Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial.

INTRODUCTION: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data. METHODS: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6-8 hours apart). RESULTS: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) (p = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common. CONCLUSIONS: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The "sham" device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844.

Psychological, clinical, and therapeutic predictors of the outcome of detoxification in a large clinical population of medication-overuse headache: A six-month follow-up of the COMOESTAS Project.

AIM: To identify factors that may be predictors of the outcome of a detoxification treatment in medication-overuse headache. METHODS: Consecutive patients entering a detoxification program in six centres in Europe and Latin America were evaluated and followed up for 6 months. We evaluated anxious and depressive symptomatology (though patients with severe psychiatric comorbidity were excluded), quality of life, headache-related disability, headache characteristics, and prophylaxis upon discharge. RESULTS: Of the 492 patients who completed the six-month follow up, 407 ceased overuse following the detoxification (non overusers), another 23 ceased overuse following detoxification but relapsed during the follow-up. In the 407 non-overusers, headache acquired an episodic pattern in 287 subjects (responders). At the multivariate analyses, lower depression scores (odds ratio = 0.891; p = 0.001) predicted ceasing overuse. The primary headache diagnosis - migraine with respect to tension-type headache (odds ratio = 0.224; p = 0.001) or migraine plus tension-type headache (odds ratio = 0.467; p = 0.002) - and the preventive treatment with flunarizine (compared to no such treatment) (odds ratio = 0.891; p = 0.001) predicted being a responder. A longer duration of chronic headache (odds ratio = 1.053; p = 0.032) predicted relapse into overuse. Quality of life and disability were not associated with any of the outcomes. CONCLUSIONS: Though exploratory in nature, these findings point to specific factors that are associated with a positive outcome of medication-overuse headache management, while identifying others that may be associated with a negative outcome. Evaluation of the presence/absence of these factors may help to optimize the management of this challenging groups of chronic headache sufferers.

Changes in anxiety and depression symptoms associated to the outcome of MOH: A post-hoc analysis of the Comoestas Project.

Aims To evaluate the impact of treatment success on depression and anxiety symptoms in medication-overuse headache (MOH) and whether depression and anxiety can be predictors of treatment outcome. Methods All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion over a six-month period. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. Results A total of 663 MOH patients were evaluated, and 492 completed the entire protocol. Of these, 287 ceased overuse and reverted to an episodic pattern (responders) and 23 relapsed into overuse. At the final evaluation, the number of patients with depressive symptoms was reduced by 63.2% among responders ( p < 0.001) and did not change in relapsers ( p = 0.13). Anxious symptomatology was reduced by 43.1% in responders ( ps < 0.001) and did not change in relapsers ( p = 0.69). At the multivariate analysis, intake of a prophylactic drug and absence of symptoms of depression at six months emerged as prognostic factors for being a responder (OR 2.406; p = 0.002 and OR 1.989; p = 0.019 respectively), while lack of antidepressant drugs and presence of symptoms of depression at six months were prognostic factors for relapse into overuse (OR 3.745; p = 0.004 and OR 3.439; p = 0.031 respectively). Conclusions Symptomatology referred to affective state and anxiety can be significantly reduced by the treatment of MOH. Baseline levels of depression and anxiety do not generally predict the outcome at six months. Their persistence may represent a trait of patients with a negative outcome, rather than the consequence of a treatment failure.

Cluster headache and other TACs: Pathophysiology and neurostimulation options.

BACKGROUND: The trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders. There are several issues that remain unresolved in the understanding of the pathophysiology of the TACs, although activation of the trigeminal-autonomic reflex and ipsilateral hypothalamic activation both play a central role. The discovery of the central role of the hypothalamus led to its use as a therapeutic target. After the good results obtained with hypothalamic stimulation, other peripheral neuromodulation targets were tried in the management of refractory cluster headache (CH) and other TACs. METHODS: This review is a summary both of CH pathophysiology and of efficacy of the different neuromodulation techniques. RESULTS: In chronic cluster headache (CCH) patients, hypothalamic deep brain stimulation (DBS) produced a decrease in attack frequency of more than 50% in 60% of patients. Occipital nerve stimulation (ONS) also elicited favorable outcomes with a reduction of more than 50% of attacks in around 70% of patients with medically intractable CCH. Stimulation of the sphenopalatine ganglion (SPG) with a miniaturized implanted stimulator produced a clinically significant improvement in 68% of patients (acute, preventive, or both). Vagus nerve stimulation (VNS) with a portable device used in conjunction with standard of care in CH patients resulted in a reduction in the number of attacks. DBS and ONS have been used successfully in some cases of other TACs, including hemicrania continua (HC) and short-lasting unilateral headache attacks (SUNHA). CONCLUSIONS: DBS has good results, but it is a more invasive technique and can generate serious adverse events. ONS has good results, but frequent and not serious adverse events. SPG stimulation (SPGS) is also efficacious in the acute and prophylactic treatment of refractory cluster headache. At this moment, ONS and SPG stimulation techniques are recommended as first line therapy in refractory cluster patients. New recent non-invasive approaches such as the non-invasive vagal nerve stimulator (nVNS) have shown efficacy in a few trials and could be an interesting alternative in the management of CH, but require more testing and positive randomized controlled trials.

Sphenopalatine ganglion stimulation in cluster headache and other types of headache.

Objectives The cluster headache is the most excruciatingly painful primary headache. In some patients, neither preventive treatment nor acute treatment is effective or treatment is poorly tolerated. The sphenopalatine ganglion (SPG) has an important role in the pathophysiology of cluster headache and, for this reason, SPG stimulation has been used to treat cluster headache. Methods We have reviewed the published literature on the role of the SPG in cluster headache and the use of different treatments targeting the SPG. Results Multiple procedures have been used over the SPG to treat pain and trigemino-autonomic symptoms in patients with refractory cluster headache. After obtaining good results in a small number of patients, a miniaturized stimulator was developed. Stimulation of the SPG with this device proved to be efficacious in acute and preventive treatment in a clinical trial involving patients with chronic refractory cluster headache. Implantation of the device is minimally invasive and the most frequent side-effects are mild, such as paraesthesia and pain over the maxillary area. In patients who have used the SPG device for longer than one year, the therapeutic effect remains effective and the side-effects decrease. Conclusions The reported studies have demonstrated that SPG stimulation is a safe and effective treatment for chronic cluster headache. Long-term studies have shown that the effect remains over time and this treatment could be a good choice in patients with chronic refractory headache. We need more data about its potential use in other forms of headache, such as other trigemino-autonomic headaches or migraine.

Optimal management of severe nausea and vomiting in migraine: improving patient outcomes.

Migraine is a common and potentially disabling disorder for patients, with wide-reaching implications for health care services, society, and the economy. Nausea and vomiting during migraine attacks are common symptoms that affect at least 60% of patients suffering from migraines. These symptoms are often more disabling than the headache itself, causing a great burden on the patient's life. Nausea and vomiting may delay the use of oral abortive medication or interfere with oral drug absorption. Therefore, they can hinder significantly the management and treatment of migraine (which is usually given orally). The main treatment of pain-associated symptoms of migraine (such as nausea and vomiting) is to stop the migraine attack itself as soon as possible, with the effective drugs at the effective doses, seeking if necessary alternative routes of administration. In some cases, intravenous antiemetic drugs are able to relieve a migraine attack and associated symptoms like nausea and vomiting. We performed an exhaustive PubMed search of the English literature to find studies about management of migraine and its associated symptoms. Search terms were migraine, nausea, and vomiting. We did not limit our search to a specific time period. We focused on clinical efficacy and tolerance of the various drugs and procedures based on data from human studies. We included the best available studies for each discussed drug or procedure. These ranged from randomized controlled trials for some treatments to small case series for others. Recently updated books and manuals on neurology and headache were also consulted. We herein review the efficacy of the different approaches in order to manage nausea and vomiting for migraine patents.