Efficacy of a Fixed Combination
Objective: To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study.
Background: A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans.
Methods: One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache.
Results: Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P < .01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated.
Conclusions: This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.
A fixed combination of indomethacin, prochlorperazine, and caffeine (IndoProCaf) (Difmetre) is the most commonly used drug in Italy for the acute treatment of migraine. In contrast to other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin is structurally related to serotonin and has central analgesic and cranial vasoconstrictor properties. Indomethacin is the treatment of choice for chronic paroxysmal hemicrania. Recently, other headaches were found to be completely or partially responsive to indomethacin. Prochlorperazine is a phenothiazine antiemetic also shown to be effective for the acute treatment of migraine in some clinical trials. Intramuscular or intravenous prochlorperazine is considered as adjunct first-line therapy for migraine attacks in emergency departments or doctors' offices, while rectal prochlorperazine is an adjunct in the treatment of acute migraine with nausea and vomiting. The analgesic effect of prochlorperazine could be due to the inhibition of the D2 heteroreceptor located on the cholinergic neurons. Caffeine induces central cholinergic analgesia. The addition of caffeine to NSAIDs produces a significant dose-dependent improvement of pain, including headache. Based on 30 clinical studies involving more than 10000 patients over 20 years, it was shown that approximately 40% more of a dose of an analgesic is required to obtain the same pain relief of an analgesic plus caffeine.
Sumatriptan (Imigran) is the first commercially available and most widely prescribed of the serotonin 5-HT1B/1D agonists known as triptans. Sumatriptan is considered the gold standard in controlled trials of drugs used in the treatment of migraine. The efficacy and tolerability of newer-developed triptans and other fixed combinations were compared with sumatriptan in several clinical trials. The primary end point in most studies with triptans was the proportion of patients with headache relief (ie, improvement of headache severity to mild or no pain 2 hours postdose). More recently, the proportion of patients who become pain-free 2 hours postdose, before any rescue medication is taken, is considered the preferred and clinically most relevant primary end point. No studies have been published comparing IndoProCaf and sumatriptan, despite the wide use of these drugs in Italy.
This study was designed to compare the efficacy of IndoProCaf with sumatriptan (both rectally administered) using the proportion of patients who were pain-free (at 2 hours postdose) as the primary efficacy parameter.
Objective: To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study.
Background: A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans.
Methods: One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache.
Results: Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P < .01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated.
Conclusions: This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.
A fixed combination of indomethacin, prochlorperazine, and caffeine (IndoProCaf) (Difmetre) is the most commonly used drug in Italy for the acute treatment of migraine. In contrast to other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin is structurally related to serotonin and has central analgesic and cranial vasoconstrictor properties. Indomethacin is the treatment of choice for chronic paroxysmal hemicrania. Recently, other headaches were found to be completely or partially responsive to indomethacin. Prochlorperazine is a phenothiazine antiemetic also shown to be effective for the acute treatment of migraine in some clinical trials. Intramuscular or intravenous prochlorperazine is considered as adjunct first-line therapy for migraine attacks in emergency departments or doctors' offices, while rectal prochlorperazine is an adjunct in the treatment of acute migraine with nausea and vomiting. The analgesic effect of prochlorperazine could be due to the inhibition of the D2 heteroreceptor located on the cholinergic neurons. Caffeine induces central cholinergic analgesia. The addition of caffeine to NSAIDs produces a significant dose-dependent improvement of pain, including headache. Based on 30 clinical studies involving more than 10000 patients over 20 years, it was shown that approximately 40% more of a dose of an analgesic is required to obtain the same pain relief of an analgesic plus caffeine.
Sumatriptan (Imigran) is the first commercially available and most widely prescribed of the serotonin 5-HT1B/1D agonists known as triptans. Sumatriptan is considered the gold standard in controlled trials of drugs used in the treatment of migraine. The efficacy and tolerability of newer-developed triptans and other fixed combinations were compared with sumatriptan in several clinical trials. The primary end point in most studies with triptans was the proportion of patients with headache relief (ie, improvement of headache severity to mild or no pain 2 hours postdose). More recently, the proportion of patients who become pain-free 2 hours postdose, before any rescue medication is taken, is considered the preferred and clinically most relevant primary end point. No studies have been published comparing IndoProCaf and sumatriptan, despite the wide use of these drugs in Italy.
This study was designed to compare the efficacy of IndoProCaf with sumatriptan (both rectally administered) using the proportion of patients who were pain-free (at 2 hours postdose) as the primary efficacy parameter.