Intravenous Ibuprofen for Acute Treatment of Migraine

A Double-blind, Randomized, Placebo-controlled Pilot Study

Hsiangkuo Yuan MD, PhD; John G. Curran BS; Scott W. Keith PhD; Mary M. Hopkins BSN; Stephen D. Silberstein MD


Headache. 2021;61(9):1432-1440. 

In This Article

Abstract and Introduction


Objective: To evaluate the efficacy and safety of intravenous (IV) Ibuprofen for acute treatment of migraine.

Background: IV nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. To date, only three IV NSAIDs (ketorolac, ibuprofen, and meloxicam) are available in the United States for use in moderate and severe pain, but no placebo-controlled trial is available for migraine. We performed a single-center, double-blind, randomized, placebo-controlled pilot study to evaluate the efficacy and safety of IV ibuprofen as an acute treatment of migraine (NCT01230411).

Methods: Individuals with episodic migraine were screened at the Jefferson Headache Center. Qualified subjects were treated for migraine attacks within 2–72 h following the headache onset with either 800 mg of IV ibuprofen or placebo in 250 ml saline bolus. Migraine pain intensity (4-point Likert scale) and associated symptoms were assessed at predetermined time points (0.25, 0.5, 1, 1.5, 2, 4, 8, 24 h). The primary endpoint was pain relief at 2 h after infusion. Important secondary endpoints included pain freedom at 2 h, sustained relief over 24 h, use of rescue therapy, and absence of associated symptoms. Adverse events (AEs) were also collected.

Results: Seventy-four participants were enrolled between 2011 and 2017. Forty-four subjects (female 33/44; 75.0%) with mean (SD) age 41.0 (11.2) 11.2 years came for the treatment. All treated subjects (n = 44) were included in the analysis. Among them, 23 were randomized to receive IV ibuprofen. Both groups were demographically similar except for longer migraine duration (i.e., years lived with disease) in the active treatment than in the placebo group. At 2 h posttreatment, pain relief was found in 74% (17/23) and 48% (10/21) after IV ibuprofen and placebo, respectively (odds ratio [OR] 3.12, 95% CI: 0.88–11.0; p = 0.078). Other secondary endpoints at 2 and 24 h were not significant. The longitudinal repeated-measures analysis within 2 h on ibuprofen treatment showed significant pain relief (OR 2.47, 95% CI 1.08–5.7; p = 0.033) and absence of associated symptoms: photophobia (OR 4.0, 95% CI 1.57–10.3; p = 0.004), phonophobia (OR 3.12, 95% CI 1.16–8.4; p = 0.025), and osmophobia (OR 3.45, 95% CI 1.01–11.8; p = 0.048). AEs were observed in seven subjects in both groups, with arm pain being the most common. No serious AE was reported.

Conclusion: This study did not meet the primary endpoint but showed pain relief and elimination of several associated symptoms within 2 h on repeated-measures analysis. Although limited by small sample size and high placebo response, our results indicate that IV ibuprofen may be a safe and effective option for acute treatment of migraine, but more extensive studies are necessary.


Migraine, a neurovascular disorder involving the trigeminovascular system, is the second most common cause of years lived with disability globally.[1] Patients with migraine had total annual costs (direct, indirect) that were $8924 higher than demographically similar individuals without evidence of migraine.[2] During migraine attacks, patients may experience a reduced ability to function, where some may require bed rest or emergency room visits.[3,4] However, migraine treatments are not always satisfactory. In a sample of Migraine in America Symptoms and Treatment study, more than 95% of participants using oral acute migraine medication reported at least one unmet treatment need, such as inadequate treatment response and demanding attack characteristics.[5] An effective treatment strategy remains a critical part in reducing the disability, burden, and cost of care for these patients.

Patients presenting to an ambulatory setting or emergency room with a severe migraine have a limited number of treatment options. First-line treatment includes intravenous (IV) fluid, antidopaminergic agents, steroids, dihydroergotamine (DHE), and nonsteroidal anti-inflammatory drugs (NSAIDs).[6] In contrast to opioids, NSAIDs are not addictive and do not cause urinary retention, constipation, or ileus. Unlike antidopaminergic agents, NSAIDs are associated with no extrapyramidal side effects. They have fewer gastrointestinal (GI) and vasoconstrictive adverse effects than DHE. Unlike triptans and combination analgesics that can cause rebound headaches, in fact, NSAIDs may protect against migraine chronification, especially if taken fewer than 10 days per month.[7] However, the use of oral NSAIDs is sometimes not an option, particularly in patients with severe migraine who may have emesis and gastroparesis. IV NSAIDs can be an effective alternative for acute migraine relief in the emergency room.[8] To date, there are three IV NSAIDs (ketorolac, ibuprofen, and meloxicam) approved by the Food and Drug Administration (FDA) for use in moderate to severe pain. Ketorolac 30–60 mg IV/intramuscular (IM) is the only parenteral NSAID that has been assessed by the American Headache Society with a level B evidence for acute treatment of migraine.[9] It may be offered to adults who present to the emergency room with migraine (Level C).[10] However, only active controlled trials were performed on IV ketorolac for migraine; the placebo effect of IV ketorolac in patients with migraine was not assessed.[11–14]

IV ibuprofen (Cumberland Pharmaceuticals Inc., Nashville, TN, USA) has been approved by the FDA to treat pain and fever. Due to its balanced cyclooxygenase inhibition profile, ibuprofen has less bleeding risk than more cyclooxygenase-selective NSAIDs.[15] IV ibuprofen is as effective as IV ketorolac for treating perioperative pain.[16–18] IV ibuprofen may thus offer another parenteral NSAID option for acute headache treatment, but its efficacy in migraine is not well known. We hypothesized that IV ibuprofen reduces migraine pain intensity at 2 h after infusion. This pilot study assessed the efficacy and tolerability of injectable ibuprofen to treat migraine headaches in the ambulatory setting.