Introduction

Migraine is a chronic neurovascular disorder characterized by recurrent attacks of headache accompanied by gastro-intestinal and neurological symptoms that typically last from 4 to 72 hours¹. The prevalence in adult populations ranges from 0.7% to 22%, with the highest prevalence in both men and women between the ages of 25 and 55 years². Migraine also poses a significant burden on the health care system in terms of the cost of prescription drugs and care in inpatient, outpatient and emergency settings³. Approaches to treating migraine include nonpharmacologic and pharmacologic treatments for acute migraine and for its prophylaxis. Pharmacologic treatment of migraine attacks primarily aims at alleviating head pain and symptoms accompanying migraine, avoiding headache recurrence, restoring patient’s ability to function, and minimizing the use of rescue medications⁴. These goals are normally achieved with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), opioids, ergotamines, and triptans. New strategies in acute treatment have recently been investigated, for example, calcitonin gene-related peptide (CGRP) receptor antagonists and serotonin 5-HT_1F receptor agonists⁵.

Sumatriptan, the first available triptan, is a selective agonist for 5-HT_1B and 5-HT_1D receptors. The anti-migraine effect results from three main mechanisms of action, i.e. cranial vasoconstriction, peripheral trigeminal inhibition, and inhibition of transmission through second order neurons of the trigeminocervical complex⁶. In moderate to severe migraine, sumatriptan 100 mg has been reported to have similar efficacy to zolmitriptan 5 mg⁷ and almotriptan 12.5 mg and 25 mg⁸ and be superior to naratriptan 2.5 mg⁹. A 50 mg dose has been shown to be as effective as effervescent aspirin 1000 mg but associated with higher incidence of adverse events¹⁰.

Naproxen is an effective nonselective inhibitor of cyclo-oxygenase (COX), resulting in the inhibition of prostaglandin synthesis mediated via both COX-1 and COX-2. Naproxen sodium improved the solubility of naproxen, achieving fast absorption and rapid onset of action. The recent meta-analysis has demonstrated that naproxen sodium is effective in reducing headache intensity, rendering patients pain-free within 2 hours, improving nausea, photophobia, and phonophobia, and sustaining headache relief and pain-free from 2 hours through 24 hours after dosing¹¹.

As both sumatriptan and naproxen sodium have been reported to be effective in treating migraine attack through different mechanisms of action, combining sumatriptan and naproxen sodium may offer more favourable clinical benefits over monotherapy with either agent. In April, 2008, the US Food and Drug Administration approved sumatriptan-naproxen fixed combination tablet developed specifically to target multiple migraine mechanisms. We therefore undertook a systematic review and meta-analysis of the available evidence to evaluate the efficacy and safety of sumatriptan plus naproxen sodium compared with sumatriptan alone in an attempt to determine its therapeutic benefit in the treatment of migraine attacks.

Methods

Identification of studies

Study selection

Data extraction and quality assessment

Statistical analysis

Results

Study characteristics

Figure 1 summarizes the process of identifying eligible studies. We identified 9 published papers^16-23 reporting the results of 10 randomized controlled trials of sumatriptan plus naproxen sodium in the treatment of migraine. All were published in English. Of these, four trials compared sumatriptan-naproxen sodium against placebo ^20-23 and one was also placebo-controlled and measured prostaglandin levels in the saliva of individuals during menstrual migraine²⁴. These five trials were excluded. One trial each reported the number of recurrence in relation to the number of attacks treated¹⁶ and function, productivity, and satisfaction outcomes¹⁹. They were then further excluded. The remaining two papers involving the results of 3 trials met our inclusion criteria for meta-analysis^{17, 18}. It was noted that one paper¹⁸ reported the results from two trials and, therefore, was treated as two separated studies. All the studies included in our systematic review were of high quality. Doses of sumatriptan were 50 ^{mg17 or 85 mg18 and naproxen sodium 500 mg. Characteristics of the included trials are presented in the Table.}

Figure 1

Fig 1 Study selection process

Figure 2

Table. Characteristics of randomized controlled trials of sumatriptan plus naproxen sodium in acute migraine treatment

Efficacy

Headache relief

Pain-free at 2 hr

Relief of migraine-associated symptoms

Sustained headache relief

Headache relief from 2 hours through 24 hours after dosing was better with sumatriptan plus naproxen sodium than with sumatriptan alone. The pooled risk difference of 0.13 (95% CI 0.08-0.17) corresponded to the mean number needed to treat of 8 (95% CI 6-13).

Figure 3

Fig 2 Efficacy of sumatriptan plus naproxen sodium versus sumatriptan in acute migraine attack

Sustained pain-free

Headache recurrence

Safety

Discussion

A combination tablet containing sumatriptan 85 mg (as sumatriptan succinate) and naproxen sodium 500 mg has recently been approved by the US Food and Drug Administration for the acute treatment of migraine¹⁸. As triptans and NSAIDs target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine headaches, it is not surprising that the combination therapy is more effective than sumatriptan monotherapy in the acute treatment of migraine as shown in our meta-analysis. Sumatriptan 50 or 85 mg plus naproxen sodium 500 mg was associated with more patients achieving headache relief, pain-free response, sustained headache relief, sustained pain-free response, and relief of migraine-associated symptoms. The risk of headache recurrence significantly reduced with combination therapy compared with sumatriptan monotherapy. The risk of adverse events did not differ between the two groups. The adverse events commonly reported were somnolence, dizziness, paresthesia, and tinnitus.

The International Headache Society (IHS) recommends that the proportion of patients with pain-free at 2 hours be used as a primary efficacy measure in clinical trials of drugs in migraine as it is clinically relevant and reflects patients’ expectations²⁵. Headache relief at 2 hours, sustained pain-free, and time to meaningful pain relief can be used as secondary efficacy measures. Despite the IHS recommendation and its limited clinical relevance, headache relief (or headache response) has been commonly used as the primary endpoint in many trials in migraine. As migraine is often related with associated symptoms namely nausea, photophobia, and phonophobia, it is also important that drugs used for migraine attack be effective against these symptoms²⁵. The three trials included in our meta-analysis reported the primary efficacy measure in terms of headache relief at 2 hours postdose. We, therefore, used it as the primary outcome in this meta-analysis. The secondary efficacy measures comprised headache relief at 4 hours, pain-free at 2 hours, sustained headache relief, sustained pain-free, relief of migraine-associated symptoms at 2 hours, and headache recurrence. All these measures were included in our meta-analysis.

Migraine pathophysiology involves a combination of events, including the cortical spreading depression (CSD) and the release of inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide which have direct effect on perivascular nociceptors. CSD also triggers the complex mechanisms of afferent and efferent trigeminal vascular events by stimulating the release of CGRP from the trigeminovascular system. PGE2 has also been shown to stimulate CGRP release from the primary cultures of adult rat trigeminal neurons²⁶. The superiority of sumatriptan plus naproxen sodium over sumatriptan alone can be explained by dual mechanisms targeting both serotonergic dysmodulation and inflammation in migraine. Triptans and NSAIDs target different aspects of the vascular and inflammatory processes hypothesized to underlie migraine headaches. Triptans reduce CGRP-mediated vasodilation, inhibit the release of inflammatory mediators from trigeminal nerves, and decrease the transmission of pain impulses to the trigeminal nucleus caudalis^{27, 28}. In particular, sumatriptan acts as 5-HT_1B/1D receptor agonist. 5-HT_1B receptors are expressed mainly on cranial blood vessels whereas 5-HT_1D receptors are expressed on presynaptic trigeminal nerve. Stimulation of 5-HT_1D receptors by sumatriptan will inhibit CGRP and substance P release, thus decreasing neurogenic inflammation and preventing central sensitization. NSAIDs inhibit the synthesis of prostaglandins and may mitigate meningeal inflammation while preventing or mitigating central sensitization arising from activation of glial cells in the brain stem^{29, 30}. Naproxen sodium is more water soluble and provides faster onset of action when compared with naproxen base. Naproxen sodium reversibly inhibits COX-1 and COX-2 enzymes and thereby inhibits prostaglandin synthesis. This mechanism would help reduce CGRP and substance P release from presynaptic trigeminal nerve. Therefore, the combination of sumatriptan and naproxen sodium has pharmacologic rationale since they have different mechanism of actions. Besides the favourable pharmacodynamic combination, the analgesic effects of naproxen which lasts for up to 7 hours would help prolong pain relief when used in combination with short half-life triptans²³. Sumatriptan is short-acting drug, with plasma half-life of 2-2.5 hours, therefore the recurrence of headache is common³¹.

Not all patients respond to sumatriptan. Response rates in terms of headache relief at 2 hours after treatment with oral sumatriptan has been reported to be approximately 60%³². Among the patients who do respond, about one in three experience headache recurrence within 24 hours³³. As demonstrated in our meta-analysis, sumatriptan combined with naproxen sodium further reduced the risk of headache recurrence by 36% (95% CI 20%-49%) in comparison with sumatriptan alone. Sumatriptan plus naproxen sodium thus may offer an alternative option for migraineurs who failed to response adequately to sumatripan monotherapy. Although the risks of adverse events were similar between the two regimens, the use of combination therapy should be cautious as both triptans and NSAIDs have been reported to be associated with serious cardiovascular side-effects^{5, 34}.

Our meta-analysis was not without limitation. Only published trials were included and only three studies were pooled. This may introduce a bias in favor of combination therapy. A funnel plot and the method of Egger et al.³⁵ are normally performed to assess possible publication bias in meta-analysis. However, we did not conduct such test as the number of studies included was too small. Although the trials assessing different doses of sumatriptan (50 and 85 mg) were combined, no significant heterogeneity was observed. Given its overall efficacy and tolerability as demonstrated in our meta-analysis, sumatriptan plus naproxen sodium may offer an alternative in the treatment of migraine headache in migraineurs who do not respond adequately with either sumatriptan or naproxen sodium monotherapy. Nevertheless, further trials are needed for head-to-head comparison with other active agents currently available for the acute treatment of migraine in order to clearly establish its place in oral therapy of migraine headache.

Conclusions

The combination of sumatriptan and naproxen sodium offers more clinical benefits than sumatriptan monotherapy in the treatment of moderate to severe migraine attacks in adults. Sumatriptan 50 or 85 mg plus naproxen sodium 500 mg is consistently effective in alleviating headache, rendering patients pain-free within 2 hours, improving nausea, photophobia, and phonophobia, and sustaining headache relief and pain-free from 2 hours through 24 hours after dosing. It was well-tolerated and caused no more adverse events than sumatriptan monotherapy. Further high-quality, head-to-head trials comparing the combination therapy against other active comparators are warranted to better establish its place in oral therapy in the acute treatment of migraine.

Acknowledgment

We thanks Vorachart Lertpipopmetha and Bhakanit Tepwitukgid for their help in some of data assembly.