Although common, neurocardiogenic syncope (NCS) encompasses a diversity of clinical presentations, disease states, and underlying pathophysiologic mechanisms. As such, treatment of NCS can prove quite challenging. Numerous treatment options exist for management of NCS including high salt and fluid intake, pharmacologic therapy, tilt training, isometric counterpressure maneuvers, and even implantation of cardiac pacemakers; however, NCS often proves refractory to these measures, for most of which no long-term, controlled clinical evidence of efficacy exists.A 2011 Cochrane Database meta-analysis examined the effects of pharmacologic and pacemaker therapy on patients with vasovagal or carotid sinus syncope [1]. This metaanalysis included 46 randomized controlled or randomized cross-over trials of drug therapy including beta-blockers, fludrocortisone, alpha-adrenergic agonists, selective serotonin reuptake inhibitors (SSRIs), salt tablets, anticholinergic agents, ACE inhibitors, disopyramide, and dual-chamber pacemaker implantation. The median sample size of these studies was only 42 patients, and the conclusion of the analysis was that insufficient evidence exists to support the use of pharmacologic therapy or pacemaker implants for NCS. Similarly, a more recent and comprehensive meta-analysis comprising both randomized and non-randomized studies further highlights the relative paucity of evidence for the commonly used therapies for vasovagal syncope [2]. When limiting the analysis to randomized studies, only midodrine (4 studies with n=400, odds ratio (OR) 0.19, confidence interval (CI) 0.06-0.62, p<0.05) and SSRIs (2 studies with n=131, OR 0.28, CI 0.01-0.74, p<0.05) appeared to be effective in preventing recurrent syncope. Meanwhile, beta-blockers, tilt training, and pacemaker implantation failed to show benefit in reducing syncope.Regarding device therapy for NCS, the devil remains in the details. A 2007 meta-analysis of nine randomized trials comparing pacemaker therapy with medical therapy, usual care, placebo, or different pacing algorithms revealed that permanent pacing decreased the risk of syncopal recurrence in unblinded studies (OR 0.09, CI 0.04-0.22) and studies comparing different pacemaker algorithms (OR 0.04, CI 0.0-0.23); however, in the two available double-blinded trials, there was no reduction in syncope recurrence (OR 0.83, CI 0.41-1.70) [3]. This study underscored the role of response expectancy, i.e., the awareness that a pacemaker was implanted and functioning reduced the risk of recurrent syncope (OR 0.16, CI 0.06-0.40, p=0.0001). Placebo effects have been observed in both invasive and non-invasive studies and subject response expectancy (patient expects improvement), and/or observer response expectancy (physician expects patient to improve) likely plays an important role in that NCS patients have demonstrated symptomatic improvement even without placebo [4]. This effect was particularly striking in the ISSUE 1 study, which was a prospective observational study in which 111 patients with t...