Migraine is a syndrome characterised by a paroxysmal, mostly unilateral headache as the leading symptom, varying considerably in intensity, frequency and duration. This headache is usually accompanied by autonomic nervous symptoms such as nausea, emesis, tachycardia, hypersensitivity to light and noise and occasionally by a transitory breakdown of neurologic functions.

The main forms are common migraine, classical migraine and complicated migraine. In the new classification by the International Headache Society, the terms migraine without aura, migraine with aura, and migraine with prolonged aura were introduced. Because the former terms still appear in many of the publications under review, they will also be used in this article. Migraine is a common disease with an estimated incidence of 2-10%. The onset of attacks may date back to early childhood reaching a peak in the third and fourth decades of life. The etiopathology of migraine has not been fully clarified and a causal therapy has therefore not been established. Although various symptoms associated with migraine respond to drug therapy, one should differentiate between the interruption of attacks and the prevention of migraine (i.e., treatment also during attack-free intervals).

The association between migraine and several psychiatric disorders has been well demonstrated; the most important comorbidity appears to be with mood, anxiety and panic disorders. The migraineurs have a five-fold higher risk of depression, and longitudinal studies have shown that the relationship is bidirectional in patients with depression having a three-fold higher risk of migraine. This bidirectionality suggests that migraine and depression share a common neurobiology. Moreover, compared to individuals without migraine, migraineurs are at 4-5 times greater risk for generalised anxiety disorder (GAD), at five times greater risk for obsessive compulsive disorder (OCD), and run 3-5 times higher risk of suffering from panic disorder. An increased risk is demonstrated for suicide ideation too, especially in migraine with aura.

The onset of anxiety often precedes migraine, while the risk of depression usually increases later. From a clinical point of view, the coexistence of a psychiatric disorder has many practical implications: it alters the quality of life, the total disability, the course of migraine and the final prognosis. A subgroup of migraine sufferers evolves from a stage of episodic migraine into a stage in which the pain is present almost daily (chronic migraine). Several factors have been associated with migraine clinical progression: depression and stressful life events are independent risk factors for progression and may affect other negative variables such as obesity and medications overuse. The relationship between obesity and migraine frequency is modified by depression and anxiety and the strongest effect on migraine frequency is observed in migraineurs with both depression and anxiety. A complex relationship exists with sleep disorders that may result from or may cause headache. Depression and anxiety cause disturbed sleep and sleep deprivation or excessive sleep may increase the frequency of migraine attacks. There are many clinical evidences that depression plays a role in the processing and perception of pain, and that depressed patients are more vulnerable to painful physical symptoms. Cutaneous allodynia is the perception of pain or discomfort in response to non-noxious thermal and mechanical stimuli applied to normal skin; it is a clinical marker of central sensitisation and is more common in frequent and chronic migraine. Some studies report the association between cutaneous allodynia and both anxiety and depression, which probably support the central sensitisation. Furthermore, migraine and depression are associated to other comorbid pain conditions (irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia) that share the common mechanism of central sensitisation and have common clinical correlates such as allodynia and hyperalgesia. The first clinical implication of the previous considerations is that all patients presenting with frequent episodic and chronic migraine should be screened for depression and anxiety. It has been seen that psychiatric comorbidity contributes to poor prognosis and poor quality of life, but the effect of treatments both for migraine prevention and for mood and anxiety disorders on final outcomes was not examined.

Researchers prospectively examined how psychiatric disorders relate to treatment outcome in a group of patients with primary headaches. They confirmed that psychiatric comorbidity is very frequent (two-thirds of their patients were diagnosed with one or more psychiatric disorders), and that the presence of a comorbid depressive disorder is associated with more frequent and disabling headaches, and also found that patients with psychiatric disorder improve equally as well as patients with no psychiatric disorder. In this study, patients received the “best” state-of-the-science treatment and, of course, those with a mood disorder were more likely to be prescribed antidepressant therapies. The conclusion may be that a migraine patient with psychiatric comorbidity is a difficult one; often he begins treatment with more headache days, more disability, and poorer quality of life, but has good expectations of improvement, if psychiatric comorbidity is treated. Moreover, treating anxiety and depression means to prevent central sensitisation and the evolution to chronic migraine.

Specific therapeutic guidelines for depression and anxiety in migraine are lacking. First of all, choosing a drug for migraine prevention that may worsen the psychiatric comorbid disorder, has to be avoided. This is true for flunarizine and beta-blockers in depression. When it is possible, treatment of both conditions would be accomplished with a single agent.

Between the drugs with known effect on migraine prevention, beta-blockers and flunarizine may help if anxiety is present; amitriptyline is indicated in mood disorders, but the dose required for treating migraine may be insufficient to treat the affective disorder, and larger dose may cause collateral effects. In specific cases, some drugs may play a role in both migraine and psychiatric comorbidity. Pregabalin is indicated in anxiety disorders and has recently been approved in the United States for the treatment of fibromyalgia that, as it is seen, is one of the chronic pain conditions associated with migraine and depression. Furthermore, it might be a useful alternative prophylaxis for chronic migraine.

Divalproex sodium (VPA), topiramate and lamotrigine have demonstrated efficacy in bipolar depression. The efficacy of VPA and topiramate in migraine prevention has been shown in several double blind, randomised, placebo-controlled trials and some studies suggest that lamotrigine constitutes a specific prophylactic treatment of migraine with aura. The migraineurs can sometimes derive benefit from some less traditional approaches, such as riboflavin or coenzyme Q10, which have marginal evidence in depression in specific cases. When a single agent has insufficient effect or is not tolerated, two different drugs must be used, one for migraine prevention and one for the psychiatric disorder. The American College of Physicians recommends the second-generation antidepressants as the treatment of choice for acute episodes of major depression without striking differences between selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs).

In a parallel, double-blind comparison study of flunarizine, a significant reduction in the frequency of attacks as compared with placebo was recorded. In the third month of treatment, more than 80% of the patients receiving flunarizine had no attacks. Based on these encouraging results, more double-blind trials against placebo were carried out. Six published studies with an adequate number of patients are now available. All of these studies were carried out in patients with simple or classical migraine according to the definition of the Ad Hoc Committee. The common criteria for patients in these studies was a throbbing or pulsating pain in severe attacks requiring therapy, and at least three attacks per month occurring within the last 3 months before the start of the study. In all studies, a consistently significant reduction of the frequency of attacks or the headache index was demonstrated. Therefore, the efficacy of flunarizine in migraine prophylaxis must be considered as well as established. In view of the enormous body of data documenting the efficacy of flunarizine and comparing this substance with other migraine prophylactics, more specific approaches will be of particular importance in the future. Because the benefit/risk ratio of flunarizine is comparable to that of propranolol and metoprolol, it would be useful to the practicing physician to know which type of migraine patient reacts particularly well to a given substance.
Neurol Sci. 2010;31 Suppl 1:S95-8

A migraine is a common type of headache that may occur with symptoms such as nausea, vomiting or sensitivity to light. In many people, a throbbing pain is felt only on one side of the head. Triptans have demonstrated superior efficacy in acute migraine attacks compared with other substance classes and these drugs are currently widely used for pain relief. Seven different triptans almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan and sumatriptan are marketed for the treatment of acute migraine. As only a few head-to-head studies have compared the efficacy of rizatriptan with other triptans, the comparison of the efficacy and tolerability of the different triptans cannot be based on comparative studies alone. Therefore, the present report is focused on the comparison between oral sumatriptan 100 mg and oral rizatriptan 10 mg.

Owing to the quick absorption of rizatriptan, a more rapid pain relief with rizatriptan treatment compared with sumatriptan treatment seems to be probable.

A large randomised, double-blind, placebo-controlled, triple-dummy study comparing oral treatments with rizatriptan 5 mg, rizatriptan 10 mg, sumatriptan 100 mg and placebo in 1268 patients with migraine was designed to assess the time to onset of action and the efficacy versus placebo. In each patient, treatment of one acute migraine attack was documented.

Response rates
The response rates (pain relief rates) were numerically greater with rizatriptan 10 mg than with sumatriptan 100 mg at each time point upto 2 h post-dose. Statistical significance was achieved 1 h after drug application. At 1.5 and 2 h post-dose, statistically significantly more rizatriptan 10-mg patients were pain-free compared with sumatriptan 100-mg patients (1.5 h: 24 vs. 18%, p?0.05; 2 h: 40 vs. 33%, p=0.032; Figure 1).

Time to pain relief
As patients receiving sumatriptan were significantly older, an age-adjusted analysis was conducted to correct this imbalance in the total population. The adjusted analyses showed a faster pain relief with rizatriptan 10 mg compared with sumatriptan 100 mg (hazard ratio: 1.21; p=0.032).

Safety & tolerability
Drug-related adverse events occurred less frequently with rizatriptan 10 mg compared with sumatriptan 100 mg (33 vs. 41%; p=0.014). Serious adverse events were not observed.

In an open-label, 'naturalistic' multicentre study, two migraine attacks were treated crossover, either with rizatriptan 10 mg or the oral triptan which the patients were used to. In total, 673 patients were included and outcomes were recorded using a diary and a stop watch. Significantly, more patients achieved pain relief or pain freedom when taking rizatriptan 10 mg compared with treatments with other triptans 2 h after dosing (pain relief: 88.1 vs. 81.9%; p=0.0003; pain freedom: 60.9 vs. 49.9%; p<0.0001).

Patient's preference for rizatriptan 10 mg or sumatriptan 50 mg was investigated by two rando- mised, open-label, multicentre studies. Almost twice as many patients preferred rizatriptan 10 mg to sumatriptan 50 mg (64.3 vs. 35.7%; p≤0.001). Most patients preferred rizatriptan owing to the faster pain relief.

A meta-analysis of 53 randomised, double-blind trials (12 unpublished) investigating triptan treatment in acute migraine attacks was performed to deliver further evidence supporting therapeutic decisions in clinical practice.

In most studies included in this analysis, the headache response rate at 2 h post-dose was the primary endpoint. A second endpoint used in several more recently performed studies is the proportion of patients becoming pain-free at 2 h post-dose.

Mean absolute sumatriptan 100-mg response rate at 2 h was 59% (improvement from moderate or severe to mild or no pain); the placebo-subtracted response rate was 29%. Rizatriptan 10 mg and eletriptan 80 mg showed significantly higher absolute response rates, but placebo subtracted response rate differed only numerically between rizatriptan 10 mg and sumatriptan 100 mg without reaching statistical significance.

A total of 29% of sumatriptan 100-mg patients were pain-free at 2 h. Higher pain-free rates than sumatriptan were observed with rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg. The placebo-subtracted pain free rates were significantly higher with rizatriptan 10 mg and eletriptan 80 mg compared with sumatriptan 100 mg (19%). Treatment with rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg also resulted in significantly higher sustained pain-free rates than sumatriptan 100 mg (20%). Details are presented in Figure 2.

A retrospective subgroup analysis including the data from five randomised placebo-controlled double-blind trials demonstrated that more rizatriptan patients were able to function normally (grade 4 on the scale of functional disability) at 2 h after receiving rizatriptan 10-mg medication compared with sumatriptan 100 mg (39 vs. 32%), sumatriptan 50 mg (47 vs. 42%), sumatriptan 25 mg (48 vs. 36%), naratriptan 2.5 mg (39 vs. 22%) and zolmitriptan 2.5 mg (45 vs. 36%).

Based on the data of the meta-analysis of randomised placebo-controlled trials reported by Belsey, the relative cost-effectiveness of different oral triptan therapies in the management of acute migraine attacks was calculated using cost data from six different countries. Cost-effectiveness ratios were derived from the NNT for each triptan and dose was analysed based on the mean drug acquisition costs in the six countries.

Pain-freedom after 2 h was achieved most efficiently with rizatriptan 10 mg. Rizatriptan 10-mg treatment resulted in the lowest mean drug cost per pain-free patient at 2 h in all six analysed countries, followed by eletriptan 40 mg.

The researches concluded that the differences in triptan efficacy have potential economic implications. Despite the differences in the international pricing structures, this analysis demonstrated that rizatriptan 10 mg and eletriptan 40 mg are the most cost-effective oral triptans together with a considerable degree of consistency in the hierarchy of cost-effectiveness in the six investigated countries.

An open pharmacy-based study investigated migraine treatment in 231 patients (589 documented migraine attacks) based on patient diaries. The primary objective was the triptan consumption per migraine attack (upto 24 h after the first triptan dose). A total of 149 attacks were treated with rizatriptan 10 mg, 149 with zolmitriptan 2.5 mg, 135 with sumatriptan 50 mg and 90 with naratriptan 2.5 mg. Rizatriptan 10 mg was given more frequently in severe attacks than sumatriptan 50 mg or zolmitriptan (43 vs. 37 and 33%, respectively).The tablet consumption per attack (24 h) was lower with rizatriptan 10 mg (1.24±0.56 tablets) compared with sumatriptan 50 mg (1.75±1.2 tablets; p≤0.05), zolmitriptan 5 mg (1.61±0.86 tablets; p≤0.05) and naratriptan 2.5 mg (1.46±0.62 tablets; p=0.05). 81.2% of rizatriptan 10-mg patients needed only one tablet per 24 h compared with 51.9% of sumatriptan 50-mg patients, 55.7% of zolmitriptan patients and 60% of naratriptan patients (Figure 3).

Patients receiving sumatriptan or zolmitriptan had a more than three-times greater probability of using more than one tablet per attack (sumatriptan: odds ratio: 3.71; p=0.001; zolmitriptan: odds ratio: 3.32; p=0.001) than rizatriptan 10-mg patients. In patients treated with naratriptan, this probability was more than two-times greater (odds ratio: 2.66; p=0.004).

Head-to-head comparisons and large meta-analyses of clinical studies delivered strong evidence for a superior efficacy of rizatriptan 10 mg compared with sumatriptan 50 mg and 100 mg in acute migraine attacks. With rizatriptan 10 mg, patients achieve pain relief more rapidly and a higher percentage become pain-free at 2 h. The greater efficacy of rizatriptan 10 mg also results in lower tablet consumption during the first 24 h after a migraine attack compared with sumatriptan. The vast majority of rizatriptan patients need only one tablet per attack.

One reason for the insufficient treatment of German patients suffering from migraine might be cost restrictions. In Germany, physicians have to comply with many prescription guidelines imposed by the Regional Associations of Statutory Health Insurance Physicians and are financially liable in the case of exceeding prescription limits. After generic sumatriptan became available in 2006, the percentage of German patients treated with triptans is likely to have increased. However, sumatriptan response rates are relatively low and treatment failures occur frequently. Nevertheless, the German Regional Associations of Statutory Health Insurance Physicians consider sumatriptan as the lead substance of the triptan drug class and favours the prescription of sumatriptan, but treatment with sumatriptan 100 mg is not optimal for the treatment of migraine attacks.

The placebo-subtracted response rate achieves 29% and only 29% of patients will be pain-free at 2 h. Rizatriptan 10 mg enables a more effective triptan therapy of acute migraine attacks, as it is associated with a more rapid onset of action (the time to pain relief rizatriptan 10 mg vs. sumatriptan 100 mg has a hazard ratio of 1.21; p=0.032) and a considerable higher efficacy rate (pain-free rate at 2 h: 40.8%).

A further argument in favour of rizatriptan 10 mg is the consistent efficacy. The consistency demonstrated by a study observing four acute migraine attacks, with placebo given at random in one attack and rizatriptan in the three other attacks, was the highest observed with a triptan: 60% of patients responded to rizatriptan 10 mg in all three verum-treated attacks. This higher reliability and consistency of rizatriptan 10 mg is an advantage for patients and resulted in excellent cost-effectiveness demonstrated by a great international analysis. However, these results were only demonstrated in a study including rizatriptan patients only, not in a head-to-head study.

The start of migraine treatment with generic sumatriptan 100 mg does not seem to save economic resources. The reductions of drug spending are smaller than initially expected as more sumatriptan patients need a second dose compared with rizatriptan 10 mg treated patients. Further factors increasing direct and indirect health costs in patients receiving sumatriptan might be more frequent clinic visits and an increased amount of working time lost. In conclusion, meta-analyses of double-blind placebo- controlled studies confirmed the superior efficacy and tolerability profile of rizatriptan.
Expert Rev Neurother. 2010;10(4):499-506