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Gaining on Migraines: Combination Therapy
Abstract & Commentary
By Donna Woods, DO, Southwest Arizona, Regional Medical Director, NextCare Urgent Care, Tucson, AZ, is Associate Editor for Urgent Care Alert.
Dr. Woods reports no financial relationships relevant to this field of study.
Synopsis: Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.
Source: Brandes JL, et al. Sumatriptan-naproxen for acute treatment of migraine: A randomized trial. JAMA. 2007; 297:1443-1454.
Migraines are headache attacks which are generally characterized by unilateral severe headache, accompanied by nausea, photophobia, and sometimes aura. Several complex mechanisms are involved in migraines. In the initial stage of a migraine, peripheral nerve stimulation leads to CNS vasodilation via the production of inflammatory substances. The inflammatory substances produced during this initial stage sensitize neurons centrally in the trigeminal nucleus caudalis, causing them to fire continuously regardless of input from the periphery. It is hypothesized that this central-sensitization is responsible for the "full-blown" migraine headache.
Triptans have been shown to decrease vasodilation and reduce synaptic transmission between peripheral and central neurons, thus interrupting the activation of central pathways during the early stages of migraine.
NSAIDs inhibit prostaglandin production, which may prevent or reverse central sensitization.
Several recent studies suggest that the combination of sumatriptan succinate and naproxen sodium may be useful in both acute relief and prolonged therapeutic response. This study investigates the efficacy and safety of a combination rapid-release tablet (sumatriptan 85 mg/ naproxen 500 mg) as compared with placebo and monotherapy, with either sumatriptan or naproxen in the acute treatment of migraine.
Methods: Two replicate, randomized, controlled, double-blinded studies were conducted at 118 US clinical study sites. Patients aged 18-65 were enrolled if they had 2-6 migraines per month in the preceding 3 months and if they were able to distinguish their migraines. They were excluded based on pregnancy, breast-feeding, chronic daily headaches, BP > 160/95, and the use of regular NSAIDs, ergots, or St. John's Wort. No migraine prophylaxis medication changes were allowed in the 2 weeks preceding the treatment. Patients were randomized into 4 groups, receiving sumatriptan/naproxen combo, sumatriptan 85mg, naproxen 500 mg, or placebo. They were instructed to use the study-drug at home to treat their next migraine when the pain became moderate-severe. Diary cards were given to patients to record the severity of their headache, associated symptoms, and the use of any additional rescue medications required by the patient after the first 2 hours post-treatment. These characteristics were recorded at 0.5 hrs, 1.0 hour, 1.5 hrs, 2.0 hrs, and every hour thereafter. No second dose of study medication was given. The number of patients included in the study was 1461 in Study 1 and 1495 in Study 2. The primary outcomes measured were the percentage of patients in each group with headache relief 2 hours post-study-drug and 24 hours post study-drug, as well as absence of photophobia, phonophobia, and nausea.
Results: Combination therapy was more effective than monotherapy with either sumatriptan or naproxen for headache relief at 2 hours. The incidences of headache relief at 2 hours were 65%, 55%, 44%, and 28% with sumatriptan-naproxen, sumatriptan monotherapy, naproxen monotherapy, and placebo, respectively, in study1 (P < .001 for all comparisons except combination vs sumatriptan monotherapy where P < .009). The corresponding percentages in study 2 were 57%, 50%, 43%, and 29% (P < .001 for all comparisons, except combination vs sumatriptan monotherapy was P < .03).
The absence of nausea 2 hours after dosing was slightly higher in study 1 (71% vs 65%, P < .007), but was not found to be statistically significant in Study 2.
For sustained pain-free response at 24 hours, the combination therapy was superior (25% and 23% in Studies 1 and 2, respectively; P < .01) to sumatriptan monotherapy (16% and 14%, in studies 1 and 2), naproxen monotherapy (10% and 10% in both studies), and placebo (8% and 7% in studies 1 and 2).
The percentages of patients with at least one adverse event was 27%, 24%, 13%, and 12% in patients receiving combination therapy, sumatriptan monotherapy, naproxen monotherapy, and placebo, respectively, in Study 1. In Study 2, the percentages were 26%, 28%, 14%, and 10% (P < .001 for all comparisons, except the combination drug vs sumatriptan monotherapy, in which case the p value was >.05%, and thus, not significant.
Discussion: The 2 studies published in this report suggest that acute treatment of migraine with both a triptan and an NSAID is superior to treatment with either medication individually for relief at 2 hours post-treatment, and sustained relief at 24 hours. Although these studies appear to be well done, there are some limitations. Most of the patients enrolled in these studies were Caucasian and female. Additionally, concurrent use of oral contraceptives was not adequately addressed. This study also did not compare the combination drug (single, fixed-dose tablet) to treatment with naproxen and sumatriptan as 2 separate tablets.
While no serious adverse events attributed to the study medications were reported in Study 1, one serious adverse event was reported in Study 2. A 58-year-old female patient had been treated with sumatriptan monotherapy and experienced heart palpitations, which required hospital admission. This patient had 5 risk factors for CAD. The patient was treated with aspirin, nitroglycerin, and lorazepam, and the event was reported as resolved several days later.
Common side effects of sumatriptan include flushing, weakness, drowsiness, dizziness, malaise, a feeling of warmth, and paresthesias. The incidence of cardiovascular side effects is as follows: chest pain/tightness/heaviness/pressure (1% to 2%), hyper-/hypotension (1%), palpitation (1%), and syncope (1%). There have been rare reports of myocardial infarction and sudden death,1 possibly due to coronary artery constriction.2
Although triptans are rarely associated with the serious side effect of acute coronary syndrome, there is much evidence available to suggest that they are very safe when administered to select patients. Triptans were administered to 13,664 patients as a part of a large cohort study, and no association was found between triptan treatment and stroke, other cardiovascular events, or death.3 However, in this study, triptans were only prescribed to those at less risk of cardiovascular events.
It is recommended that triptans be avoided in patients with familial hemiplegic migraine, basilar migraine, ischemic stroke, ischemic heart disease, Prinzmetal's angina, uncontrolled hypertension, and pregnancy.4 Triptans should also be avoided in patients being treated with monoamine oxidase inhibitors and ergotamine preparations.5 Triptans have also recently been associated with the risk of serotonin syndrome when administered to patients on selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs).6
Migraine headaches are a common presentation in urgent care centers. The US Headache Consortium recommends the use of migraine-specific agents (eg, triptans, DHE, ergotamine) in patients with more severe migraine and in those whose headaches respond poorly to NSAIDs or combination analgesics.7,8
Many studies have shown that combination therapy for migraines is more effective than treatment with a single drug. Many of these studies have examined adjunctive treatment with anti-emetics. Interestingly, several studies show enhanced relief of migraine pain when anti-emetics are added as an adjunct to treatment. One study randomly assigned 128 patients with migraine to chlorpromazine IV or placebo. Chlorpromazine treatment was associated with significant improvement in pain, nausea, photophobia, phonophobia, and need for rescue medication at 60 minutes, compared with placebo.9 Additionally, chlorpromazine-treated patients had a significantly reduced rate of headache recurrence at 24 hours.
Because migraine headaches can also cause gastroparesis, which can affect absorption of some oral medications, parenteral administration may be preferable. I usually start treatment with IM Toradol and Phenergan. The addition of a triptan should be considered in patients with moderate-to-severe migraines, or to those who do not respond to initial treatment. However, it is extremely important to know the contraindications to triptans well enough to screen which patients may safely benefit from this therapy.
The studies presented in this JAMA article are large, randomized, and double-blinded. However, this data should be examined critically and applied cautiously, as it was funded by GlaxoSmithKline and POZEN, the sponsor of the combination investigational drug.