and on the function of CGRP-R will be summarised. The reviewed findings highlight the major function of CGRP in migraine and the use of CGRP-R antagonists as a novel approach for the treatment of migraine attack and, perhaps, as migraine prophylactic medicines.

There is considerable discussion on the serum concentrations of 25-OH vitamin D associated with deficiency, overall health and toxicity. Currently, the upper limit of safety for daily doses is 10 000 IU and adequate concentrations are suggested to be >50 nmol l−1. Although definitive cut points have not been developed, it is accepted that serum concentrations >500 nmol l−1 (>200 ng ml−1) can be associated with adverse effects [1, 2]. There are several reports of patients who developed asymptomatic or severely symptomatic hypercalcaemia due to vitamin D supplements [3–5]. Vitamin D preparations are available worldwide as food supplements. Recently, three cases of hypervitaminosis D, hypercalcaemia and renal insufficiency in patients taking the same type of oral preparation for vitamin D supplementation were reported to the Italian National Institute of Health reporting system for natural health products. The first case was a 34-year-old woman affected by osteoporosis, atopic dermatitis and coeliac disease who had taken six capsules each day of a vitamin D supplement for 4 months before the adverse reaction. The patient was hospitalized because of hypercalcaemia and renal insufficiency. Bilateral nephrocalcinosis was seen on renal ultrasound. The patient suffered from polyuria, polydipsia, episodic emesis and dyspepsia. Fourteen days after stopping vitamin D supplementation, total calcium was 3.25 mmol l−1 (13.0 mg dl−1, normal range 2.25–2.63 mmol l−1, 9–10.5 mg dl−1), serum creatinine was 274.04 mmol l−1 (3.1 mg dl−1, normal range 44.2–132.6 mmol l−1, 0.5–1.5 mg dl−1) and serum 25-OH vitamin D (7575.36 nmol l−1, 3035.0 ng ml−1) was elevated greatly over the toxic level. The second case was a 57-year-old man with hypertension who took three capsules each day of a vitamin D supplement for 11 months, eventually developing symptoms and signs of acute renal insufficiency. Serum vitamin D values over 748.80 nmol l−1 (300 ng ml−1, laboratory upper detection limit), hypercalcaemia (3.23 mmol l−1, 12.9 mg dl−1), renal insufficiency (serum creatinine 235.14 mmol l−1, 2.66 mg dl−1) and tubular damage found on renal biopsy, were all attributed to the oral vitamin D preparation prescribed to the patient as a dietary supplement. The third case was a 47-year-old man who took seven to nine capsules daily of a vitamin D supplement for 5 months as a self-prescribed supplementation. The patient was admitted to the hospital for renal insufficiency (creatinine 221 mmol l−1, 2.5 mg dl−1). Serum vitamin D values were over 748.80 nmol l−1 (300 ng ml−1, laboratory upper detection limit) and total calcium was elevated (3.08 mmol l−1, 12.3 mg dl−1). For all three cases, no pre-existing diseases or other drugs taken by the patients could be considered as causal or contributing factors. All patients completely recovered, regaining their normal renal function 3–4 months after discontinuation of vitamin D supplementation and supportive medical treatment. In all three cases, the causal relationship between the vitamin D preparation and the adverse reaction, as assessed by the Naranjo scale [6], was defined as ‘certain’. All patients had taken the same supplement, MerluzzoVis (SerVis SRL®) capsules, that had come from two different lots with a declared vitamin D3 content of 1.5 μg (600 IU) per capsule. A liquid chromatography mass spectrometry analysis of the actual content of each capsule (performed as previously described [7]) showed values of 1320 ± 66 μg (about 52 800 IU), more than 880 times higher than what was reported on the product's label. Patient 1 therefore received approximately 316 800 IU day−1 for 4 months, patient 2 received approximately 158 400 IU day−1 for 11 months and patient 3 received approximately 422 400 IU day−1 for 5 months. When taken in correctly prescribed doses, vitamin D can be considered a safe treatment. Nevertheless the three cases here described, similar to others previously reported [3–5], suggest that vitamin D intoxication due to the use of vitamin D supplements is not rare. Vitamin D preparations do not undergo quality control for good manufacturing practice because they are ‘food supplements’. The vitamin D intoxication that occurred in these three cases was a result of inadequate quality control, resulting in the selling of a product dangerous to consumers' health. In terms of safety, most people consider a ‘food supplement’ to be much safer than a ‘drug’. Given that a preparation labelled as ‘food’ can be commonly used without a medical prescription, its content of active principles should be carefully monitored. In conclusion, the present cases of vitamin D intoxication emphasize the need to prepare supplements such as vitamin D under precise rules so that the amount of potentially toxic ingredients is the correct and safe dose. The urgent need for a more strict regulation may be extended to other food supplements containing active principles and used for health purposes.

Merkel cell carcinoma (MCC) is an uncommon malignancy originating in epidermis. The anti-tumour necrosis factor (TNF)-α is used to treat psoriasis, rheumatoid arthritis and other inflammatory diseases. We report here a case of MCC in a relatively young patient that showed exceptionally rapid progression, which is uncommon for this type of tumour. The tumour appeared after 18 months of etanercept treatment. Cessation of its rapid growth was associated with interruption of anti-TNF-α treatment. CASE REPORT A 50-year-old white woman was referred to our clinic with an erythematous nodular lesion on her neck. Approximately 3 months previously she had first noticed a small (diameter approximately 1.5 cm) nodule that had rapidly increased in size and consistency and was soon associated with bleeding episodes following mild mechanical trauma. Physical examination revealed a shiny, firm, non-tender red polypoid nodule, approximately 2 × 2 cm in size with a wide erythematous base and no clinical lymphadenopathy (Fig. 1a). The lesion was scheduled for a diagnostic incisional biopsy. At the general physical examination the patient was in good health with no specific pathological signs or symptoms, apart from psoriatic arthritis without skin manifestations. This condition had been treated during the preceding 18 months with injections of etanercept (50 mg/week), with a good clinical response. The patient stated that she had never used any other immunosuppressive drugs or had phototherapy. Two weeks after visiting our clinic, at the time scheduled for the incisional biopsy, the lesion appeared markedly enlarged (4 × 3 cm) and the patient reported pain at the site of the tumour and in adjacent neck tissue (Fig. 1b). At that time, etanercept therapy was discontinued and the patient was given 8 mg/day corticosteroid and 7.5 mg methotrexate every 10 days. Fifteen days after the biopsy, when the stitches were removed, no further growth of the tumour was observed. The patient reported that the lesion had stopped growing 2 days after the withdrawal of etanercept therapy. The histopathological diagnosis was MCC. The patient was referred to the plastic surgery department for removal of the lesion. On physical examination, no local or regional lymph nodes were detected and blood test results were normal. A computed tomography (CT) scan of the thorax and of abdomen detected no lesions. However, despite excision with wide margins, the patient developed laterocervical locoregional lymph nodal metastases 6 months later. She died 16 months after the diagnosis from systemic metastases due to MCC.