Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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OUATERNARY DERIVATIVES OF NOROXYMORPHO
~HICH RELIEVE NAUSEA AND EMESIS
The administration of therapeutic doses of morphine and
other clinically useful narcotie analgesies is often
aecompanied by unpleasant side effects on the gas-tro-
intestinal system. For instance, morphine and related
opiates such as meperidine and methadone may reta~d
intestinal mobility by causing con-traetions of -the small
bowel eireular smooth musele.
Morphine and related narcoties may also induce nausea
and increased mobility of the gastro-intes-tinal tract
resulting in emesis or vomiting~ These side effects are
eaused by direet stimulation of the chemoreeeptor trigger
zone for emesis in the area postrema of the medulla. (Goodman
and Bilman, The Pharmaeologieal Basis of Theraneu~ics, p. 502
[6`th ed. 1980]). Studies have shown that morphine and other
nareoties eause emesis in dogs. For example, Wang and
Glaviano, JPET 111:329-334 ~9143~, reported that
administration of 0.5 mg/kg of morphine intravenously to 12
dogs resulted in emesis in 9 dogs within an average of 2.
minutes. (Mg/kg refers to milligrams of morphine per
kilograms of body weight.) When 1.0 mg/kg of
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1 morphine was administered intramuscularly to 13 dogs, 12
of them vomited within an average time of 3.5 minutes.
U. S. Patent No. 4,176,186 to myself and others
disclosed treatment of intestinal immobility associated
with the use of narcotic analgesics through the
administration of guaternary derivatives of
noroxymorphone.'' It has now been discovered that the
same compounds are also useful fox the treatment, ~oth
prophylactic.and therapeutic,'of the nausea and vomiting
associated with the administration of these drugs.
'~'According to the invention, therefore, nausea and
vomiting by warm-blooded animals receiving morphine and
lS related opiates~ meperidine,-methadone or the like, may
be prevented ~r relieved by the administration of
methylnaltrexone or other quaternary derivatives of
noroxymorphone represented by the formula:
rA/~ C~13 X
` ~`b
wherein ~/0
R is allyl or a related radical such as
chloroallyl, cyclopropyl-methyl Gr propargyl, and
X is the anion of an acid, especially a chloride,
bromide, iodide or methylsulfate anion.
These compounds are administered to the animal
either prior to or . simultaneously with the
administration of the narcotic analgesic. They may be
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admini~-tered either enterally or paren-terally. There has no-t
been observed any interference with the analgesic activi-ty of
the opi~tes.
As used herein, unless the sense of the usage indicates
otherwise, the term l'morphine" refers to any narcotic
analgesic.
This invention relates to the use of quaternary
derivatives of noroxymorphone to prev~nt or relieve nausea
and vomiting associated with the administration of morphine
to warm-blooded animals. The useful compounds are
represented by the formula:
R X
I ~ CH3
r- N
wherein
R is allyl or a related radical such as chloroallyl,
cyclopropyl-methyl or propargyl, and
X is the anion of an acid, especially a chloride,
bromide, iodide or methylsulfate anion.
!
The compounds are synthesized as described in United
5tates Patent No. 4,176,I86. A particularly preferred
noroxymorphone derivative is methylnaltrexone, but other
compounds represented by the above formula are also suitable.
Methylnaltrexone or other noroxymorphone deriva-tives may
be administered to the patient either
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1 enterally or parenterally. However, a preferred method
of administration is by injection. Nausea and emesis
may follow after even a single does sf morphine, unlikP
intestinal immobility which is usually the effect of
chronic repeated usage of the drug. Consequently, it is
contemplated that-the patient will be given an injection
of methylnaltrexone prior to surgery or other occasion
when morphine is used to treat acute pain.
As illustrated :-by :~he ~ifollowing Controls and
Examples, our studies show that methylnaltrexone
inhibits emesis when administered either together with
the morphine or before the morphine is administered. It
is thought that methylnaltrexone- or other quaternary
noroxymorphone derivatives may be administered up to two
hours before the administration of morphine, but that
period may be variable. In our studies,
methylnaltrexone was administered intramuscularly by
means of a syringé. Methylnaltrexone may also be
administered enteraIly or parenterally by other means.
It has been found to be effective in dosages in the
range of about 0.05 mg/kg to about 1.0 mg~kg for each 1
mg/kg of administered morphine. It was found effective
when administered in the same syringe as morphine and
also when administered up to about one hour before the
administration of morphine.
The effect of methylnaltrexone in reversing the
emetic effects of morphine is illustrated herein. The
unit of mg/kg refers to milligrams of substance
administered per kilograms of body weight.
. ~ CONTROL 1 AND EXAMPLE_1
one mg/kg of morphine was administered
intramuscularly to five dogs. Four dogs vomited. In
each instance, vomiting occurred within four minutes.
On a different day the same dose of morphine was
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1 administered intramuscularly to the same five dogs in
the same syringe with 1 mg/kg of methylnaltrexone. None
of the dogs vomited.
CONTROL 2 AND EXAMPLE 2
Six dogs were given intramuscular doses of 1 mg/kg
of morphine. All six dogs vomited. On an ~dditional
day the same dose of morphine was combined with 0.5
mg/kg of methylnaltraxone and administered in the same
syringe to the same dogs. None of the dogs vomited.
CONTROL 3 AND EXAMPLE 3
one mg/kg of morphine was administered
intramuscularly to three dogs. All three dogs vomited.
On an additional day the morphine was combined with 0.25
mg/kg of methylnaltrexone and administered in the same
syringe. None of the dogs vomited.
CONTROL 4 AND EXAMPLE 4
Methylnaltrexone was administered to two dogs prior
to the administration of 1 mg/kg morphine. In one dog,
0.5 mg/kg of methylnaltrexone was administered
intramuscularly 15 minutes before the morphine. No
vomiting occurred. In the second dog, the same dose o~
methylnal~rexone was administered 30 minutes before the
administration of morphine. No vomiting occurred.
CONTROL 5 AND EXAMPLE 5
O. 05 mg/kg methylnaltrexone was administered
intravenously to four dogs one minute prior to the
administration of 1.0 mg/kg morphine. No vomiting
occurred in any of the dogs. On a different day, the
same animals were given 1.0 mg/kg morphine without the
administration of methylnaltrexone. All four dogs
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The administration of methylnaltrexone alone was found
to produce no noticeable effec-ts in the animals. Previous
studies with larger doses of methylnaltrexone have
demonstrated that unlike the non-quaternary naltrexone,
methylnaltrexone does no-t precipitate withdrawal systems in
morphine-tolerant dogs. Russell et al., Eur~ J. Pharmacol.
78:255-261 ~19823. Methylnaltrexone has not been found -to
interfere with the analgesic activity of morphine or
narcotics.
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