Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine

Published - Written by Rebecca Berger, MD

Written by Rebecca Berger, MD


Julie is a 12-year-old girl who comes to your office to discuss her migraines. She has been suffering from classic migraines since she was 9 years old. She typically experiences migraines 1 to 2 times per week that last for a few hours and are characterized by throbbing unilateral headache, photophobia, and nausea. Julie often misses school because of her debilitating symptoms. Julie’s mother is with her in the office today; she also suffers from migraines, but topiramate treatment for the last 8 years has reduced the frequency of her migraines. Julie and her mother ask whether Julie would benefit from taking topiramate.

Current guidelines for the treatment and prophylaxis of migraines in pediatric and adolescent patients are based on expert consensus, not evidence. Currently, no medications are FDA-approved for the prevention of migraines in children. A survey of pediatric headache specialists indicated that amitriptyline and topiramate are the two medications prescribed most often for pediatric migraine prevention.

In this week’s issue of NEJM, the phase 3, multicenter, double-blind, placebo-controlled CHAMP trial compared the effects of amitriptyline, topiramate, or placebo in 361 children and adolescents (age range, 8–17 years) with a diagnosis of migraine. Inclusion criteria were baseline headache frequency ≥4 days per month and at least mild headache-related disability. Patients were required to complete a daily headache diary and the PedMIDAS questionnaire to assess the effect of migraines on school, home, play, and social activities.

The 24-week trial was stopped early for futility, with no significant difference among the three groups in the primary outcome of a ≥50% reduction from baseline in the number of headache days (52% , 55%, and 61% of patients in the amitriptyline topiramate, and placebo groups, respectively (P=0.26 for amitriptyline vs. placebo, P=0.48 for topiramate vs. placebo, and P=0.49 for amitriptyline vs. topiramate). Disability scores also did not differ among the three groups. When compared with patients in the placebo group, patients in the amitriptyline group reported higher rates of fatigue (30% vs. 14%, P=0.01) and dry mouth (25% vs. 12%, P=0.03); patients in the topiramate group reported higher rates of parasthesias (31% vs. 8%, P<0.001) and weight loss (8% vs. 0%, P=0.02). Of the 12 serious adverse events reported during treatment, there were three cases of altered mood and one case of syncope in the amitriptyline group and one suicide attempt in the topiramate group.

This important negative trial found no difference in headache frequency or disability scores among children and adolescents who received topiramate, amitriptyline, or placebo. The large placebo effect in this trial is notable, with 61% of placebo recipients experiencing the primary outcome of a 50% reduction in headache days, similar to rates in the two active treatment arms. However, the high incidence of adverse events in the active treatment groups suggests that the benefits of prescribing these medications do not outweigh the harms.

It is difficult for clinicians to know what to do with such a large placebo effect — should we be prescribing placebos? In an accompanying editorial, Dr. Jeffrey Jackson from the Department of Medicine at the Medical College of Wisconsin writes, “Unlike practitioners in the 1800s, who often prescribed ‘the blue pill’ (composed primarily of chalk), modern doctors feel uncomfortable with deception. There is clinical evidence that provider reassurance and empathy and the addressing of patient concerns can reduce symptom burden and improve functioning for numerous somatic conditions.” He adds, “At this point, reaching for the prescription pad may not be the best answer for pediatricians caring for patients with migraine headache.”

When you share the results of the CHAMP trial with Julie and her mother, you explain that evidence does not support the efficacy of topiramate treatment in children. You discuss nonpharmacologic strategies and benign headache treatment remedies and schedule a follow-up appointment.

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Rebecca is a 2016-2017 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Columbia University College of Physicians and Surgeons in 2013 and completed internal medicine residency at Massachusetts General Hospital in 2016. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.