Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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0691-031PCA
ANTI-MIGRAINE PHARMACEUTICAL COMPOSITIONS
AND PROCESS OF USING
Field of invention
The present invention relates to a new anti-migraine pharmaceutical
compositions containing tramadol, and a prokinetic, antiemetic-antinauseant
substance.
Back r
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
electrophysio-
logical phenomena corresponding to the so-called "spreading depression"
participating
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(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 pos-
sibility 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 neuropep-
tides, 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
sumatrip-
tan and ergot alkaloids inhibit the release of the neuropeptides and interrupt
the pain-
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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 MD et al. (1989): Serotonin metabolism in migraine. Neurology 39:
1239 -
1242; R. Pramod et al. (1989): 5-HTI-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
multifac-
torial 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
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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 heat, a general sensation of weakness, a sensation
of
tightness in the chest, hypertension, coronary heat disease, a myocardial
infarction and
angina pectoris can occur as undesirable effects.
Thus, although it has been known to combine some analgesics with an-
tiemetics, 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
prepara-
tions 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, US 5,437,874, EP 695 546, EP 774 253); acetylsalicylic
acid or the
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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 heart disease, hypertension and myocardial
infarction can
occur.
An alternative class of analgesics, the opioid analgesics are generally also
unsuitable for such use, partly because of their dependence-creating effect,
and also
their tendency to cause constipation which works against the desired analgetic
effect
which is reduced in the case of a full stomach.
Tramadol is a centrally acting analgesic having a weak opioid binding
activity and a complimentary weak inhibition of reuptake of norepinephrine and
serotonin. Unlike morphine, tramadol does not show a histamine release. It
was,
however, not considered to be used in preference to opioids, because it is
known to
cause nausea, vomiting, sweating, dryness of the mouth, dizziness and
drowsiness can
occasionally occur. Gastrointestinal complaints or different types of mental
effects are
infrequently also observed. Therefore, tramadol has not been successfully used
against
migraine pain.
WO 97/18801 describes the combination of tramadol with antinauseant
substances, particularly in a controlled release dosage form. There is,
however, no
prior suggestion of using such combinations for the treatment of migraines.
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6
There is therefore a great need for a reliable
analgesic, which has few side effects and a good activity in
the case of moderately severe to severe migraine attacks.
Summarv of the invention
It is an object of the present invention to provide an
improved anti-migraine agent against moderately severe to
severe migraine attacks.
According to one aspect of the present invention, there
is provided a use of a composition comprising an antiemetic
and tramadol for the treatment of a migraine.
According to another aspect of the present invention,
there is provided a use of a composition comprising an
antiemetic and tramadol for the preparation of a medicament
for the treatment of a migraine.
According to still another aspect of the present
invention, there is provided a commercial package comprising
(a) a composition comprising an antiemetic and tramadol and
(b) instructions for use of the composition for the treatment
of a migraine.
According to yet another aspect of the present
invention, there is provided a composition comprising a
pharmacologically effective amount of both an antiemetic
compound and of tramadol for use as an antimigraine agent.
The present invention is an anti-migraine composition
containing tramadol and a prokinetic antiemetic antinauseant
substance, including dopamine antagonists, phenothiazine, 5HT3
antagonists, and antihistamines (hereinafter singly and
collectively referred to as "antiemetics"). It has been
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6a
surprisingly found that in accordance with the present
invention tramadol was also found to be an exception among
opioid analgesics, which does not produce the serious side
effects which are typically seen in the use of opioids. Not
only is the constipation-causing side effect of opioid
analgesics effectively suppressed by combining tramadol with
such an antiemetic, but additionally the analgesic action is
also unexpectedly potentiated by the antiemetic, and the
absorption and compatibility of tramadol is increased by the
combination of the present invention. Yet further analgesic
activity can be provided by a further combination with one or
more conventional analgesics, such as an NSAID, thus also to
provide an antiinflammatory effect.
As used throughout the specification and the claims,
"tramadol" means 2-[dimethylamino)methyl]-1- (3-methoxyphenyl)
cyclohexanol, or its pharmaceutically acceptable salts,
esters, and enantiomers. Tramadol is an analgesic, which is
pharmacologicaly effective in the case of moderately severe to
severe pain. It belongs to the group of opioids with a weak
activity. In comparison to~ other opioids, tramadol is
distinguished by a lesser development of tolerance with
respect to the analgesic effect and by the fact that the side
effects, typical of an opiate, are largely absent and that
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the potential for developing a dependence is very slight. The analgesic effect
of
tramadol includes opioid as well as non-opioid components, the latter by way
of the
release of serotonin (5-HT) and the inhibition of the resorption of serotonin
and
noradrenalin in the central nervous system (CNS). These non-opioidal
components
provide a significant contribution to the analgesic effect of tramadol.
Noradrenaline
resorption is inhibited predominantly by the (-)-enantiomer and the release of
seroto-
nin, as well as the inhibition of the resorption of serotonin from the
synaptic cleft is
produced predominantly by the (+) enantiomer. Both enantiomers contribute to
the
analgesic effect in man.
As used throughout the specification and the claims, compounds with
prokinetic activity, the main representatives of which include metoclopramide,
domperi-
done, prochlorperazine, trifluoroperazine, promethazine, dimenhydrinate,
cinnarizine,
cyclizine, ondansetron, granisetron, and tropisetron in addition to their role
as antiemet-
ics in the present invention also potentiating the analgesic efficacy of
tramadol, they are
also pharmacologically active to increase the tonus of the lower
gastroesophageal
sphincter and to stimulate and accelerate the emptying of the stomach and the
passage
through the small intestine, which emptying is otherwise disturbed or
otherwise
hindered by the migraine, and also as antiemetics to suppress nausea, retching
and
vomiting. The antiemetics are conventionally also indicated in the case of
gastroparesis,
which can occur postoperatively, and also in the case of some basic diseases
(such as
diabetes mellitus, etc.). They are also given in the case of functional
dyspepsia
(irritated stomach), as the cause of the latter is suspected to be a disorder
of gastroin-
testinal motility. Any reference in the disclosure and the claims to an
"antiemetic" is
meant to include its pharmaceutically acceptable salt and esters.
It was noted with surprise that, as a result of the use of the combination
of tramadol and an antiemetic, the migraine attacks can be effectively cut
short and the
occurrence of nausea and vomiting are be prevented. This was all the more
surprising,
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since tramadol itself can cause nausea and vomiting or intensify these
symptoms that
accompany migraines. For this reason, tramadol was regarded in the past as
being
unsuitable as a sole active for the treatment of migraines.
S By combining tramadol with an antiemetic, most suitably with metoclopra-
mide, it is possible to make the more highly effective analgesic tramadol
available for
the treatment of moderately severe to severe pain, including the treatment of
mi-
graines. With the combination of the present invention the compatibility of
tramadol
can be improved, the absorption of tramadol in the gastrointestinal tract can
be
accelerated and the occurrence of accompanying symptoms of migraines, namely
nausea
and vomiting, can be prevented.
Tramadol and antiemetics, are also suitable as partners in using these
compositions from the point of view of their pharmacodynamic and
pharmacokinetic
properties. The duration of the analgesic effect of tramadol is about 4 to 7
hours, with
a terminal elimination half life of about 5 - 6 hours. The duration of the
prokinetic
effect of e.g. metoclopramide and domperidone is about 1 to 2 hours and that
of the
antiemetic effect about 3 to 5 hours. The half life time is about 4 to 6
hours.
In a further embodiment of the process of the present invention, the
combinations can additionally be used with suitably from about 1% wt. to about
15%
wt. of a non-steroidal antiinflammatory drug (NSAID) such as acetylsalicylic
acid,
ibuprofen, naproxen and paracetamol. By these means, on the one hand, a
different
analgesic mechanism is created by an effect of tramadol on the central nervous
system,
and the analgesic and antiinflammatory effect of non-steroidal
antiinflammatory drugs
on both the central and peripheral nervous systems. Therefore, these
combinations
with an NSAID can be of particular importance in the case of therapy-resistant
forms
of migraines. On the other hand, the total dose of tramadol or of the
additional
combination partner having analgesic activity can be reduced without loss of
effect on
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the pain, without undesirable side effects such as gastrointestinal disorders
in the case
of the NSAIDs.
The composition of the present invention can be administered in any
suitable dosage form such as tablets, effervescent tablets, capsules,
granulates, powders,
sustained release tablets, sustained release capsules (single and multiple
unit formula-
tions), ampoules for intravenous and intramuscular injection and in the form
of infusion
solutions, suspensions, suppositories or in any other suitable dosage form.
The sustained release dosage forms of the present invention can contain
the active ingredient completely or partly in the sustained release form with
or without
an initial, immediate dosing of the actives.
The active ingredients can be present jointly or partially or completely in
separate formulations, so that it is possible to administer them separately as
well as at
different times. If the active ingredients are present only in separate
formulations,
these formulations are suitably matched to one another and each contains a
respective
active ingredient within the dosage unit in the same amounts and corresponding
ratios
by weight, in which they can and would be present in a combined dosage form.
The
active ingredients can also be present in the form of their pharmaceutically
usable salts
in any of these pharmaceutical dosage forms. Oral pharmaceutical compositions,
dosage forms which contain a combination of the actives, are deemed to be most
suitable.
Pharmaceutical preparations containing these combinations in their given
amounts, are suitably formulated with physiologically compatible carriers
and/or diluents
and/or inactive ingredients in the desired manner. Examples of carriers and
inactive
ingredients include gelatin, natural sugars such as cane sugar or lactose,
lecithin, pectin,
starch (such as corn starch or amylose), cyclodextrins and cyclodextrin
derivatives,
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dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid,
tylose, talcum,
lycopodium, silica, calcium hydrogen phosphate, cellulose, cellulose
derivatives such as
methyloxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose,
hydroxyprop-
ylmethyl cellulose phthalate, Clz-zz fatty acids, emulsifiers, oils and fats,
particularly also
vegetable glycerin esters and polyglycerin esters of saturated fatty acids,
monohydric or
polyhydric alcohols and polyglycols, such as polyethylene glycols, esters of
aliphatic
saturated or unsaturated Cz_zz fatty acids with monohydric, Cl_zo aliphatic or
polyhydric
alcohols, such as glycols, glycerin, diethylene glycol, 1,2-propylene glycol,
sorbitol, and
mannitol.
Further inactive ingredients can suitably include materials, which bring
about disintegration (so-called disintegrants), crosslinked
polyvinylpyrrolidone, sodium
carboxymethyl starch, sodium carboxymethyl cellulose and microcrystalline
cellulose.
Known coating agents can likewise be used. Polymers, as well as copolymers of
acrylic
acid and/or methacrylic acid and/or their esters, zero, ethylcellulose,
ethylcellulose
succinate and shellac are particularly suitable.
As plasticizers for coatings, citrate and tartrate esters, glycerin and
glycerin esters and polyethylene glycol of different chain lengths can be
used. Water or
physiologically compatible organic solvents, such as alcohols and fatty
alcohols, can be
suitably employed for the preparation of solutions or suspensions.
For liquid preparations, it may be necessary to use preservatives, such as
potassium sorbate, methyl-4-hydroxy benzoate or propyl 4-hydroxybenzoate, anti-
oxidants, such as ascorbic acid, and a taste improver such as peppermint oil.
Customary solubilizers or emulsifiers, such as polyvinylpyrrolidone and
polysorbate 80 can be used in preparing the compositions. Further examples of
carriers and inactive ingredients include those described, for example in H.P.
Fiedler
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"Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and Angrenzende Gebiete
(Encyclo-
pedia of Inactive Ingredients for Pharmaceuticals, Cosmetics and Adjoining
Fields)".
Anti-migraine preparations, which contain the combinations of antieme-
tics with prokinetic effect and of tramadol, the composition can suitably
contain from
about 5% wt. to about 30 % by weight of the antiemetic. Suitably the weight
ratio of
the compounds is from about 1 : 4 to about 1 : 10. Individual doses of these
pharma-
ceutical preparations can contain from about 5 to about 50 mg of an
antiemetic, and
from about 50 to about 400 mg of tramadol. Moreover, the daily dose should
suitably
contain from about 20 to about 80 mg of antiemetic and from about 200 to about
400
mg of tramadol. Depending on the therapeutic indication, the daily dose can be
administered all at once, or in the form of from about 2 to about 4 partial
doses per
day. In general, the administration in from about 2 to about 4 partial doses
per day is
most suitable.
The following examples exemplify the invention in further detail.
Example 1
Preparation of a metoclopramide solution
Purified water (802.4 g) is added to a suitable container, and 4.7 g of
metoclopramide hydrochloride 1H20, 0.1 g of ascorbic acid, 170.1 g of
sorbitol, 2.8 g of
potassium sorbate and a pre-dissolved solution of 18.9 g of 96% ethanol (v/v),
0.7 g of
methyl 4-hydroxybenzoate and 0.3 g of propyl 4-hydroxybenzoate are added with
stirring, with the stirring continued until all the components are dissolved.
The solution
is filtered through a suitable filter.
Formulation Percentage (w/wl
metoclopramide hydrochloride. H20 0.47
ascorbic acid 0.01
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sorbitol 17.01
potassium sorbate 0.28
96% ethanol (v/v) 1.89
methyl 4-hydroxy benzoate 0.07
propyl 4-hydroxybenzoate 0.03
purified water 80.24
The solution is filled into a suitable dropper bottle.
Example 2
Preparation of a metoclopramide solution
Purified water (484.2 g) is added to a suitable container and 100 g of
metoclopramide hydrochloride, 1.5 g of potassium sorbate, 161.8 of 96% ethanol
(v/v),
124.5 g of 1,2-propylene glycol, 200 g of refined sugar, 1.0 g of polysorbate
80 and 1.0
g of peppermint oil are added with stirring, the stirring being continued
until all the
components are dissolved. The solution is filtered through a suitable filter.
Formulation Percentage (w/w)
tramadol hydrochloride 9.3
potassium sorbate 0.1
96% ethanol (v/v) 15.1
1,2-propylene glycol 11.6
refined sugar 18.6
polysorbate 80 0.1
peppermint oil 0.1
purified water 45.1
The solution is filled into a suitable dropper bottle.
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Example 3
Sustained release tramadol - metoclo"pramide pellets
Preparation of active ingredient-containing cores
A tramadol hydrochloride/metoclopramide hydrochloride 1H20/Aerosil~
200 mixture (4824 g) is applied with approximately 2200 g of a 15% solution of
ethylcellulose/shellac (6 : 4) in approximately 96% ethanol (v/v) on 1000 g of
neutral
pellets of a suitable size (with a diameter, for example, of between 0.5 and
0.6 mm) in
a coated-tablet kettle. The cores obtained were subsequently dried and
screened (0.8 -
1.4 mm).
Application of the membrane
A membrane is applied on 6.15 kg of the active ingredient-containing
cores, so prepared, in that 470 g of a 15% solution of ethylcellulose/shellac
(6 : 4) in
96% ethanol (v/v) are applied. Talcum (700 g) is powdered in as release agent.
Formulation Percentage~w/w)
tramadol hydrochloride 57.8
metoclopramide hydrochloride. H20 11.6
neutral pellets 14.4
ethylcellulose 3.5
shellac 2.3
Aerosil 200 0.3
talcum 10.1
96% ethanol (v/v) to volume
Release of active ingredient
The in vitro release of tramadol hydrochloride from the sustained release
pellets of the example is determined by the method of USP 23/NF 18 in
Apparatus 3.
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The temperature of the release medium is 37°C, the sample tubes are
lifted at the rate
of 20 lifts per minute and the amount of test solution per test interval is
175 mL.
The investigation is commenced with the test solution at a pH of 1.5.
After the first hour, the tubes with the samples are changed in 175 mL of test
solution
at pH 4.5, after the second hour in a test solution at pH 6.9, after the
fourth hour in a
test solution at pH 6.9, after the sixth hour in a test solution at pH 7.2
and, after the
eighth hour, in a test solution of pH 7.5. The amount of active ingredient,
released
into the solution medium at the aforementioned times, is determined
spectrophoto-
metrically. The following release values are determined for tramadol
hydrochloride.
Time - hours Percentage by weight of
active ingredient released
1 39
2 57
4 70
6 78
8 84
12 93
The in vitro release curve of the sustained release pellets is shown in
Fig. 1.
Example 4
Tramadol - metoclonramide capsules
Preparation of the filling composition for the capsules
Tramadol hydrochloride (323 g), 6.5 g of metoclopramide hydrochloride.
H20, 597 g of calcium hydrogen phosphate, 0.5 g of colloidal silica sold under
the
trademark Aerosil~ 200, and 1.0 g of magnesium stearate are screened and mixed
in a
suitable mixer.
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Formulation Percentaa~,(w/w)
tramadol hydrochloride 32.3
metoclopramide hydrochloride. HZO 6.5
calcium hydrogen phosphate 59.7
Aerosil~ 200 0.5
magnesium stearate 1.0
Preparation of the capsules
The filling composition for the capsules (155 mg nominally) is filled by
means of a suitable machine into hard gelatin capsules of suitable size.
Example 5
Drink-producin tablets
A powder blend was prepared from 251 g tramadol-HCI, 25 g metoclo-
pramide-HC1.H20, 4 g Aerosilh" 200, SOg Aspartame"", 100 g crospovidone, 700 g
microcrystalline cellulose, 819.5 lactose monohydrate, 37.5 g flavoring (e.g.
strawberry),
10g sodium dodecyl sulfate, and 3 g magnesium stearate. The ingredients were
screened and mixed in a blender.
The composition of the mixture was
Formula Percentage (w/w)
tramadol-HCl 12.55
metoclopramide-HCl.HzO 1.25
Aerosil'm 200 0.2
Aspartame'"' 2.5
crospovidone 5.0
microcrystalline cellulose 35.0
lactose monohydrate 40.0
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flavoring 1.88
sodium dodecyl sulfate ~ 0.5
magnesium stearate 0.15
The powder blend was compressed into tablets (nominally 400 g each).
Example 6
Treatment of migraines with tramadol/metoclopramide
Patients were treated for medium to intensive migraine attacks which
could no longer be satisfactorily treated with weaker NSAID analgesics, such
as
acetylsalicylic acid, ibuprofen, or paracetamol.
The intensity of the migraine headaches and the marked accompanying
symptoms that were present prior to treatment, were documented to obtain a
baseline
for the evaluation of the treatment results. The intensity of pain before and
after
administration of the treatment were recorded on a 100 mm long VAS scale and
were
determined 30 mins., and then 1, 2, 4, 6 and 12 hours later. The noting of the
effects
that accompanied the migraine headaches, and their changes after
administration of the
drug treatment were recorded on a plural step verbal rating scale. The
patient's
general subjective impressions were also recorded.
Eight patients (7 female and 1 male) with an average age of 44.7 years
(between ages 35 and 63), an average height of 169.3 cm (between 159 and 186
cm),
and an average body weight of 70.4kg (between 55 and 103kg), were treated.
All patients satisfied the operational and diagnostic criteria of the IHS for
the diagnosis of migraines and have had at least 5 migraine attacks lasting 4-
72 hours
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prior to the commencement of the treatment. The headaches were strongly along
one
side, and their intensity was exacerbated by bodily activity. All of the
patients were
nauseous, and sensitive to noises during their attacks. 28% of the patients
also had
vomiting episodes, and 43% were sensitive to light. The migraines have
preexisted in
the average since 15.3 years (between 2 and 38 years), and the mean frequency
of
attacks was 4.1 days per month (between 2 and 8 days per month).
During the test period of 4 months the patients suffered 11 acute
migraine attacks which were treated with a free combination of tramadol and
meto-
clopramide. All patients were administered an oral single dose of 100 mg
tramadol (2
tramadol capsules sold by Arzneimittelwerk Dresden, each containing SOmg
tramadol-
HCl), and l0mg metoclopramide solution (30 drops of metoclopramide sold by
Temmler, in 5 mg solution).
Before the documented treatments, the migraine pains of the patients
were characterized as from intensive to very intensive. The initial pain as a
mean
value on the VAS scale was 75 ~ 7 mm (between 62 and 83 mm).
The pains of two patients who each were treated for two migraine attacks
during the 4 month test period, did not result in any improvement in their
conditions,
and were declared to be nonresponsive to the treatment, and were excluded from
the
analysis of the test results. The remaining 6 patients were treated for 7
attacks during
the test period. Their headaches were recorded on the same 100 long VAS scale
which was also customarily used for other pain studies.
The headaches were evaluated on the following basis:
0 mm no headaches (stage 0)
1-30 mm light headaches (stage 1)
31-60 mm medium heavy headaches (stage 2)
61-100 mm strong to very strong headaches (stage 3)
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CA 02262267 1999-02-19
In migraine studies the criteria for results are determined as the percentage
of
patients in the case of which an improvement of their headache (from stage 3
to stage
2, or stage 1 or stage 0) is obtained within a predetermined time period
(usually after
2 or 4 hours).
The results are summarized in the following table which shows for the
tramadol/metoclopramide responding patients the differences between the
intensities of
their initial headaches measured on the VAS scale at 30 mins., and 1, 2, 4, 6,
and 12
hours after administration of 100 mg tramadol and lOmg methoclopramide (with
the
values within parentheses showing the change in headache intensity).
PaG~nt0 0,5 1h 2h 4h 8h 12h
h h
mm mm '~ ~ % mm % W % mm % mm %
mm m
VS 82 - (- -14 (- - (- - (- - (- - (-100)
2 3.2) 22.8)24 38,7)27 43,8)28 46,2) 82
'
KM 83 -19 (- - (- - (- -81 (- -45(- -43 (-
22,9)42 50,8)80 72,3) 73,5) 64,2) 51.8)
VS 81 2 (2,b)-9 (-11.1)-21 (-25,91-37 (-4b,7)-81(-100)-81 (-100)
CM 70 - (- - (- - (- - (- - (- - (-
37 52.9)37 52.9)38 64,3)30 42.9)30 42.9) 29 41.4)
SS 72 - (- - (- -87 (- - (- - (-100)- (-100)
a 8,3) 92 44,4) A3,1)70 97,2)72 72
MK 80 - (- - (- - (- - (- - (-100)- (-100)
70 87,5)85 81,3)69 73,5)46 68,9)80 80
RH 77 2 (2.8)1 (1,3) - (-100)- (-100)- (-100)
77 77 77
can 76 -18.87(-14,26)-18,29(- J8,41(- - (- - (- - (-
37,38) 51,15)49.6788,61)69 77,48)9,45 84,76)
Std.dev7
28,88(34,01)22,68(28,27)24,81(31,97)19,58(26,94)23,88(28,32)20,19(28,22)
The following table additionally summarizes the treatment results on a
percentage basis showing the improvement in the headache degree staging from 3
to 2
or to 1 or 0, as a function of time after oral application of 100 mg tramadol
and 10
mg metoclopramide solution.
18
CA 02262267 1999-02-19
Time No. of patients Improvement from Sta;~e 3-~2 to 1~0
(hours) (n=8) (% patients)
0,5 2 25
1 5 62
2 6 75
4 6 75
6 6 75
12 6 75
The headaches have improved on the average after administration of the free
combination of tramadol and metoclopramide in the group of the patients
responding
to treatment, within already 30 mins by 24.3%, and after 2 hours by 51.1%,
related to
the starting pain. After 4 and 6 hours, respectively, the reduction in pain
intensity was
on the average 65.6% and 77.5% (See the first Table).
For the entire group of patients, including the non-responders, an efficacy
(improvement of headaches from strong or medium strong to light or pain-free)
of
25% was obtained after 30 minutes, and 75% after 2 hours (see the second
Table).
The foregoing data show that the tramadol/metoclopramide combination is a
much more promising agent for the treatment of moderate or strong acute
migraine
headaches than e.g. NSAIDs, ergotamine preparations, triptanes and other
mixtures.
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