The Journal of Emergency Medicine, Vol. 56, No. 4, pp. 455–456, 2019 Ó 2019 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter Editorial , THINK OF KETAMINE FOR HEADACHE comparing 1–2 doses of intranasal ketamine (0.75 mg/kg, with the option for 0.25 mg/kg 30 min later) to i.v. metoclo- Primary headache syndromes represent a significant pramide (10 mg) and diphenhydramine (25 mg) (9).Pro- burden of care in the emergency department (ED). Man- viders could opt to administer i.v. ketorolac (30 mg) or agement challenges include refractory, recurrent, or pro- dexamethasone (10 mg) in the control arm (9). Ketamine longed symptoms (1,2). Standard treatment varies, but displayed a clinically significant decrease in pain at often entails administration of parenteral dopamine 30 min (mean change in VAS 29.0 mm), though it was not antagonists, nonsteroidal anti-inflammatory drugs superior to the control arm (mean change in VAS (NSAIDs), fluids, corticosteroids, or diphenhydramine 22.2 mm) (9). A decrease in 13–18 mm has been described (1,2). Dopamine antagonists are an equivalent or as clinically significant (1,3). The intervention and control preferred treatment to NSAIDs, and some consider arm showed similar rates of adverse effects (65.4 and them first-line treatment; however, dopamine antagonists 66.7%, respectively); though there was a higher incidence can cause extrapyramidal effects, for example, restless- of mood changes and feelings of unreality in the ketamine ness or akathisia (5–46% of recipients) and diphenhydra- group, the study was not powered to detect these mine is often given to limit these effects (2,3). differences (9). The majority (80%) of the control arm addi- As an N-methyl-D-aspartate receptor antagonist, keta- tionally received i.v. ketorolac, which implies a similar mine is effective in acute pain management in the ED, effectiveness of intranasal ketamine to the combined admin- and both i.v. and intranasal ketamine have gained traction istration of i.v. diphenhydramine, metoclopramide, and in ED management of acute pain of various etiologies NSAID therapy at 30 min (9). The disparate outcomes (1,4). Evidence regarding ketamine in management of demonstrated by previously published literature on keta- primary headache syndromes has been conflicted (1,5–7). mine in management of primary headache compared to Afridi et al. demonstrated superiority of intranasal the THINK trial may be reflective of variations in ketamine ketamine over intranasal midazolam to decrease migraine dosing, routes, or rate of infusion, or by the selection of me- aura severity (6). In a randomized cross-over trial of 17 pa- toclopramide rather than other dopamine antagonists. tients, subcutaneous ketamine (0.08 mg/kg) displayed supe- Amidst the current opioid epidemic, comfort with rior migraine control compared with placebo (7).InanED- ketamine as a viable intervention for pain relief adds based, prospective placebo-controlled trial of 34 subjects, to the emergency medicine provider’s armamentarium i.v. bolus ketamine (0.2 mg/kg) showed no benefit in man- of nonopioid analgesics and, therefore, the investiga- agement of headache (5). tion of ketamine to manage pain from primary head- A prospective comparison of i.v. diphenhydramine ache is appealing. Further, the intranasal route of (25 mg) and prochlorperazine (10 mg) to i.v. ketamine administration may limit the need for placement of (0.3 mg/kg) and ondansetron in 54 patients was halted i.v. lines or administration of multiple parenteral med- early due to providers’ concern for ketamine-induced ications in this population. dysphoria (1). The prochlorperazine/diphenhydramine Given that the authors had prospectively registered the arm demonstrated superior improvement in patients’ vi- trial as a superiority trial, an admirable level of scientific sual analogue scales (VAS) pain scores at 45 and rigor dictated that Benish et al. did not claim noninferior- 60 min; there was not a significant difference in rates of ity of ketamine to a combined dopamine antagonist/ vomiting, restlessness, need for rescue medications, or diphenhydramine treatment strategy. An external valida- serious adverse events (1). Notably, the i.v. ketamine tion in a noninferiority trial would further strengthen the was administered as a 2-min “push” rather than infusion. case for intranasal ketamine as a first-line agent in the A 15-min infusion of ketamine decreases sedation or feel- management of primary headache. ings of unreality compared to push administration (8). The inclusion criteria for THINK generalize to ED pa- The THINK (Treatment of Headache with Intranasal Ke- tients with “benign” headache. The THINK trial supports tamine) trial is a timely addition to the literature (9).Benish ketamine as an alternative consideration for first-line or et al. report a well-designed, prospective, single-blind trial adjunctive therapy in management of primary headaches 455 456 Editorial in the ED, as well as in the setting of drug shortages or 2. Friedman BW, Esses D, Solorzano C, et al. A randomized controlled contraindications to dopamine antagonist or NSAID ther- trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med 2008;52:399–406. apy (QTc prolongation or renal insufficiency). 3. Gaffigan ME, Bruner DI, Wason C, Pritchard A, Frumkin K. A ran- domized controlled trial of intravenous haloperidol vs. intravenous metoclopramide for acute migraine therapy in the emergency depart- Robert Goodnough, MD ment. J Emerg Med 2015;49:326–34. Department of Emergency Medicine 4. Motov S, Drapkin J, Likourezos A, et al. Continuous intravenous University of California San Francisco sub-dissociative dose ketamine infusion for managing pain in the San Francisco, California emergency department. West J Emerg Med 2018;19:559–66. 5. Etchison A, Bos L, Ray M, et al. Low-dose ketamine does not California Poison Control System improve migraine in the emergency department: a randomized San Francisco Division placebo-controlled trial. 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