Abstract
Rizatriptan wafer is a 5HT1B/1D agonist for use in the acute treatment of migraine. It is a freeze-fried formulation, approved for oral administration, which dissolves on the tongue and is swallowed with saliva. In this study the efficacy of sublingually administered rizatriptan 10-mg wafer was evaluated in a randomized, double-blind, placebo-controlled, out-patient study involving 39 migraineurs. Patients were instructed to treat a migraine at the onset of pain in order to evaluate time of onset of pain relief and pain relief at 1 h. The average time to onset of relief was 25 min for patients treated with rizatriptan wafer and 27 min for patients treated with placebo. At 1 h, 50% of the patients receiving rizatriptan wafer and 50% of the patients receiving placebo experienced significant relief. Implications and potential reasons for a high placebo response are discussed.
Introduction
Previous studies have indicated that speed of onset of pain relief is the quality most desired by migraine patients (1). Oral medications are currently the most frequently prescribed migraine formulations on the market. Unfortunately, these oral medications have a relatively slow onset of action compared with parenteral formulations. Medications using alternative routes of administration with a rapid time to onset are available, e.g. subcutaneous sumatriptan injections, which in studies have demonstrated a significant improvement compared with placebo within 15 min of dosing (2). However, many patients prefer oral formulations over injectables. In January 1998, intranasal sumatriptan was introduced to the US market and in some studies demonstrated an onset of action of 15 min compared with placebo (2). Although intranasal sumatriptan has been fairly well received, there continue to be reports of patients not administering the nasal spray properly, resulting in an unpleasant taste. Therefore, many patients end up going back to oral medications.
Currently, the only approved sublingual abortive medication available for migraine treatment is ergotamine tartrate. Theoretically, a sublingual medication could provide advantages over an oral medication by way of rapid onset of action (absorbed into the bloodstream via the sublingual mucosa) and convenience for patients unable to tolerate oral medications due to nausea and vomiting. A sublingual medication also avoids the difficult administration procedures and pain often encountered with other parenteral medications.
Rizatriptan wafer is a relatively new oral migraine medication that is placed on the tongue, where it quickly dissolves and is swallowed with saliva and absorbed from the stomach. Recent studies have indicated a response rate of up to 74% for the wafer at 2 h post-dose (10 mg) (3). Although rizatriptan wafer is not indicated for sublingual use, anecdotal reports suggest that when used sublingually, the wafer has increased effectiveness with a greater speed of onset. An effective sublingual migraine medication with a rapid time to onset of relief would appear to meet successfully many of the important criteria for migraineurs. This study evaluated the efficacy of rizatriptan wafer vs. placebo when used sublingually at the onset of acute migraine.
Methods
This randomized, double-blind, placebo-controlled, out-patient study examined the efficacy of rizatriptan wafer (10 mg) when used sublingually at the onset of acute migraine attacks. The study population consisted of 39 migraine patients who met International Headache Society (IHS) criteria for migraine with or without aura (4). The patients were randomized to either placebo or active medication, both of which were identical in appearance and packaging, and both of which were peppermint flavoured. Patients were instructed to treat a single migraine attack at the onset of pain by placing the medication sublingually until it was fully dissolved. Using a stopwatch the patients then recorded in a diary the time elapsed between dosing and the point at which they experienced significant subjective relief. If significant subjective relief was not reached within 1 h of dosing the patients were allowed to use a rescue medication. Patients were instructed to avoid dosing if they had experienced a migraine within the previous 24 h or if they had previously treated their current migraine with any medications.
Results
A total of 39 patients entered the study. Thirty of these patients took study medication and returned their diaries, and of these 30 patients 15 experienced significant relief within 1 h (50%). The data from these 15 patients were evaluated for the average to time to onset of relief (Table 1). The average time to onset of significant relief for those patients receiving rizatriptan wafer was 25 min vs. an average time to onset of significant relief of 27 min for those patients receiving placebo (t = 1.25, NS).
Time to onset of relief
Out of the 16 patients who treated with rizatriptan wafer, eight (50%) experienced significant subjective relief within 1 h, and out of the 14 patients who treated with placebo, seven (50%) experienced significant subjective relief within 1 h. As with the average time to onset of relief, the overall response rate to rizatriptan wafer was not statistically different from that of placebo.
Discussion
The results of our study indicate that sublingual rizatriptan wafer was no more effective than sublingual placebo in treating acute migraine at the onset of pain. However, both medication and placebo demonstrated an overall effectiveness and response rate comparable to rizatriptan oral medication, which has been shown to have a 45% response rate at 1 h post-dose (3). In our study, the response rate within 1 h was 50% for both placebo and rizatriptan wafer and the time to onset of significant subjective relief was 25 min and 27 min for the wafer and placebo, respectively. The protocol for the sublingual rizatriptan wafer study differed from the oral rizatriptan wafer study in that our protocol instructed patients to treat the migraine at the onset of pain opposed to waiting for the presence of moderate to severe pain. Another difference in the two protocols involved the onset of pain relief. In our study pain relief was determined by when the patient experienced ‘significant relief’, which was subjectively assessed by the patient, whereas in the oral study the onset of pain relief was determined by a scale, in which the patient's pain level needed to decrease from moderate or severe to mild or none.
In looking at the results of the two studies, a high placebo response (50%) is seen in the sublingual rizatriptan wafer study, whereas a more common placebo response (21%) is demonstrated in the oral rizatriptan wafer study. Two factors potentially contributing to the high placebo response in our study may have been the favourable peppermint flavour of the wafer and the route of administration itself. The sublingual sensation that the patient experiences could aid in advancing the idea of a fast-acting and potent medication.
The protocol instructions requiring the patient to dose at the onset of migraine pain may also have acted to amplify positive results. In clinical practice, patients are generally instructed to treat their migraines at the onset of pain, resulting in a greater probability that the migraine will be aborted (5). With the intention of producing a more realistic evaluation of effectiveness and time to onset of relief present in ‘real-life’ treatment situations, patients in our study were instructed to treat their migraine at the onset of pain. However, when treating at the onset, there is the potential that patients may misinterpret non-migraine headache pain for an impending migraine, and thus treat this headache, only to have it naturally subside after a short period of time. This may explain why four patients (three receiving rizatriptan wafer and one receiving placebo) achieved significant relief within 10 min of administration (Table 1). This phenomenon, combined with a low number of evaluable patients, could also contribute to a high number of placebo responders.
All of these factors influencing a placebo response would be expected to affect equally the performance of sublingual rizatriptan wafer. If the active medication was not absorbed sublingually it would still probably be swallowed and absorbed via the gastrointestinal tract, in which case improved effectiveness over placebo would be expected to be seen. Why this was not demonstrated in the results may be explained once again by low patient numbers and also by the results only accounting for the first hour post-dose, prohibiting the wafer from demonstrating any possible superiority to placebo during the period beyond the first hour of treatment.
This sublingual trial of rizatriptan wafer is not directly comparable to other rizatriptan trials due to differences in the route of administration, stage of pain during which the migraine is treated, and qualifications for the onset of relief. It is apparent that to assess more accurately the efficacy of rizatriptan wafer used sublingually vs. placebo used sublingually, additional trials need to be completed.
It is apparent that clarifying the results of this study may only be achieved with additional trials involving a larger number of patients, a protocol analysing a greater period of time post-dose, and possibly a revised protocol dictating at what pain level patients are to treat their migraine.