Combining therapies for the treatment of migraine: is there a role?

Migraine is a highly prevalent disorder manifesting clinically as headache attacks of moderate-to-severe or severe intensity. The head pain has peculiar characteristics and is usually associated with nausea, photophobia and phonophobia. Migraine attacks may have a variable frequency, promoting disability and -considerable economic and social losses [1–5].

The preventive treatment of migraine should be considered when frequent, severe and long-lasting headache attacks occur. In addition, the excessive and/or regular use of symptomatic medications as well as contraindications, ineffectiveness and serious adverse events from rescue therapies are the main reasons for prescribing medications on a daily basis in order to reduce the frequency of headache episodes [6,7]. Despite the progressive knowledge of migraine pathophysiology and increasing recognition that cortical hyperexcitability, as a result of an imbalance between γ-aminobutyric acid (GABA)ergic inhibition and amino acid-mediated excitation, plays a crucial role in migraine mechanisms, the new and emerging prophylactic agents along with the major medication groups traditionally used, are not efficacious in all patients [8].

Thus, combining different classes of pharmacologic agents could lead to an advantage in efficacy for those patients who were unable to present reduction of the headache frequency with the use of monotherapy. In addition, the combination of more than one drug may promote a synergic effect through the action on different pathophysiologic mechanisms involved in migraine, which could result in a better -outcome and allow the use of lower dosages.

In fact there are data, although not always derived from controlled studies, regarding the superiority of combination therapy for migraine prevention. A study evaluated 52 migraine patients with a history of not responding to a calcium channel blocker, β-blocker or sodium valproate. A combination of propranolol or nadolol plus sodium valproate at the previous dosages was tested. Among the patients treated with the combination, 56% showed a greater than 50% reduction in headache frequency compared with 0% when monotherapy was used. The tolerability with the combination was also acceptable [9].

We also observed that combining a β-blocker and a tricyclic antidepressant plus a calcium channel blocker also provided a better response with regard to headache frequency decrease when compared with the isolated use of each one of these substances. In addition, the use of lower doses was -possible and the -tolerability of the combination was not significantly different from that presented by the patients with the use of each of the medications [10].

Recently, anticonvulsants with neuromodulation activity such as topiramate have been used successfully for migraine prevention. These drugs demonstrate multiple mechanisms of action and can influence ion channels, GABA receptors and glutamate receptors simultaneously [11,12]. The possible combination of an anticonvulsant drug acting on cortical hyperexcitability plus a drug acting on the central serotonergic and noradrenergic systems as a triclyclic antidepressant is potentially attractive for clinical practice. In addition, the common and unpleasant side effect of weight gain observed with most of the traditional prophylactic agents, and specifically with the triciclyc antidepressants, may be counterbalanced by the simultaneous use of topiramate which may represent an additional reason to choose this pharmacologic agent for migraine -prevention [13].

With regard to the acute treatment of the attacks, the objective is to restore the patient to normal function by rapidly and consistently alleviating the head pain and associated symptoms without side effects and recurrence of the attack within 24 h [14].

Clinicians know that some patients respond well to simple analgesics such as aspirin and acetaminophen, or other nonspecific treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and combination analgesics in a monotherapeutic approach [15], but despite the advent of newer, specific and highly effective migraine acute therapies known as triptans or selective 5-HT_1B/1D agonists, most patients still want a rapid onset of complete pain relief [16,17], which cannot be provided by most of the current individual options for migraine treatment, -especially when administered orally [17,18].

Although the triptans provide a positive impact on patient care and clinical practice, they are still far from ideal. Monotherapy using these agents does not result in rapid, consistent and complete relief of migraine and migraine aura in all patients [19,20]. Up to 31% of patients taking a triptan may discontinue its use due to lack of efficacy, headache recurrence, cost and/or side effects [21–23].

On the other hand, evidence has demonstrated that migraine is a complex disorder which seems to involve different pathophysiologic mechanisms characterized by low serotonin, neurogenic inflammation and dopaminergic hypersensitivity. This suggests that addressing one of the involved biologic systems will always stand below the ideal with regard to the efficacy of the treatment [19,23]. These facts point to a path resulting in the combination of drugs aimed at different mechanisms and -systems involved in a migraine attack.

In fact, the conservative approach of monotherapy addressing each of the biologic systems involved in migraine may result in definite, but often suboptimal, relief of a migraine attack. Therefore, it follows logically that polytherapy targeting more than one of these systems should be more efficacious than addressing only a single mechanism involved in migraine pathophysiology [19,24]. In -addition, achieving a rapid onset of action could be able to function before the central sensitization and development of cutaneous -allodynia, providing a better consistency across multiple attacks [25].

The evidence supporting the role of a synergistic effect of drug combinations in migraine is not new and existed prior to the introduction of the triptans. It was demonstrated that combining therapies results in a better outcome. The use of metoclopramide before the intake of an ergot derivative [26], the combination of a dopamine antagonist, a simple analgesic and an attempt to sleep (although the addition of an ergot preparation was necessary to some of the patients) [27], and the combination of IV dihydro-ergotamine plus prochlorperazine [28], have all proven to be highly effective in treating migraine attacks compared with single-drug approaches. We have demonstrated that the combination of a triptan plus a NSAID reduces headache recurrence in clinical practice and may be more efficacious. The combination of sumatriptan 100 mg with 200 mg of tolfenamic acid and 550 mg of naproxen sodium decreased the recurrence rate from 62.5 to 23.8% and from 59 to 25.5% (p < 0.0003), respectively [29,30].

Rizatriptan 10 mg combined with the long plasma half-life cyclooxygenase-2 inhibitor rofecoxib 25 mg reduced recurrence, provided better sustained pain-free rates and demonstrated a trend for better efficacy rates with regard to headache and nausea relief when compared with the single use of rizatriptan [31]. The combination of 10 mg rizatriptan plus 50 mg rofecoxib was more efficient than rizatriptan alone and the combination of rizatriptan plus 200 mg tolfenamic acid with regard to pain-free rates at 2 h and photophobia at 2- and 4-h timepoints. Recurrence was also significantly reduced with both combinations in comparison with rizatriptan alone [32]. These studies were not controlled (with the exception of the combination of sumatriptan plus naproxen sodium) but suggest an advantage of combining a triptan with an NSAID.

Although this evidence suggests better outcomes with the combination of drugs acting on different mechanisms involved in migraine, no rigorous clinical trials have yielded convincing evidence of synergic or even addictive effects of a second or third pharmacologic agent. Despite the attempts to build a theoretical case, polytherapy for migraine prevention remains speculative. Acute treatments combining different agents appears to look more reasonable. However, drug combinations in migraine treatment are common among specialists and may allow the use of lower doses of individual medications, therefore maintaining or improving tolerability. Fortunately, interesting recent progress in the understanding of migraine has led to the ability to develop rational polytherapeutic regimens and controlled trials. However, proving the advantage of such -combinations is anxiously anticipated [19,24].

Conclusion

We therefore suggest that the subset of patients not having achieved a headache frequency reduction of over 50% with the correct use (time and dosages) of at least three single migraine preventive agents should undergo combination therapy with a β-blocker and/or a triclyclic antidepressant plus a anticonvulsant (sodium divalproate or topiramate). In addition, patients also not having achieved a pain-free status in up to 2 h or not presenting sustained pain free for 24 h in at least five previous migraine attacks with their current acute treatment options should also try combination therapy with simple analgesics or a NSAID plus a triptan or a gastro kinetic drug such as 20 mg metoclopramide, 30 mg domperidone or 200 mg trimebutine. The simultaneous use of these three classes of substances may be considered for those still remaining unresponsive to the proposed treatment objectives. Moreover, changing the strategy of utilization for the chosen drugs should also be considered. For those patients with rapid-developing severe headache, a combination of 3–6 mg injectable sumatriptan plus 50–100 mg rectal indomethacin appears to be very effective. If nausea is a critical issue for that specific patient, the use of rectal metoclopramide or the administration of oral domperidone at the first sign of the attack may also be useful.