Your Migraine Cocktail Didn’t Work? Shake it Up!

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Acute migraine causes 1.2 million visits to the US emergency departments annually. Headache is the fifth leading cause of patients presenting to the emergency department (ED) in the United States. [3] We have previously discussed evidence behind the traditional ‘Migraine Cocktail’ here. In this post, we will address adjunctive therapies when the first-line treatments haven’t broken your headache.

Droperidol

Droperidol is a butyrophenone that exhibits potent central dopamine antagonism. Dopamine receptors are located in the cerebral vasculature and dopamine hypersensitivity may play a role in the pathogenesis of migraine. [2,3] Droperidol is inexpensive, rapid acting, and has a short half-life, but a sordid history. It was widely used prior to 2001, at which time the United States Food and Drug Administration (FDA) instituted a black box warning due to concerns of QT prolongation and potential arrhythmia. Shortly after this occurred, a review of the literature supporting the initial black box warning was performed and published in Annals of Emergency Medicine. The authors concluded that the evidence did not suggest a causal relationship between therapeutic droperidol administration and life-threatening cardiac events. [4,5] In recent years, more studies have been performed to evaluate the safety of this medication. A retrospective observational cohort study published in the American Journal of Emergency Medicine in 2020 analyzed 6,881 visits during which patients received droperidol. No fatalities or fatal arrhythmias were seen among this large cohort of patients. [2] Other studies have been performed in which droperidol was used as an antiemetic or for pain relief in different populations.  While one study showed a small increase in the QT interval, other studies did not. More importantly, no studies showed evidence of QT-related arrhythmias or cardiac events due to use of droperidol. [4-8]  In total, the available data suggest that droperidol is safe to use in the emergency department.

A meta-analysis performed in 2014 concluded that 2.5mg intravenously (IV) or 5mg intramuscularly (IM) of droperidol was superior to placebo and as effective as alternative drugs (prochlorperazine, olanzapine, and meperidine) in the treatment of migraines. Included studies showed over 60% of patients had greater than 50% reduction in pain at 30 minutes and over 90% at 60 minutes. [26] Doses of more than 2.5mg IV did not lead to more pain relief and were associated with an increased incidence of side effects, most commonly akathisia (6.1% to 27.9% of patients) and sedation (6.7% to 15.3% of patients). [3]

Haloperidol

Haloperidol is another butyrophenone that exhibits potent central dopamine antagonism. It also has some affinity for Dopamine-1 receptors, 5-HT2 serotonin receptors, and α1 adrenergic receptors. [9] While haloperidol has also been shown to lead to QT prolongation, this only occurs at higher doses and essentially no fatal QT-related arrhythmias were detected with doses of 2mg IV. [2] Although haloperidol has been less studied for its use in migraines, studies have shown that 2.5mg IV haloperidol is more effective than placebo, with 64.9% of patients reporting more than 50% reduction in pain at 60 minutes, and 58.6% were pain free at time of discharge. [9,11] One study has also compared haloperidol to metoclopramide and showed 5mg haloperidol is as safe and effective as 10mg metoclopramide and might even lead to lower need for rescue medications. [12] Akathisia is a frequent adverse effect, occurring in up to 13.8% of patients. [9]

Magnesium

Magnesium is an intracellular cation that has been associated with both the function of serotonin and regulation of vascular tone, which are both mechanisms that implicate its role in the treatment of migraine. [13] A meta-analysis by The American Headache Society (AHS) in 2016 summarized three randomized controlled trials utilizing magnesium for the management of acute migraine. [15] One study showed that when 2g magnesium sulfate was compared to placebo, with the co-administration of metoclopramide in both groups, there was no statistically significant difference in the primary outcome, which was improvement on a VAS between baseline and ED discharge, though more patients randomized to placebo improved by ≥50% on the VAS. [16] Two studies compared 1g magnesium sulfate with placebo, one found greater headache relief and headache freedom at 30 and 60 minutes among those patients with migraine with aura, though not among those without aura. [17] A third study compared 1g IV magnesium to 10mg IV metoclopramide plus 8mg dexamethasone and found greater decreases in pain intensity at 20 minutes, 60 minutes, and 120 minutes in the magnesium group as compared to dexamethasone plus metoclopramide (18). These conflicting studies led the AHS to state they could not make a recommendation regarding the use of magnesium for migraines. No clear dose related effect can be inferred given more benefit was noted in the studies in which 1g was used versus 2g.

More recent data suggest magnesium may be a reasonable option in managing migraine. A study in 2017 in Iran also compared 1g magnesium sulfate to 30mg ketorolac, and found that the improvement in VAS pain score in the magnesium sulfate group was greater than in the ketorolac group at 60 and 120 minutes. [14] A 2021 study published in the American Journal of Emergency Medicine compared 1g magnesium sulfate to 10mg metoclopramide and to 10mg prochlorperazine. No statistically significant differences in change in pain scores were found between all three treatment arms at 30, 60, or 120 minutes from administration. A post hoc non-inferiority analysis revealed that when compared to prochlorperazine and metoclopramide, IV magnesium was non-inferior. It is important to note that due to the COVID pandemic, the study was halted early and thus underpowered. [13]

Ketamine

Ketamine is a non-competitive n-methyl-D-aspartate (NMDA) antagonist that has both analgesic and dissociative properties. [19] It is believed to prevent cortical spreading depression, a neurologic process that is a possible cause of migraine. [21,22] It is typically used for procedural sedation at dissociative doses (1 – 1.5 mg/kg) and at low doses (0.3mg/kg) for pain control. [20]

In a 2018 study 0.2mg/kg ketamine was not shown to be more effective for the treatment of migraines when compared to placebo. [23] A 2019 study in The Journal of Emergency Medicine, showed that intranasal (IN) ketamine 0.75 mg/kg (max 75mg) was not superior to anti-dopaminergic medications, but might be comparable, and could be a good option when IV access is difficult or not desirable. [24] If given IV, ketamine should be pushed slowly, over 3 to 5 minutes, to decrease feelings of depersonalization and with adequate monitoring. [26] More research should be done at possibly higher doses to truly evaluate the potential of ketamine in the treatment of migraine.

Propofol   

Propofol is a gamma aminobutyric acid (GABA) receptor agonist, which results in its sedative and anticonvulsant effects. Propofol’s anesthetic effects on the central nervous system may diminish the central sensitization causing allodynia and hyperalgesia, which may be the mechanism of pain relief in migraine patients. [27] Evidence for the use of propofol in migraine is limited, more likely due to logistical barriers and known side effects of hypotension and possible apnea. However, a 2020 pilot study performed in Melbourne, Australia, randomized patients to 1mg/kg of propofol (slow push over 1 minute), or that emergency department’s more common treatments (prochlorperazine, metoclopramide, magnesium, IV fluids, morphine, ondansetron). Although a small study with only 30 patients undergoing randomization, the time to discharge from the ED was on average 290 minutes in the group treated with propofol versus 554.5 minutes in the comparator group. No episodes of SBP <100 were noted and only two patients had recorded hypoxia (O2 88%) or required jaw thrust. [27]  A 2019 meta-analysis that covers the use of propofol to treat migraine included a number of small but promising studies. [28] Amongst these is a study comparing propofol with sumatriptan, a common abortive agent. Propofol was administered as a 30-40mg bolus followed by 10 to 20 mg intermittent bolus doses to sedate the patients to Ramsey score of 3 to 4. Pain intensity was significantly lower in the propofol group 30 minutes after treatment but no difference was found at 60 or 120 minutes. [29] Whilst this study did not show adverse effects of hypotension (defined as a 20% reduction in initial blood pressure), this is a known side effect of propofol and the use of this medication would require the patient be in a room with appropriate monitoring and could necessitate more time-consuming care given its potential side effects.   

Valproic Acid

Valproic acid increases GABA levels in the brain, reduces serotonergic cell activity in the dorsal raphe nucleus, and reduces central activation in the trigeminal nucleus caudalis. [30] It also reduces neurogenic inflammation through GABA antagonism. A 2020 meta-analysis set out to evaluate and summarize the safety and efficacy of intravenous sodium valproate/valproic acid (iVPA) for the management of acute migraine (31).  Within this meta-analysis a study showed that when 1g VPA was compared to 10mg metoclopramide and 30mg ketorolac, VPA led to less improvement in headache at 60 minutes. [31,32] A different RCT showed that the change in median VAS scores over 60 minutes after 500mg VPA was significantly lower than with 10mg IV prochlorperazine when evaluating reduction of pain and nausea (32). An RCT compared 400mg iVPA to 6mg SQ sumatriptan and found VPA to be as effective in reduction of pain scores. A different RCT compared 15mg/kg of VPA to 6mg SQ sumatriptan but found response to treatment in valproate group was faster and more effective at 60 minutes compared to the sumatriptan group. Although exact dosing was not reported, it is possible that higher doses led to different results in these two studies. The literature thus supports that valproic acid is inferior to antidopaminergic medications, but at least comparable to Sumatriptan. It seems reasonable to use it as an alternative or salvage therapy.

Steroids

The pathogenesis of migraine might involve a sterile neurogenic inflammation, and corticosteroids theoretically mitigate this inflammation. Studies have shown that dexamethasone is not superior to placebo, or comparable to other treatments in the acute treatment of migraines. [33]  However, several meta-analyses have concluded that dexamethasone can be useful in reducing the recurrence of migraines. [33-36] One study showed that single dose parenteral dexamethasone is associated with a 26% relative reduction in headache recurrence. [36] The ideal dosage of dexamethasone remains unclear since the studies used dosages ranging from 8mg-24mg.  

Sphenopalatine Ganglion Block

There are multiple theories that try to explain how the sphenopalatine ganglion (SPG) block treats migraine pain. One theory discusses the stimulation of the trigemino-autonomic reflex leading to parasympathetic outflow from the SPG, causing vasodilatation of cranial blood vessels that happens during migraine. [37,39] Another possible effect of SPG block is modulation of sensory processes in the trigeminal nucleus caudalis via the afferent sensory fibers, which may change pain processing center and reduce central sensitization to pain that is commonly seen in migraine. [38,39] A 2015 RCT compared performing a block with 0.5% bupivacaine 0.3mL to placebo and found no difference in pain reduction at 15 minutes (40). The physicians used a device called Tx360 to perform this (Figure 1). This study however did not assess for change in pain after the 15-minute mark and only used bupivacaine, which can take longer to peak in effect. As a secondary outcome, at 24 hours, more patients in the bupivacaine group were headache free. An uncontrolled retrospective trial in 2018 assessed the efficacy and safety of this block for migraine pain using the Sphenocath device (Figure 2).  In this study 2ml 2% lidocaine was administered in each nostril. Over 20% of patients were noted to have >50% headache improvement at 15 minutes and 2 hours and this was maintained at 24 hours. [39] Refer to this ALiEM video on how to perform the block without the use of specialized devices.

In summary, due to the multi-factorial nature of headache, it is critical that we have a diverse set of tools to aid our patients. It is always important to consider secondary causes of headache (blood, mass, infection, etc) when typical therapies are not efficacious, however we hope this review will give you the tools to trial some innovative methods of improving patient care.

Post by Martina Diaz, MD

Dr. Diaz is a PGY-1 in Emergency Medicine at the University of Cincinnati

Editing by Chris Shaw, MD and Ryan LaFollette, MD

Dr. Shaw is a PGY-4 in Emergency Medicine at the University of Cincinnati heading to OHSU for medical critical care and Dr. LaFollette is an Assistant Program Director at the University of Cincinnati

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