U.S. patent application number 10/407888 was filed with the patent office on 2003-09-18 for analgesic compositions comprising anti-epileptic compounds and methods of using same.
Invention is credited to Magnus, Leslie, Saltel, Douglas A..
Application Number | 20030176505 10/407888 |
Document ID | / |
Family ID | 22015361 |
Filed Date | 2003-09-18 |
United States Patent
Application |
20030176505 |
Kind Code |
A1 |
Magnus, Leslie ; et
al. |
September 18, 2003 |
Analgesic compositions comprising anti-epileptic compounds and
methods of using same
Abstract
The present invention is directed to novel combinations of
anti-epileptic compounds that demonstrate pain alleviating
properties, with compounds selected from the group consisting of
analgesics, NMDA receptor antagonists, and NSAIDs and
pharmaceutical compositions comprising same. It has been discovered
that the administration of anti-epileptic compounds that
demonstrate pain alleviating properties in these novel combinations
results in an improved reduction in the frequency and severity of
pain. It is also believed that the incidence of unwanted side
effects can be reduced by these novel combinations in comparison to
using higher doses of a single agent treatment to achieve a similar
therapeutic effect. The present invention is also directed to
methods of using effective amounts of the novel pharmaceutical
compositions to treat pain in mammals.
Inventors: |
Magnus, Leslie; (Livingston,
NJ) ; Saltel, Douglas A.; (Summit, NJ) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
22015361 |
Appl. No.: |
10/407888 |
Filed: |
April 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10407888 |
Apr 4, 2003 |
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09463116 |
Jan 18, 2000 |
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6593368 |
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09463116 |
Jan 18, 2000 |
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PCT/US98/17083 |
Aug 18, 1998 |
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60058207 |
Sep 8, 1997 |
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Current U.S.
Class: |
514/561 ;
514/162; 514/406; 514/570 |
Current CPC
Class: |
A61K 31/195 20130101;
A61P 29/02 20180101; A61P 25/08 20180101; A61K 31/415 20130101;
A61K 31/47 20130101; A61P 29/00 20180101; A61K 31/195 20130101;
A61K 31/19 20130101; A61K 31/195 20130101; A61K 2300/00 20130101;
A61K 31/415 20130101; A61K 2300/00 20130101; A61K 31/47 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/561 ;
514/162; 514/406; 514/570 |
International
Class: |
A61K 031/415; A61K
031/195; A61K 031/192 |
Claims
What is claimed is:
1. A combination of an effective amount of at least one
anti-epileptic compound having pain alleviating properties and an
effective amount of at least one compound selected from the group
consisting of NMDA receptor antagonists, NSAIDs, and
analgesics.
2. The combination of claim 1 wherein the anti-epileptic compound
is a compound of Formula I 3wherein R.sub.1 is hydrogen or a lower
alkyl; n is an integer of from 4 to 6; and the cyclic ring is
optionally substituted. and the pharmaceutically acceptable salts
thereof.
3. The combination of claim 1 wherein the anti-epileptic compound
is gabapentin.
4. The combination of claim 1 wherein the anti-epileptic compound
is a compound of Formula II 4wherein R.sub.11 is a straight or
branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl
having from 3 to 6 carbon atoms; R.sub.12 is hydrogen or methyl;
and R.sub.13 is hydrogen, methyl, or carboxyl; or an individual
diastereomeric or enantiomeric isomer thereof; or a
pharmaceutically acceptable salt thereof
5. The combination of claim 1 wherein the anti-epileptic compound
is pregabalin.
6. A combination of an effective amount of at least one
anti-epileptic compound having pain alleviating properties and an
effective amount of a NMDA receptor antagonist.
7. The combination of claim 6 wherein the anti-epileptic compound
is gabapentin.
8. The combination of claim 6 wherein the anti-epileptic compound
is pregabalin.
9. A combination of an effective amount of at least one
anti-epileptic compound having pain alleviating properties and an
effective amount of a NSAID.
10. The combination of claim 9 wherein the anti-epileptic compound
is gabapentin.
11. The combination of claim 9 wherein the anti-epileptic compound
is pregabalin.
12. The combination of claim 9 wherein the anti-epileptic compound
is NSAID is naproxen.
13. A combination of an effective amount of at least one
anti-epileptic compound having pain alleviating properties and an
effective amount of a narcotic analgesic, with the proviso that
morphine is not included as a narcotic analgesic.
14. The combination of claim 13 wherein the anti-epileptic compound
is gabapentin.
15. The combination of claim 13 wherein the anti-epileptic compound
is pregabalin.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to novel combinations of
anti-epileptic compounds that demonstrate pain alleviating
properties, with compounds selected from the group consisting of
analgesics, N-methyl-D-aspartate (NMDA) receptor antagonists and
non-steroidal anti-inflammatory drugs (NSAIDs) and pharmaceutical
compositions comprising same. It has been discovered that the
administration of anti-epileptic compounds that demonstrate pain
alleviating properties in these novel combinations results in an
improved reduction in the frequency and severity of pain. It is
also believed that the incidence of unwanted side effects can be
reduced by these novel combinations in comparison to using higher
doses of a single agent treatment to achieve a similar therapeutic
effect. The present invention is also directed to methods of using
effective amounts of the novel pharmaceutical compositions to treat
pain in mammals.
BACKGROUND OF THE INVENTION
[0002] A number of treatments involving the administration of
single drugs are currently recommended for pain relief. The single
administration of narcotic and non-narcotic analgesics and NSAIDs
have been shown to display pain alleviating properties. Some
anti-epileptics, such as gabapentin and pregabalin, have also
demonstrated pain alleviating properties.
[0003] Despite the benefits derived from current single drug pain
relief regimens, these regimens have disadvantages. One area of
concern relates to the incidence of unwanted side effects caused by
many of the pain treatment regimens available today. Narcotic
analgesics, such as morphine, are sparingly prescribed for pain
because of the well-known addictive effects and significant central
nervous system (CNS) side effects and gastrointestinal side effects
resulting from their single administration. Another class of drugs
often used alone for treatment of pain, non-steroidal
anti-inflammatory drugs, such as ibuprofen and naproxen, are
criticized for their irritation of the gastrointestinal tract.
[0004] Another concern of current pain treatment regimens relates
to their effectiveness. Many single active ingredients employed in
current pain relief regimens cannot achieve adequate pain
alleviation even at their maximum therapeutic approved doses in
some severe pain states. In addition to not achieving adequate pain
alleviation, increasing the drug dose may produce an increase in
unwanted side effects such as cognitive impairment, nausea, and
constipation.
[0005] In view of these concerns, it is evident that there is a
need for an improved pain regimen that provides an improved
therapeutic benefit (ie, reduced severity and/or frequency of pain)
and/or reduces the incidence of unwanted side effects caused by
many of the current regimens.
SUMMARY OF THE INVENTION
[0006] The inventors have now surprisingly found that
anti-epileptic compounds having pain alleviating properties, when
co-administered with compounds selected from the group consisting
of analgesics. NMDA receptor antagonists, and NSAIDs, result in
unexpected improved pain relief.
[0007] The present invention is directed to novel combinations for
alleviating pain, the combinations comprising of anti-epileptic
compounds, such as gabapentin and pregabalin, that have displayed
pain alleviating properties, and compounds selected from the group
consisting of NMDA receptor antagonists, analgesics, and NSAIDs. It
is also believed that the incidence of unwanted side effects can be
reduced by co-administration of these compounds with anti-epileptic
compounds having pain alleviating properties in comparison to using
higher doses of a single agent treatment to achieve a similar
therapeutic effect.
[0008] The present invention is also directed to pharmaceutical
compositions comprising the novel combinations of certain
anti-epileptic compounds with compounds selected from the group
consisting of NMDA receptor antagonists, analgesics, and NSAIDs.
The active ingredients are combined with at least one
pharmaceutically acceptable carrier. The novel pharmaceutical
compositions are prepared in a wide variety of pharmaceutical
delivery systems known to those of skill in the art, preferably
oral and parenteral dosage forms.
[0009] The present invention is also directed to methods of
treating mammals suffering from pain with the novel pharmaceutical
composition to alleviate pain. The method comprises the step of
administering the pharmaceutical compositions comprising the novel
anti-epileptic combinations to mammals in need of pain relief.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 shows the anti-hyperalgesic actions of fixed 1:1 (1
part by weight of gabapentin to 1 part by weight of naproxen
sodium) combinations of gabapentin and naproxen sodium at various
dosages.
[0011] FIG. 2 shows the anti-hyperalgesic actions of fixed 50:1 (50
parts by weight of gabapentin to 1 part by weight of naproxen
sodium) combinations of gabapentin and naproxen sodium at various
dosages.
DETAIL DESCRIPTION OF THE INVENTION
[0012] It has now been unexpectedly found in accordance with the
present invention that analgesic effects can be enhanced by the
co-administration of anti-epileptic compounds that demonstrate pain
alleviating properties together with compounds selected from the
group consisting of analgesics, NSAIDs, and NMDA receptor
antagonists. As used herein, the term "co-administration" is meant
to include the administration of anti-epileptic compounds, before,
during, or after administration of compounds selected from the
group consisting of NMDA receptor antagonists, analgesics, and
NSAIDs.
[0013] One advantage of using the novel combinations described
herein is the reduced severity and/or frequency of pain. Another
potential advantage is the overall improvement in pain control,
which can include a reduction in the dosage and unwanted side
effects.
[0014] Analgesics used in this invention can be, for example,
non-narcotic analgesics or narcotic analgesic compounds.
[0015] Non-narcotic analgesics are generally defined to be those
compounds that relieve pain without being addictive. A non-limiting
example of a non-narcotic analgesic includes acetaminophen.
[0016] Narcotic analgesics are generally defined to be those
compounds that are addictive when administered to treat a mammal
for pain. Non-limiting examples of narcotic analgesics include
opiates, opiate derivatives, opioids, and their pharmaceutically
acceptable salts. Specific non-limiting examples of narcotic
analgesics include alfentanyl, alphaprodine, anileridine,
bezitramide. codeine, dihydrocodeine, diphenoxylate. ethylmorphine,
fentanyl. heroin, hydrocodone, hydromorphone, isomethadone.
levomethorphan, morphine, neperidine, phenomorphan, phenoperidine,
piritradide, pholcodine, proheptazoine, properidine, propiran,
racemoramide, thebacon, trimeperidine, and the pharmaceutically
acceptable salts thereof
[0017] NMDA receptor antagonists which can be used in the novel
combination are compounds that block or reduce the effects of NMDA
at the NMDA subclass of neuronal glutamate receptors. NMDA
receptors are areas in the central nervous system that are
selectively excited by NMDA and exert a biological effect when NMDA
is bound to them. Non-limiting examples of NMDA receptor
antagonists include dextromethorphan and ketamine.
[0018] The term "NSAID", as used to describe other compounds useful
in the novel combination herein, is intended to be a non-steroidal
anti-inflammatory compound. NSAIDs are categorized by virtue of
their ability to inhibit cyclooxygenase. Cyclooxygenase 1 and
cyclooxygenase 2 are the two major isoforms of cyclooxygenase and
most standard NSAIDs are mixed inhibitors of the two isoforms. Most
standard NSAIDs fall within one of the following five structural
categories: (1) propionic acid derivatives, such as ibuprofen,
naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid
derivatives, such as tolmetin and sulindac; (3) fenamic acid
derivatives, such as mefenamic acid and meclofenamic acid; (4)
biphenylcarboxylic acid derivatives, such as diflunisal and
flufenisal; and (5) oxicams, such as piroxim, sudoxicam, and
isoxican. Other useful NSAIDs include aspirin.
[0019] Another class of NSAID has recently been described which
selectively inhibits cyclooxygenase 2. These compounds reduce pain
and inhibit the inflammatory response without damaging the gastric
mucosa, a common toxicity observed with the mixed inhibitors.
(Z)-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-imino-4-t-
hiazolidinone methanesulfonate (1:1), celecoxib, meloxicam, and
their pharmaceutically acceptable salts are examples of selective
cyclooxygenase 2 inhibitors.
[0020] The term "anti-epileptic compound" is generally defined to
be a pharmaceutically acceptable active ingredient that treats
disorders characterized by recurring attacks of motor, sensory, or
psychic malfunction with or without unconsciousness or convulsive
movements. Non-limiting examples of anti-epileptic compounds having
analgesic activity include gabapentin, pregabalin, carbamazepine,
lamotrigine, phenytoin, fosphenytoin, and analogues thereof.
[0021] The term "pain alleviating properties" is generally defined
herein to include the expressions "pain-suppressing,"
"pain-reducing", and "pain-inhibiting" as the invention is
applicable to the alleviation of existing pain, as well as the
suppression or inhibition of pain which would otherwise ensue from
the imminent pain-causing event.
[0022] In a preferred embodiment of the present invention,
anti-epileptic compounds having pain alleviating properties include
those that have the following Formula I: 1
[0023] wherein R.sub.1 is hydrogen or a lower alkyl; n is an
integer of from 4 to 6; and the cyclic ring is optionally
substituted, and the pharmaceutically acceptable salts thereof. The
term lower alkyl includes straight or branched chain alkyl groups
of up to eight carbon atoms. An especially preferred embodiment
utilizes a compound of Formula I where R.sub.1 is hydrogen and n is
5, which compound is 1-(aminomethyl)-cyclohe- xane acetic acid,
known generically as gabapentin.
[0024] Other preferred compounds of Formula I above include, but
are not limited to, ethyl 1-aminomethyl-1-cyclohexane-acetate,
1-aminomethyl-1-cycloheptane-acetic acid,
1-aminomethyl-1-cyclopentane-ac- etic acid,
methyl-1-aminomethyl-1-cyclohexane-acetate, n-butyl 1-aminomethyl-1
-cyclohexane-acetate, methyl 1-aminomethyl-1-cycloheptane-
-acetate, n-butyl 1-aminomethyl-1 -cycloheptane-acetate, toluene
sulfonate, 1-aminomethyl-1-cyclopentane-acetate, benzene-sulfonate,
and n-butyl 1-aminomethyl-1-cyclopentane-acetate.
[0025] Other preferred compounds of Formula I above, wherein the
cyclic ring is substituted for example with alkyl such as methyl or
ethyl, include, but are not limited to
(1-aminomethyl-3-methylcyclohexyl)acetic acid,
(1-aminomethyl-3-methylcyclopentyl)acetic acid, and
(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.
[0026] In another preferred embodiment of the present invention,
anti-epileptic compounds having pain alleviating properties include
those that are included in Formula II: 2
[0027] wherein R.sub.11 is a straight or branched alkyl of from 1
to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon
atoms; R.sub.12 is hydrogen or methyl; and R.sub.13 is hydrogen,
methyl, or carboxyl; or an individual diastereomeric or
enantiomeric isomer thereof; or a pharmaceutically acceptable salt
thereof
[0028] The most preferred compound of Formula II is where R.sub.12
and R.sub.13 are both hydrogen, and R.sub.11 is
--(CH.sub.2).sub.0-2-iC.sub.4- H.sub.9 as an (R), (S), or (R,S)
isomer. A more preferred embodiment of the invention utilizes
3-aminomethyl-5-methyl-hexanoic acid, and especially
(S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as
pregabalin. Another preferred compound is
3-(1-aminoethyl)-5methylhexanoic acid.
[0029] In the preferred embodiment of the present invention, the
combination will be comprised of compounds of Formula I in
combination with the compound selected from the group consisting of
NSAIDs, analgesics, and NMDA receptor antagonists. In a more
preferred embodiment of the present invention, the combination will
contain the compound, gabapentin, as the anti-epileptic drug.
[0030] In addition to its pain alleviating properties, gabapentin
is extremely well-tolerated and has been demonstrated to be
virtually free of drug interactions. The unique properties and
mechanism of action of anti-epileptic compounds like gabapentin,
which demonstrate pain alleviating properties would allow it to be
used in the combinations described above with the benefit of
providing better pain relief than if it were used not in
combination. An added benefit of using the combination would be to
use reduced quantities of medication, thereby potentially reducing
adverse events for the patient.
[0031] The amount of the active ingredients in the combinations
will vary depending on the mammal to which the combinations are
administered, the type of pain to be treated, other active
ingredients present, etc. Generally, the amount of the
anti-epileptic compound(s) and the other active compound for a
given composition and dosage form can be readily determined
employing routine procedures.
[0032] The present invention is also directed to methods of
treating mammals to alleviate pain by the co-administration of an
anti-epileptic compounds that have pain alleviating properties and
a compound selected from the group consisting of analgesics,
NSAIDS, and NMDA receptor antagonists. The types of treatable pain
experienced by mammals is varied and known to medical
practitioners. Non-limiting examples of mammalian pain include
centrally mediated pain, peripherally mediated pain, structural or
soft tissue injury related pain, progressive disease related pain
(i.e., oncology) and neuropathic pain states, all of which would
include both acute (i.e., acute injury or trauma, pre and
post-surgical, headache such as a migraine), chronic (i.e.,
neuropathic pain conditions such diabetic peripheral neuropathy and
post-herpatic neuralgia) and inflammatory condition (i.e., osteo or
rheumatoid arthritis, sequela to acute injury or trauma) pain
states.
[0033] Pharmaceutical compositions containing the combination of
the present invention or its salts are produced by formulating the
active compound in dosage unit form with a pharmaceutical carrier.
Some examples of suitable dosage unit forms are tablets, capsules,
pills, powders, aqueous and nonaqueous oral solutions and
suspensions, and parenteral solutions packaged in containers
containing either one or some larger number of dosage units and
capable of being subdivided into individual doses. Some examples of
suitable pharmaceutical carriers, including pharmaceutical
diluents, are gelatin capsules; sugars such as lactose and sucrose;
starches such as corn starch and potato starch cellulose
derivatives such as sodium carboxymethyl cellulose, ethyl
cellulose, methyl cellulose, and cellulose acetate phthalate;
gelatin; talc; stearic acid; magnesium stearate; vegetable oils
such as peanut oil, cottonseed oil, sesame oil, olive oil, corn
oil, and oil of theobroma; propylene glycol, glycerin, sorbitol;
polyethylene glycol; water, agar, alginic acid; isotonic saline,
and phosphate buffer solutions; as well as other compatible
substances normally used in pharmaceutical formulations. The
compositions of the invention can also contain other components
such as coloring agents, flavoring agents, and/or preservatives.
These materials, if present, are usually used in relatively small
amounts. The compositions can, if desired, also contain other
suitable pharmacologically active components.
[0034] Preferred routes of administration of the subject
combinations are oral or parenteral. Dosing will vary depending
upon the mammal and a number of other factors.
EXAMPLES
Example 1
[0035] The aim of this experiment was to characterize the
antinociceptive and anti-inflammatory effects of gabapentin
administered in combination with a prototypic NSAID in the rat. In
this example, gabapentin, naproxen sodium, and the combination of
gabapentin and naproxen sodium were evaluated in a standard rat
carrageenan footpad thermal hyperalgesia assay. This assay utilizes
an extract of seaweed (carrageenan) that, when injected into the
footpad of test animals, causes a sterile inflammation, thereby
lowering the pain threshold. Anti-epileptic agents having analgesic
properties, such as gabapentin, raise the pain threshold back to
normal, thereby enabling the animal to tolerate an external source
of pain for a longer period of time relative to untreated control
animals.
[0036] As shown in FIG. 1, gabapentin and naproxen sodium were
given alone (gabapentin at 120 min after dosing; naproxen sodium at
120 min after dosing). Each data point represents the mean and
standard error of mean. Data for each drug were fitted by least
squares linear regression to a straight line. The theoretical
dose-additive line for a 1:1 dose ratio was determined (dotted
line) as described (Tallarida, 1992). The experimental
determination of a 1:1 dose ratio was determined
(gabapentin-naproxen sodium mixture 1:1) and was found to be
significantly different than the theoretical dose-additive line.
Thus, a supra-additive effect was determined for the combination of
the two treatments given simultaneously. As shown in FIG. 2, the
experiment was performed as described in FIG. 1 and similarly a
supra-additive effect was determined for the combination of the two
treatments given simultaneously, except that the theoretical
dose-additive line (dotted line) and experimental data (open boxes)
were both determined for a 50:1 ratio of gabapentin dose to
naproxen sodium dose.
[0037] To summarize, the data showed that both gabapentin (3-100
mg/kg PO) and naproxen sodium (0.3-30 mg/kg PO) caused
anti-hyperalgesic actions in the rat carrageenan footpad model
(Hargreaves test). Combinations in a fixed ratio (1 mg gabapentin/1
mg naproxen sodium or 1:1 ratio) were anti-hyperalgesic, and
produced a significantly supra-additive effect (synergistic
action). For example, with a 1:1 dose ratio, dosages of naproxen
sodium (0.05 mg/kg) plus gabapentin (0.05 mg/kg) that were both
less than {fraction (1/10)}th of the ED.sub.50 dose of the
respective compounds alone, produced maximal antihyperalgesic
effects when given in combination (see Table 1). Combinations in a
fixed ratio (50 mg gabapentin/1 mg naproxen sodium) also were
anti-hyperalgesic, with a significant tendency towards a greater
than additive effect.
[0038] The data establish that the combination of gabapentin and
naproxen sodium is synergistic in its ability to relieve acute and
chronic pain. The data also establish that the most preferred
combination of gabapentin plus naproxen sodium is in a fixed-ratio
combination near 1:1 (within some reasonable limit).
1TABLE 1 ED.sub.50 VALUES DETERMINED FOR GABAPENTIN, NAPROXEN AND
TWO FIXED-RATIO COMBINATIONS IN THE CARRAGEENAN RAT FOOTPAD THERMAL
HYPERALGESIA TEST. DRUG TREATMENT ED.sub.50.dagger. Gabapentin 17
mg/kg (2.4-46 mg/kg).dagger. Naproxen sodium 0.36 mg/kg (0.007-1.26
mg/kg).dagger. Theoretical 1:1 0.7 mg/kg combined total
(gabapentin:naproxen) [0.35 mg/kg gabapentin plus 0.35 mg/kg
naproxen] Experimental 1:1 0.00022 mg/kg combined total
(gabapentin:naproxen) (nd. -0.0020).dagger. [0.00011 mg/kg
gabapentin plus 0.00011 mg/kg naproxen]** Theoretical 50:1 9.0
mg/kg combined total (gabapentin:naproxen) [8.8 mg/kg gabapentin
plus 0.18 mg/kg naproxen] Experimental 50:1 0.77 mg/kg combined
total (gabapentin:naproxen) (0.06-3.18 mg/kg).dagger. [0.75 mg/kg
gabapentin plus 0.015 mg/kg naproxen]* .dagger.95% confidence
limits of experimental ED50 values are shown in parentheses.
*Significantly less than additive theoretical combined ED.sub.50, p
< 0.05. **Significantly less than additive theoretical combined
ED.sub.50, p < 0.001. n.d.--not determined
[0039] Animals
[0040] Male Sprague-Dawley rats (200-250 g. Sasco Laboratories)
were used. Rats were group housed 5/cage on a 12-hour light:dark
cycle with free access to food and water. Rats received only one
dose of a drug or drug combination. All drugs were administered
orally by gavage.
[0041] Experimental Design
[0042] Dose-effect curves were first determined for (1) gabapentin
by itself and (2) a prototypic NSAID (e.g., naproxen) by itself The
ED.sub.50 value and 95% confidence limits of each agent was
determined, as was the time to peak effect. After determination of
these values, dose effect curves were generated for gabapentin
administered in a fixed dose ratio with the NSAID; the drugs were
administered so that their peak effects were coincident. ED.sub.50
values and 95% confidence limits were then determined for the drugs
in combination.
[0043] Measures of Antinociception
[0044] Carrageenan-induced thermal hyperalgesia: Rats were
acclimated to a testing chamber whose glass floor was maintained at
25.degree. C. Thirty minutes later a high intensity beam of light
was focused through the glass on the ventral surface of each
hindpaw, and the latency to reflex withdrawal of the paw from the
light beam was measured to the nearest 0.1 second. This latency was
termed the paw flick latency (PFL). Two measurements of PFL spaced
20 minutes apart were made for each paw, and the second measurement
was taken as the baseline response latency. After determination of
baseline PFL, 100 .mu.L of 2% lambda-carrageenan was injected in
the plantar surface of one hindpaw and the animal returned to the
testing chamber. Two hours later, when thermal hyperalgesia was
maximal and stable, either vehicle, gabapentin, naproxen. or
gabapentin and naproxen was administered by gavage. Response
latencies for the ipsilateral and contralateral hindpaws were then
redetermined 15, 30, 45, 60, 90 and 120 minutes later. Data for
further analysis were taken 120 minutes after oral dosing.
[0045] Statistical Analysis
[0046] Data were expressed as the mean .+-.SEM. Two-way analyses of
variance for repeated measures was used to compare the effects of
drug to that of vehicle. Dose-effect lines for gabapentin and the
NSAID were constructed using individual data and fitted with least
squares linear regression analysis to determine ED.sub.50 values
and 95% confidence limits. A similar analysis was conducted for the
drugs in combination using the total dose administered. Since
parallel dose-effect lines were obtained for gabapentin, naproxen,
and the combination of gabapentin and naproxen, then a parallel
line assay was conducted as described by Tallarida (Tallarida,
1992; Tallarida, et al; 1989). This analysis compared the position
of the experimentally-derived dose-effect line for the combination
to the position of the theoretical dose-additive line. A
significant shift to the left or the right of the theoretical
dose-additive line indicates that the drugs interacted in a
supra-additive (synergistic) or an infra-additive manner
(antagonistic), respectively.
[0047] The preceeding examples were presented so that the present
invention may be better understood and are intended for purposes of
illustration only and should not be construed to limit the scope of
the invention, as defined by the claims appended hereto.
* * * * *