Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-02-09
2002-04-23
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S619000
Reexamination Certificate
active
06376550
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new process for using pharmaceutical compositions containing tramadol, and an antiemetic-antinauseant substance for the treatment of migraines and migraine-like headaches.
BACKGROUND
Migraine is a disease with recurring attacks of headaches, which last between 4 and 72 hours. Migraine attacks predominantly are unilateral, dull at the beginning and then pulsing headaches occur with moderate to severe intensity. Typical accompanying symptoms of migraines are hypersensitivity towards light and sound, pallor, nausea and vomiting and without neurological focal attack, as a prodromal stage.
The (usual) migraine without aura is differentiated from the (classical) migraine with aura, which always commences with a characteristic scintillating scotoma. A complicated migraine exists if the visual disorders last for days or other neurological focal symptoms occur with the known special forms of the retinal, basilar, ophthal-moplegic, aphasic or hemiplegic migraine.
There are different ideas concerning the pathomechanism of the migraine. Earlier hemodynamic ideas, according to which the initial neurological attacks are triggered by regional, intracranial vasoconstriction and the subsequent pulsing headache by extracranial vasodilation with pain conduction over the nervus opththalmicus and nervus trigeminus, explain the processes during the migraine only inadequately.
The regional cerebral blood flow is reduced during a migraine with aura occipital, the slow migration of the cortical oligemia with crossing over of the supply regions of individual arteries suggesting that not only vasomotor, but also electrophysiological phenomena corresponding to the so-called “spreading depression” participating (Spierings ELH (1988); Recent advances in understanding of migraine. Headache 28; 655-658).
Other findings suggest that the accompanying headaches are triggered not only by an extracranial vasodilation, but also by a central lowering of the pain threshold, IEGs (immediate early genes) being activated in the cells of the spinal cord and of the brain stem after noxic stimulation (M. Zimmermann (1955); Neurobiology of the Pain System, Neuroforum 1/95; 34-45).
A different theory—the neurogenic inflammation model—offers a possibility of explaining the blood flow change as well as the increased pain sensitivity of the vessels during migraine attacks. According to this theory, the increased pain sensitivity is brought about by an increased sensitization of the sensory perivascular fibers of the trigeminovascular system. Vascular pulsations, which normally are not capable of initiating painful sensations, are potent pain stimuli due to this increased sensitization, and bring about the pulsing, throbbing migraine pain. The neurogenic inflammation is initiated by noxic stimulation of the perivascular nerve fibers of the meningeal blood vessels. From the nerve ends, which probably are nociceptors at the same time, neuropeptides such as P. neurokinin A and CGRP (calcitonin-gene related peptides), which are capable of initiating the neurogenic inflammation, are secreted. During a migraine attack, CGRP can also be detected in increasing amounts in the venous blood of the head.
A vicious circle is set in motion due to the secretion of the neuropeptides, wherein a peptide release leads to vasodilation and to an increase in capillary permeability, resulting in an increased stimulation of nociceptors which, in turn, leads to a yet increased release of peptides. The known antimigraine actives, such as sumatriptan and ergot alkaloids inhibit the release of the neuropeptides and interrupt the pain-initiating cycle (M. Zimmermann: Chronic Pain and its Causes, Deutsches Arzteblatt 93, vol. 43, 1996 A-2749-2752).
Other findings suggest a primary neurogenic hypothalamic dysfunction, during which the vasoactive serotonin, which is secreted in a reduced amount from the nuclei of the raphe of the brain stem during the migraine attack, plays a key role (Ferrari M D et al. (1989): Serotonin metabolism in migraine. Neurology 39: 1239-1242; R. Pramod et al. (1989): 5-HT
1
-like receptor agonists and the pathophysiology of migraine. Trends in Pharmacological Sciences 10, 200-204).
Regardless of many hypotheses and complicated models, the patho-mechanisms of the migraine are not understood as yet. The migraine has a multifactorial genesis with a genetic disposition and external (such as alcohol) and internal (such as hormone) trigger mechanisms. It is not a psychosomatic disease, although psychic factors can trigger an attack.
Frequent side effects of ergotamine and dihydroergotamine which are the drugs of choice for treating migraines, are nausea, retching, vomiting, headaches, muscle pain and a general sensation of coldness. These are symptoms which, under a false assumption of a continuing migraine attack, may cause the compositions to be taken repeatedly and thus can lead to an overdosage. Persistent headaches may result from frequent use, and this fosters ergotamine abuse. Circulation disorders, coronary heart disease, occlusive arterial disease, hypertension and anginal disorders occur as serious side effects. Ergot alkaloids must not be used during pregnancy, while nursing or by children below the age of 12.
Sumatriptan and its derivatives (almotriptan, eletriptan, naratriptan, rizatriptan, zolmitriptan) are very effective migraine remedies which, when used orally, are superior to individual substances, such as ergotamine, acetylsalicylic acid or metoclopramide. Sumatriptan is contraindicated for children, during pregnancy, while nursing, and for patients above the age of 65 or having coronary heart disease. A sensation of pressure and heart, a general sensation of weakness, a sensation of tightness in the chest, hypertension, coronary heart disease, a myocardial infarction and angina pectoris can occur as undesirable effects.
Thus, although it has been known to combine some analgesics with antiemetics, these are either weak analgesics (e.g. paracetamol or salicylates) that are not useful against moderate to severe migraine pain. Strong analgesics, such as ergot compounds or sumatriptan, are unreliable, because they are known to have adverse cardiac and other undesirable side effects, and also to cause nausea.
Metoclopramide and domperidone have been used in combination with ergot compounds because of their prokinetic effects, and also because of their effect on symptoms such as nausea and vomiting, which frequently occur as symptoms that accompany a migraine.
The medicinal treatment of migraines is symptomatic in nature and does not represent a cure. Mixed preparations of non-opioid analgesics and mixed preparations of ergot alkaloids are not recommended, since they themselves can cause headaches when used for a prolonged period and particularly when used daily. Furthermore, liver and kidney damage, such as analgesic nephropathy are possible consequences of the long-term use of analgesic combination. Because of the possibility that they will be misused or result in dependence, opioid analgesics are generally not suitable for the treatment of migraines.
The following specific combinations, in particular, are known from the patent literature for the treatment of migraines: paracetamol and metoclopramide (EP 011 489, EP 011 490, U.S. Pat. No. 5,437,874, EP 695 546, EP 774 253); acetylsalicylic acid or the 1-lysine derivative thereof and metoclopramide (EP 605 031); and analgesics (such as acetylsalicylic acid), antiemetics (such as metoclopramide) and an antacid (CA 20 20 018). The above analgesic combinations are generally suitable for the treatment of mild migraine attacks. They are not suitable, however for the treatment of moderately severe to severe migraines. In the case of severe migraines, ergot alkaloids, in combination with an antiemetic or sumatriptan, are generally indicated.
It is a disadvantage that, under treatment with ergot alkaloids or sumatriptan, a large number of, in some cases, serious cardiovascular side effects, such as angina pectoris, coronary
Momberger Helmut
Raber Marc
ASTA Medica AG
Goodwin Proctor LLP
Spivack Phyllis G.
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