Proton pump inhibitors (PPIs) are recommended as a first-line therapy when chest pain is thought to be caused by esophageal spasm. Both long- and short-acting nitrates have been shown to provide some relief of pain caused by esophageal spasm. Calcium channel blockers decrease the amplitude and duration of esophageal spasms, but their use does not consistently result in better analgesia than achieved with placebo. This chapter discusses the use of anticholinergic agents such as atropine, hyoscyamine, or propantheline bromide decrease peristaltic contractions and reduce esophageal sphincter tone. There is evidence supporting the use of antidepressants such as tricyclics, trazodone, and SSRIs for treating chest pain caused by esophageal spasm. Regardless of their possible utility in the long term, antidepressants are not likely to be of help in the acute management of esophageal spasm pain in the ED.