Abstract
Gastroparesis frequently happens during migraine attacks, postponing the onset of action of orally administered drugs. Furthermore, triptans seem to work better in the earlier phases of the migraine attacks. Therefore, associating a gastrokinetic drug with a triptan may translate into better efficacy and higher consistency of response. Trimebutine is an opioid derivative with exclusive action on receptors of the Meissner and Auerbach plexus throughout the digestive tube. It has no absorption or central penetration. Herein we contrast the combination of rizatriptan plus trimebutine with rizatriptan alone in the acute treatment of migraine. Forty patients with migraine consecutively seen in our clinic were randomized to treat two consecutive moderate or severe attacks with one tablet of 10 mg rizatriptan plus one capsule of 200 mg trimebutine and two attacks with the same triptan and placebo, in counterbalanced order. We collected information on the severity of the attack, as well as presence of nausea and photophobia at the time of drug intake, and after 1, 2 and 4 h. Recurrence and adverse events were also contrasted. Sixty-four attacks were treated with each drug regimen. At 1 h post-dose, 30 (46.8±) of 64 attacks treated with the combination resolved completely, vs. eight (12.5±) of the rizatriptan-treated attacks, a difference of 34± (P < 0.01). At 2 h postdose, 47 (73.4±) attacks treated with the combination vs. 20 (31.2±) of those treated with rizatriptan alone resolved completely, a difference of 42± (95± confidence interval 26, 58, P < 0.001). Regarding nausea and photophobia, the combination was also associated with significantly better response. Recurrence was similar among the two drug regimens, as well as adverse events. The combination rizatriptan and trimebutine is more effective than rizatriptan alone. The combination does not increase adverse events or recurrence of pain.
Introduction
Migraine is a highly prevalent disorder, associated with important unmet treatment needs (1–3). The objective of acute migraine therapy is to restore the patient's ability to function by rapidly and consistently alleviating the head pain and the associated symptoms (4).
Although the triptans represented a tremendous positive impact on migraine care, they are still far from the optimum. Monotherapy using these selective 5-HT1B/1D agonists, especially if given orally, does not result in rapid, consistent and complete relief of migraine in all patients (5). As a result, up to 31% of patients taking a triptan may discontinue its use due to lack of efficacy, headache recurrence, cost and/or side-effects (6–8). Rizatriptan is a second-generation triptan (9) whose efficacy has been evaluated in numerous studies (5, 10, 11).
The pathophysiology of migraine is complex and related to different neurochemical systems. It involves at least a dysfunction in the serotoninergic pathways, neurogenic inflammation and dopaminergic hypersensitivity. Theoretically, addressing one of the involved biological systems may be less than ideal with regard to the efficacy of the treatment (12–14).
The timing of specific acute migraine treatments seems to have important implications in the efficacy of the drugs. There are possible explanations for the low consistency rates of response seen with the oral triptans (5, 7). First, it is known that the their onset of action may be delayed by gastroparesis, a process often accompanying migraine attacks (15). There is also the additional risk that migraine-induced nausea culminates in vomit. Additionally, triptans per se may prolong the gastric emptying time by activating 5-HT1 receptors on gastric myenteric neurons (16). On the other hand, rizatriptan, like the other triptans, seems to work better when given at the earlier stages of a migraine attack (17). Finally, recent evidence suggests that triptans work better if administered before cutaneous allodynia (central sensitization) develops (18).
Early acute treatment of migraine attack may, theoretically, be achieved by giving a triptan an the very onset of a migraine attack or by facilitating its absorption. Trimebutine (β-(dimetylamino)-β-ethylfenethylalcohol-3,4,5-trimetoxibenzoate) is an opioid derivative with exclusive action on κ, µ and δ receptors of the Meissner (submucous) and Auerbach (mioentheric) plexus throughout the digestive tract. It has no analgesic effect. It also does not penetrate the blood–brain barrier (19, 20). Clinical studies, as well as clinical experience, support the concept that daily use of trimebutine is safe (21). The aim of this study was therefore to evaluate whether the combination of rizatriptan plus trimebutine would provide better pain-free rates, compared with rizatriptan alone.
Methods
Our sample consisted of 40 subjects. They were consecutive patients seen at our headache centre, who agreed to participate and met no exclusion criteria. The main inclusion criteria were migraine with or without aura, according to the criteria proposed by the second edition of the International Classification of Headache Disorders (ICHD-2) (22), with age ranging from 18 to 65 years and two to eight migraine attacks per month. Previous use (which occurred in the minority of our patients) of a triptan other than rizatriptan was not an exclusion criterion. The main exclusion criteria for women were childbearing age without adequate contraceptive methods, use of any concomitant gastrokinetic drug, previous use of rizatriptan, contraindications to the use of triptan, and significan psychiatric or physical disease (based on clinical judgement).
After agreeing to participate, subjects were randomized to treat two consecutive moderate or severe attacks with one tablet of 10 mg rizatriptan plus one capsule of 200 mg trimebutine and two attacks with the same triptan and placebo, in counterbalanced order.
The study drugs were delivered in two boxes with two regular tablets of rizatriptan 10 mg and two capsules of either placebo or trimebutine. The study was designed as double-blind, randomized, cross-over. Trimebutine was placebo-controlled.
All patients had to fill out a detailed headache calendar as well as give their written informed consent. The primary endpoint, defined a priori, was the difference in the proportion of treated attacks that were pain free at 2 h. Secondary endpoints included headache recurrence (moderate or severe pain from 2 to 24 h of treatment in a patient who responded to headache treatment) and presence of associated symptoms.
Tolerability was assessed at all time points. Side-effects were defined as any unexpected symptom or sign appearing after the administration of study medication.
Statistical analysis was performed using the repeated measures analysis of variance (
The study was approved by an institutional ethics committee.
Results
A total of 40 subjects were randomized to treatment. Of these, 32 (80%), 24 (75%) women and eight (25%) men (mean age of 39.7 years), treated at least one moderate or severe attack and made a follow-up visit. Four (12.5%) patients were lost to follow-up without giving any information about treatment and another four (12.5%) were not able to fill out the reports properly and/or did not follow the protocol, having taken the study drugs only during mild attacks.
However, all these 32 subjects treated all attacks, an important fact, since the intention-to-treat (ITT, treated at least one valid attack) and the per-protocol population (completers) is exactly the same. Subanalyses could therefore not be performed.
Our population consisted of 32 subjects, who treated a total of 64 moderate or severe attacks with each drug regimen. At 1 h postdose, 30 (46.8%) of 64 attacks treated with the combination resolved completely, vs. eight (12.5%) of the rizatriptan-treated attacks, a difference of 34% [95% confidence interval (CI) 19, 49, P < 0.01).
At 2 h postdose, 47 (73.4%) attacks treated with the combination vs. 20 (31.2%) of those treated with rizatriptan alone resolved completely, a difference of 42% (95% CI 26, 58, P < 0.001).
Finally, at 4 h postdose, 51 (79.7%) of the attacks treated with the combination and 20 (31.2% of the attacks treated with rizatriptan had resolved, a difference of 47% (95% CI 32, 62, P < 0.001) (Fig. 1).
Pain free rates comparing rizatriptan plus trimebutine (□) with rizatriptan alone (▪).
The recurrence rate was similar in the two drug regimens (31.2%). Regarding nausea and photophobia, the combination vs. rizatriptan alone provided a significantly higher proportion of attacks without the symptoms. At 1 h, 49 (76.5%) vs. 15 (23.4%) of the attacks had no nausea, and 47 (73.4%) vs. 17 (26.7%) attacks had no photophobia (P < 0.001 for both comparisons).
Sustained pain free (defined as pain free at 2 h and no recurrence) occurred in 22 (46.8%) of those receiving the combination, compared with four (20%) of those receiving rizatriptan alone (P < 0.01).
Adverse events were present in 18 attacks (28.1%) treated with rizatriptan and in 21 (32.8%) attacks with the combination. Dizziness and somnolence were the most common effects in the two groups.
Discussion
This was a double-blind, randomized, cross-over study demonstrating the superiority of the combination rizatriptan plus trimebutine over rizatriptan alone for the acute treatment of migraine attacks. It has its limitations since, although we controlled trimebutine for placebo, this was not a four-arm study, where some patients received trimebutine alone and some placebo alone. From our data we cannot claim that trimebutine does not have analgesic properties. However, several studies have shown that trimebutine alone does not relieve pain in animals (19, 20) or in humans (21, 23, 24).
Combination therapy using gastrokinetic drugs in the acute treatment of migraine has been proved effective. A randomized, double-blind, three-way cross-over comparison of 1 g paracetamol plus either domperidone 30 mg, domperidone 20 mg or placebo, taken at onset of headache, was carried out in 46 patients. A significant difference was observed in the duration of the migraine attack: a median of 17.5 h with paracetamol alone was reduced to 12.0 h with the addition of domperidone 20 mg, and to 12.0 h with domperidone 30 mg. No significant adverse events were reported. A reduction in pain intensity and nausea was noted but this was not statistically significant. It was concluded that domperidone shortens the duration of a migraine attack and may help reduce headache and associated symptoms (25). In another study, sumatriptan 50 mg was compared with the combination sumatriptan 50 mg plus metoclopramide 10 mg in a double-blind, randomized, cross-over study of 16 migraineurs who had failed to receive adequate relief from triptans. In this study, 44% of the patients achieved relief with the combination compared with 31% of those receiving sumatriptan alone. However, pain-free measures were not evaluated and no differences were reported with regard to associated symptoms (14).
We have previously suggested that triptans combined with non-steroidal anti-inflammatory drugs are better, in terms of efficacy and sustained pain-free measures, than the isolated use of a triptan (25–28). However, although the reasons for combining a triptan with a gastrokinetic drug, or even a non-triptan with a gastrokinetic drug, have been presented in the past (29), we never expected that a non-competitive spasmolytic agent with moderate opiate receptor affinity and devoid of central penetration could have a reinforcing effect on the efficacy of rizatriptan. The crucial question of whether trimebutine alone is effective in reducing the headache and associated symptoms of a migraine attack can not be adequately answered at this time. In clinical practice trimebutine is not effective and clinical studies suggest but do not prove that trimebutine has absolutely no analgesic effects (30).
Although the potential involvement of dopamine in peripheral gastric stasis observed in migraine is not addressed with the addition of trimebutine to rizatriptan, nor the potentially useful action on 5-HT4 receptor in order to facilitate coordinated gastrointestinal motor activity to relieve stasis and perhaps nausea (29), we believe that this well-tolerated opioid peripheral agonist (30) may represent an additional resource in the available arsenal to treat migraine attacks. In an era of potential new agents for the acute treatment of migraine, raising the efficacy of already safe and available drugs through the combination of traditional medications may represent an attractive option. Further studies with more patients and attacks are warranted.