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The Combination of Naratriptan and Prochlorperazine in
Migraine Treatment
Gretchen Tietjen MD; Kathy Athanas RN et al.
Posted: August 2005  
Headache 2005;45:751-762

Objective:   Understanding the pathophysiological mechanisms of migraine had led to treatment with serotonin agonists, most notably the triptans, the first being sumatriptan. Naratriptan is a longer acting triptan, which is well tolerated, and has been associated with a relatively low rate of headache recurrence. Compared with some of the other triptans, it has a slower onset of action and lower efficacy at 2 hours. Dopamine is also purported to play a role in the pathophysiology of migraine. Dopamine receptor antagonists, have been shown to be highly effective in resolving the headache as well as the nausea associated with migraine and they have a relatively fast onset of action. Prochlorperazine, for example, is well tolerated, and has proven efficacy in migraine, at least when given in an intravenous route. Both oral and rectal administration have a peak onset of action 1 hour and can be used in a home regimen. We hypothesize that the addition of a fast peaking, shorter-acting dopamine antagonist may improve the time to response in persons using Naratriptan and increase the likelihood of a complete pain-free response. Our objective in this study was to evaluate the tolerability of, and the response to, oral Naratriptan alone and in combination with a rectal suppository of prochlorperazine, in migraineurs who had previously not had adequate relief with Naratriptan.

Discussion:   Naratriptan is a well-tolerated long-acting triptan. As has recently been reported, long-acting triptans have less efficacy at 2 hours, compared to the shorter acting drugs in the same class. Evaluation of our primary endpoint supported this finding, with only two persons reporting pain-free status at 2 hours. Addition of the fast acting prochlorperazine did not improve this endpoint, with no one reporting to be pain free at 2 hours. Given the 6-hour half-life of Naratriptan, our finding that the pain-free status at 4 hours was substantially higher (50%) than at the 2-hour time point (12.5%) was expected. Our finding that Naratriptan provided meaningful relief in over two-thirds of the migraine attacks is similar to reports in the literature. Naratriptan as compared to the combination regimen is superior in satisfaction with degree of relief, and was preferred over the combination. The small number of subjects and insufficient power for crossover analysis, limits the ability to draw firm conclusions, but this data suggest that the combination is neither beneficial in accelerating the onset of action nor in increasing the overall efficacy, as compared to naratriptan alone. The combination regimen did appear to confer early benefit with regards to clinical disability and treatment of nausea, but this was not sustained at the 4-hour time point. Both regimens were very well tolerated, and specifically, there were no reports of light-headedness, chest pains, or paresthesias. The lackluster performance of the combination was reflected in the fact that it was preferred in only 3 of 17 paired trials. Some subjects stated that they would prefer an oral preparation to a rectal suppository for ease of use, but the trial design avoided bias by using a suppository in both regimens. Larger studies with dopamine antagonists might be beneficial to support or refute our findings, but pairing triptans with other classes of medication, such as nonsteroidal anti-inflammatory drugs, may hold more promise for added benefit.