Abstract
The efficacy of triptans in the treatment of migraine was recently contested. How high is then the maximum effect of a triptan?
After subcutaneous naratriptan 10 mg a 88% pain-free response was observed. This result was obtained despite the fact that more half of the patients had a migraine duration of > 4 h. These results indicate that subcutaneous naratriptan in a high dose can overcome central sensitization that occurs in migraine attacks.
It was recently stated that: ‘Although the availability of triptans—selective agonists of serotonin (5-hydroxytryptamine [5-HT]) receptors that activate 5-HT1B and 5-HT1D (5HT1B/1D) receptor—has greatly improved the acute treatment of migraine, many patients have no response to triptans, complete pain relief is the exception rather than the rule, and their vasoconstrictory properties cause concern among doctors and patients alike. Thus, new approaches to the managements of migraine are needed’ (1).
Why are not all migraine patients responding to the migraine-specific triptans? How high is the maximum effect of a triptan?
For oral triptans the maximum response for headache relief is approximately 70% when treating moderate or severe headache with rizatriptan 10 mg or eletriptan 40 mg (2, 3). The pain-free response, the currently suggested more strict primary efficacy measure (4), is approximately 40% after rizatriptan 10 mg when treating moderate or severe headache (2), and the pain-free response increases to 70% when mild migraine is treated early with rizatriptan 10 mg (5). However, the highest pain-free response rates were found after subcutaneous naratriptan when treating moderate (35%) or severe (65%) migraine headaches in a double-blind, placebo-controlled, in-clinic, randomized clinical trial (6). The pain-free response for placebo was 17% (n = 63), which increased with increasing doses of subcutaneous naratriptan: 0.5 mg = 30% (n = 60), 1 mg = 44% (n = 55), 2.5 mg = 60% (n = 42), 5 mg = 79% (n = 34) and 10 mg = 88% (n = 34) (Fig. 1) (6). So despite a limited number of patients, a clear cut dose–response curve with maximum responses for the two highest doses was established in this trial (6). For subcutaneous sumatriptan 6 mg (n = 47) the pain-free response was 55% (6). Natriptan 10 mg was superior to sumatriptan 6 mg: difference +33% (95% confidence interval: +15% to +51%). The most likely explanation for this superiority of naratriptan is the fact that it is two to three times more potent than sumatriptan at the 5-HT1B/1D receptor in some animal models relevant to migraine (7). Unfortunately, naratriptan was developed further as an oral form only in a low dose of 2.5 mg, which causes no more adverse events than placebo but results in only a 23% pain-free response (2, 8, 9).
Pain-free response after 2 h for placebo, subcutaneous sumatriptan (Su) 6 mg and subcutaneous naratriptan (Na) 0.5–10 mg (6). For number of patients in each treatment group, see text.
The high pain-free response rates for subcutaneous naratriptan 5 mg (79%) and 10 mg (88%) in this in-clinic study were obtained despite the fact that 59% (10 mg) to 68% (5 mg) of patients had a migraine duration of > 4 h (6). Most of the patients should by then have developed central sensitization with cutaneous allodynia (10). The results indicate that central sensitization can be overcome by subcutaneous naratriptan, in contrast to results with subcutaneous sumatriptan 6 mg, where only non-allodynic patients responded in one study (11). The possible influence of central sensitization on the response to triptans thus needs further investigation.
In conclusion, after subcutaneous naratriptan 10 mg complete pain relief is the rule rather than the exception. Most patients respond to a triptan if the right drug and the right formulation are used.
Competing interests
P.T-H. has consulted for and conducted studies for AlmirallProdesfarma, Johnson & Johnson, Pfizer, Pozen Inc. and Vanguard.