Pharmaceutical products providing enhanced analgesia

An analgesic composition comprising capsaicin or a capsaicin analogue and an analgesic selected from the class of non-steroidal anti-inflammatory, antipyretic and analgesic drugs is disclosed. This combination has been found to exhibit unexpectedly enhanced analgesic activity in humans and lower animals without a corresponding increase in undesirable side effects.

TECHNICAL FIELD 
The present invention relates to analgesic compositions comprising 
capsaicin or a capsaicin analog combined with a drug selected from the 
class of nonsteroidal anti-inflammatory, antipyretic and analgesic 
compounds. These compositions, when administered to humans or lower 
animals, provide a synergistic analgesic effect while minimizing 
undesirable side effects and toxicity. 
Capsaicin and its derivatives appear to produce and analgesic effect 
through a mechanism largely unrelated to that of the other two categories 
of analgesics, opioids (narcotics) and non-steroidal analgesics 
(aspirin-like drugs). Since both capsaicin and the non-steroidals produce 
an analgesic effect, although apparently through different mechanisms, it 
might be expected that their combined effect would be at best additive. 
However, tests have shown that the analgesic effect of the combination is 
not merely the sum of the effects of each component, but rather an 
unexpected, greatly enhanced synergistic effect. Furthermore, the 
undesirable side effects of the two categories of analgesics are not 
closely related and the addition of the second analgesic does not appear 
to potentiate the side effects of the first. It is therefore possible to 
combine the two analgesics in such a dosage as to provide greatly enhanced 
analgesia with no enhancement of side effects. Depending on the dosages 
employed, the capsaicin may either potentiate the degree of analgesia 
beyond that obtainable using the non-steroidal alone, or it may induce 
analgesia at dosages where no analgesic effect is obtained from either 
component alone. 
BACKGROUND OF THE INVENTION 
Traditionally, analgesics have fallen into two broad categories. Simple, 
non-narcotic analgesics, such as aspirin, which appear to work by 
inhibition of prostaglandin synthetase, are effective against pain of 
integumental origin such as headache and muscle aches, but are often 
ineffective in controlling deeper, more intense pain. Furthermore, they 
may cause undesirable side effects even at therapeutic dosages. The most 
common of these side effects is a propensity to induce dyspepsia and 
gastrointestinal bleeding. At higher dosages, the salicylates may have 
toxic effects on the central nervous system consisting of stimulation 
(including convulsions) followed by depression. Headache, dizziness, 
mental confusion, hearing difficulties and hyperventilation may also 
occur. Gastrointestinal symptoms may include epigastric distress, nausea 
and vomiting. The narcotic analgesics appear to work through interaction 
with the endorphin/enkephalin receptor system of the central nervous 
system and are useful in controlling pain which is too intense to be 
controlled by the weaker, non-narcotic analgesics. However, 
centrally-acting narcotic analgesics have several serious undesirable side 
effects, including the development of physical dependence and tolerance, 
sedation, respiratory depression, hypotension, increase in cerebrospinal 
fluid pressure, nausea, vomiting and constipation. In some patients, 
particularly the chronically ill, the narcotic side effects make it 
impossible to administer dosages sufficient to adequately control pain 
over the required time period. 
This invention combines capsaicin or a capsaicin analog with a drug from 
the class or non-narcotic, non-steroidal anti-inflammatory, antipyretic 
and analgesic compounds (often referred to as an "aspirin-like" drug, 
since the prototypical compound is aspirin), producing a synergistic 
increase in analgesia without a corresponding increase in side effects. 
The degree of analgesia produced by this combination has been found in 
some cases to be equivalent to that formerly obtainable only through the 
use of narcotics. Thus, the claimed combination makes it possible to 
control pain which is too severe to be adequately controlled by the 
non-steroidals alone, while avoiding the serious side effects and 
addiction potential inherent in the use of opioids. 
It has been recently discovered that capsaicin, a natural product of 
certain species of the genus Capsicium, induces analgesia. Capsaicin 
(8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin 
(N-vanillyl-nonanamide) are disclosed as analgesics in U.S. Pat. No. 
4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicin 
has also been discussed in the chemical and medical literature, including 
Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al, 
Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 and Holzer et 
al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No. 4,238,505, 
Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilide for use in 
producing analgesia in animals. European Patent Application No. 0089710, 
LaHann, et al, published Sept. 28, 1983, describes hydroxyphenylacetamides 
with analgesic and anti-irritant activity. Similarly, analgesic and 
antiirritant activity is disclosed for N-vanillylsulfonamides in U.S. Pat. 
No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; N-vanillylureas in 
European Patent Application No. 0068590, Buckwalter, et al, published Jan. 
5, 1983; N-vanillylcarbamates in European Patent Application No. 0068592, 
Buckwalter, et al, published Jan. 5, 1983, N-[(substituted 
phenyl)methyl]alkynlamides in U.S. patent application Ser. No. 514,204, 
Janusz, et al, Filed July 14, 1983, now U.S. Pat. No. 4,532,139, issued 
July 30, 1985; methylene substituted N-[(substituted 
phenyl)methyl]-alkanamides in U.S. patent application Ser. No. 514,205, 
Janusz, et al, filed July 14, 1983, now U.S. Pat. No. 4,544,668, issued 
Oct. 1, 1985, N[(substituted phenyl)methyl]-cis-monounsaturated 
alkenamides in U.S. patent application Ser. No. 514,206, LaHann, et al, 
filed July 14, 1983, now U.S. Pat. No. 4,493,848, issued Jan. 14, 1985, 
and N-[substituted phenyl)methyl-]diunsaturated amides in U.S. patent 
application Ser. No. 514,207, LaHann, et al, filed July 14, 1983, now U.S. 
Pat. No. 4,544,669, issued Oct. 1, 1985. However, none of these references 
suggest in any way the desirability of concurrent administration of 
capsaicin or a capsaicin derivative with a non-steroidal. Further, the art 
suggests that it is extremely difficult to predict when a synergistic 
effect will be obtained from the concurrent administration of two 
pharmaceutical compounds which take effect through different mechanisms. 
Although there are many patents which disclose analgesic and 
anti-inflammatory compositions containing a combination of two or more 
mechanistically unrelated analgesic and/or anti-inflammatory compounds, 
none of these compounds has a structure at all similar to that of 
capsaicin See U.S. Pat. No. 4,404,210, Schmidt, issued Sept. 13, 1983; 
U.S. Pat. No. 4,083,981, Yamamoto, issued Apr. 11, 1978; U.S. Pat. No. 
4,315,936, Capetola et al, issued Feb. 16, 1982; U.S. Pat. No. 4,379,789, 
Capetola et al, issued Apr. 12, 1983; and U.S. Pat. No. 4,275,059, Flora, 
et al, issued June 23, 1981. 
Thus, based on the art, one could not have predicted that the combination 
of capsaicin or a capsaicin analog with a non-steroidal would result in a 
synergistic increase in analgesia. 
SUMMARY OF THE INVENTION 
It has now been found that combinations of capsaicin derivatives of the 
general formula 
##STR1## 
wherein R.sub.1 is OH or OCH.sub.3, R.sub.2 is OH or a short-chain ester, 
X is 
##STR2## 
and R is a C.sub.5 -C.sub.11 alkyl, C.sub.5 -C.sub.11 alkenyl, C.sub.11 
-C.sub.23 cis alkenyl, C.sub.11 -C.sub.23 alkynyl, C.sub.11 -C.sub.23 
alkadienyl, or C.sub.11 -C.sub.23 methylene substituted alkane, with a 
non-steroidal analgesic at weight ratios of capsaicinoid to non-steroidal 
from about 20:1 to 1:20, and preferably from about 10:1 to 1:10, provide 
unexpectedly enhanced analgesic activity in humans and lower animals 
without a corresponding increase in undesirable side effects. 
Another aspect of the present invention comprises the method of alleviating 
pain in humans and lower animals by concurrent administration of a safe 
and effective amount of the analgesic composition described above. 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
By the term "comprising" as used herein is meant that various other inert 
ingredients, compatible drugs and medicaments, and steps can be employed 
in the compositions and methods of the present invention as long as the 
critical capsaicinoid/non-steroidal combination is present in the 
compositions and is used in the manner disclosed. The term "comprising" 
thus encompasses and includes the more restrictive terms "consisting 
essentially of" and "consisting of" which characterize the use of the 
compositions and methods disclosed herein. 
By "compatible" herein is meant that the components of the composition are 
capable of being commingled without interacting in a manner which would 
substantially decrease the analgesic efficacy of the total composition 
under ordinary use situations. 
By "administer concurrently" is meant either the administration of a single 
composition containing both the capsaicinoid and the non-steroidal, or the 
administration of the capsaicinoid and the non-steroidal as separate 
compositions within a short enough time period that the effective result 
is equivalent to that obtained when both compounds are administered as a 
single composition. Normally this would involve two separate dosages given 
within 10 minutes of each other. However, since many capsaicinoids retain 
effectiveness over unusually long time periods (possibly up to 3 days in 
the same cases) and most non-steroidals provide effective analgesia for 
relatively short time periods (4-8 hours), it may be desirable in some 
cases to implement a therapeutic regimen whereby each component is 
administered according to a schedule determined by its own period of 
analgesic effectiveness in order to maintain optimum effectiveness of the 
combination. The preferred method of administration is as a single 
composition. 
All percentages and ratios herein are by weight unless otherwise specified. 
Compositions 
The compositions of the present invention comprise a safe and effective 
amount of: 
(a) capsaicin or a capsaicin analog, 
(b) a compound selected from the group of non-steroidal anti-inflammatory, 
antipyretic and analgesic drugs, and their pharmaceutically-acceptable 
salts; and 
(c) a pharmaceutically-acceptable carrier. 
A safe and effective amount of the composition is that amount which 
provides analgesia, thereby alleviating or preventing the pain being 
treated at a reasonable benefit/risk ratio, as is intended with any 
medical treatment. Obviously, the amount of the composition used will vary 
with such factors as the particular condition that is being treated, the 
severity of the condition, the duration of the treatment, the physical 
condition of the patient, the nature of concurrent therapy (if any), the 
method of administration, and the specific formulation and carrier 
employed. 
By the term "capsaicin or a capsaicin analog" or "capsaicinoid" is meant a 
compound of the general formula 
##STR3## 
wherein R.sub.1 is selected from the group consisting of OH and OCH.sub.3, 
R.sub.2 is selected from the group consisting of OH and 
##STR4## 
R.sub.3 is selected from the group consisting of a C.sub.1 -C.sub.4 alkyl, 
phenyl and methyl, X is selected from the group consisting of 
##STR5## 
and R is selected from the group consisting of a C.sub.5 -C.sub.11 alkyl, 
C.sub.5 -C.sub.11 alkenyl, C.sub.11 -C.sub.23 cis alkenyl, C.sub.11 
-C.sub.23 alkynyl, C.sub.11 -C.sub.23 alkadienyl and C.sub.11 -C.sub.23 
methylene substituted alkane. 
Preferred compounds include those wherein both R.sub.1 and R.sub.2 are OH 
and X is 
##STR6## 
and those wherein R.sub.1 is OCH.sub.3, R.sub.2 is OH or R.sub.3 CO and X 
is 
##STR7## 
Preferred R groups include C.sub.7 -C.sub.10 alkyls and trans alkenyls, and 
C.sub.16 -C.sub.21 cis alkenyls and alkadienyls. The preferred moieties 
within these groups include C.sub.8 H.sub.17, C.sub.9 H.sub.17 and 
C.sub.17 H.sub.33. Preferred capsaicin analogs include 
N-vanillyl-alkadienamides, N-vanillyl-alkanedienyls, and 
N-vanillyl-cis-monounsaturated alkenamides. A particularly preferred 
capsaicinoid is N-vanillyl-9Z-octadecenamide (N-vanillyloleamide). 
Preferred capsaicin analogs and methods for their preparation are described 
in the following Patents and Patent Applications, all incorporated by 
reference herein: Capsaicin (8-methyl-N-vanillyl-6E-nonenamide) and 
"synthetic" capsaicin (N-vanillylnonanamide) are disclosed as analgesics 
in U.S. Pat. No. 4,313,958, LaHann, issued Feb. 2, 1982. European Patent 
Application No. 0089710, LaHann, et al, published Sept. 28, 1983, 
describes hydroxyphenylacetamides with analgesic and anti-irritant 
activity. Similarly, analgesic and antiirritant activity is disclosed for 
N-vanillylsulfonamides in European Patent Application No. 0068591, 
Buckwalter, et al, published Jan. 5, 1983; N-vanillylureas in European 
Patent Application No. 0068590, Buckwalter, et al, published Jan. 5, 1983; 
N-vanillylcarbamates in European Patent Application No. 0068592, 
Buckwalter, et al, published Jan. 5, 1983; N-[(substituted 
phenyl)methyl]alkynylamides in U.S. patent application Ser. No. 514,204, 
Janusz, et al, filed July 14, 1983, now U.S. Pat. No. 4,532,139, issued 
July 30, 1985; methylene substituted-N-[(substituted 
phenyl)methyl]-alkanamides in U.S. patent application Ser. No. 514,205, 
Janusz, et al, filed July 14, 1983, now U.S. Pat. No. 4,544,668, issued 
Oct. 1, 1985; N[(substituted phenyl)methyl]-cismonounsaturated alkenamides 
in U.S. patent application Ser. No. 514,206, LaHann, et al, filed July 14, 
1983, now U.S. Pat. No. 4,493,848, issued Jan. 18, 1985; and 
N-[(substituted phenyl)methyl]-diunsaturated amides in U.S. patent 
application Ser. No. 514,207, LaHann, et al, filed July 14, 1983, now U.S. 
Pat. No. 4,544,669, issued Oct. 1, 1985. 
By "non-steroidal anti-inflammatory, antipyretic and analgesic drugs", or 
"non-steroidal", is meant a heterogeneous group of compounds, often 
chemically unrelated (although most of them are organic acids) which share 
certain therapeutic actions and side effects. Their therapeutic activity 
appears to depend to a large extent upon the inhibition of prostaglandin 
biosynthesis. Their primary use is to provide symptomatic relief from pain 
and inflammation associated with certain diseases, particularly 
musculoskeletal disorders such as rheumatoid arthritis and osteoarthritis. 
These compounds are often referred to as "aspirin-like drugs", since the 
prototypical compound is aspirin. The pharmacological properties and 
therapeutic uses of the compounds included within this classification are 
described in detail in Goodman and Gilman, "Analgesic-Antipyretics and 
Anti-Inflammatory Agents; Drugs Employed in the Treatment of Gout", The 
Pharmacological Basis of Therapeutics, 6th Ed., Ch. 29 (1980); Verbeeck et 
al, "Clinical Pharmacokinetics of Non-steroidal Anti-inflammatory Drugs", 
Clinical Pharmakinetics 8, pp 297-331 (1983), and Scherrer and Whitehouse, 
Antiinflammatory Agents Chemistry & Pharmacology, Vol. 1, Academic Press, 
New York (1974); all incorporated by reference herein. 
Specific classes of non-steroidals useful in the present invention are 
disclosed in detail in the following U.S. Patents, all incorporated by 
reference herein: U.S. Pat. No. 4,275,059, Flora, et al, issued June 23, 
1983, discloses salicylic acid, its pharmaceutically-acceptable salts, and 
its pharmaceutically-acceptable esters and derivatives; U.S. Pat. No. 
4,264,582, Flora, et al, issued Apr. 28, 1981, discloses 
p-(isobutylphenyl) acetic acid compounds, including the parent acid 
(ibufenac) and its salts and esters, and derivatives thereof; U.S. Pat. 
No. 4,282,214, Flora, et al, issued Aug. 4, 1981, discloses various 
phenylacetic acid derivatives, their pharmaceutically-acceptable salts, 
and their pharmaceutically-acceptable esters; U.S. Pat. No. 4,216,212, 
Flora, et al, issued Aug. 5, 1980, discloses pyrazolidine compounds, their 
pharmaceutically-acceptable salts, and their pharmaceutically-acceptable 
esters; U.S. Pat. No. 4,269,828, Flora, et al, issued May 26, 1981, 
discloses indole compounds, their pharmaceutically-acceptable salts, and 
their pharmaceutically-acceptable esters. 
Specifically preferred non-steroidals may be roughly divided into four 
general classifications. The salicylates include compounds such as 
acetylsalicylic acid (aspirin), salicylic acid, sodium salicylate, 
diflunisal, and methyl salicylate. The salicylate-like anti-inflammatory 
agents include compounds such as phenylbutazone, indomethacin, zomapirac 
acid, sulindac, fluproquazone, and mefenamic acid. The arylalkanoic acids 
include ibuprofen, naproxen, ketoprofen, fenoprofen, suprofen, 
flurbiprofen, benoxaprofen, pirprofen, and carprofen. The salicylate-like 
analgesic-antipyretics include acetaminophen and phenacetin. In some 
cases, the non-steroidals may be mixed with each other or with other drugs 
such as caffeine. Two popular analgesic combinations are aspirin, 
phenacetin and caffeine (APC) and aspirin, phenacetin and acetaminophen. 
Non-steroidals most preferred for use in the capsaicinoid-non-steroidal 
combination include acetylsalicylic acid (aspirin), ibuprofen, 
acetaminophen, diflunisal, naproxen, fenoprofen, and mefenamic acid. A 
specifically preferred combination is APC. 
Weight ratios of capsaicinoid to non-steroidal useful in the present 
invention range from about 20:1 to about 1:20, with the preferred ratio 
ranging from about 10:1 to about 1:10. The optimum weight ratio is 
dependent primarily upon the relative strength of the particular 
capsaicinoid and non-steroidal used, and the type of severity of the pain 
being treated. As a representative example, preferred weight ratios of 
capsaicinoid:acetylsalicylic acid (aspirin) may range from about 3:1 to 
about 1:3; preferred weight ratios of capsaicinoid:diflunisal may range 
from about 3:1 to about 1:3; preferred weight ratios of 
capsaicinoid:acetaminophen may range from about 3:1 to about 1:3; and 
preferred weight ratios of capsaicinoid:ibuprofen may range from about 5:1 
to about 1:5. The preferred weight ratio for the preferred combination of 
N-vanillyl-9Z-octadecenamide and aspirin is about 2:1. 
By "pharmaceutically acceptable salts" is meant those salts of the above 
disclosed acids which are toxicologically safe for topical or oral 
administration. These include the sodium, calcium, potassium, magnesium, 
ammonium, lysine, and arginine salts. 
By "pharmaceutically acceptable carrier" is meant a solid or liquid filler, 
diluent or encapsulating substance which may be safely used in systemic or 
topical administration. Depending upon the particular route of 
administration, a variety of pharmaceutically-acceptable carriers, 
well-known in the art, may be used. These include solid or liquid fillers, 
diluents, hydrotropes, surface-active agents, and encapsulating 
substances. The amount of the carrier employed in conjunction with the 
capsaicinoid/opioid combination is sufficient to provide a practical 
quantity of material per unit dose of analgesic. 
Pharmaceutically-acceptable carriers for systemic administration, that may 
be incorporated into the compositions of this invention, include sugars, 
starches, cellulose and its derivatives, malt, gelatin, talc, calcium 
sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate 
buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. 
Specific pharmaceutically-acceptable carriers are described in the 
following U.S. patent applications, all incorporated by reference herein: 
U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; European 
patent application No. 089710, LaHann, et al, published Sept. 28, 1983; 
and European patent application No. 0068592, Buckwalter, et al, published 
Jan. 5, 1983. Preferred carriers for parenteral administration include 
propylene glycol, ethyl oleate, pyrrolidone, aqueous ethanol, sesame oil, 
corn oil, and combinations thereof. 
Various oral dosage forms can be used, including such solid forms as 
tablets, capsules, granules and bulk powders. Tablets can be compressed, 
tablet triturates, enteric-coated, sugar-coated, film-coated or multiple 
compressed, containing suitable binders, lubricants, diluents, 
disintegrating agents, coloring agents, flavoring agents, flow-inducing 
agents, and melting agents. Liquid oral dosage forms include aqueous 
solutions, emulsions, suspensions, solutions and/or suspensions 
reconstituted from non-effervescent granules and effervescent preparations 
reconstituted from effervescent granules, containing suitable solvents, 
preservatives, emulsifying agents, suspending agents, diluents, 
sweeteners, melting agents, coloring, and flavoring agents. Preferred 
carriers for oral administration include ethyl oleate, methyl cellulose, 
gelatin, propylene glycol, cottonseed oil, sesame oil, peanut oil, corn 
oil, soybean oil, oil and water emulsions, and self-emulsifying oils 
either as free-flowing liquids or encapsulated in soft gelatin capsules. 
Specific examples of pharmaceutically-acceptable carriers and excipients 
that may be used to formulate oral dosage forms, which may be used in 
formulating oral dosage forms containing monoalkenamides, are described in 
U.S. Pat. No. 3,903,297. Robert, issued Sept. 2, 1975, incorporated by 
reference herein. Techniques and compositions for making solid oral dosage 
forms are described in Marshall, "Solid Oral Dosage Forms" , Modern 
Pharmaceutics, Vol. 7, (Banker and Rhodes, editors), 359-427 (1979), 
incorporated by reference herein. 
Specific systemic and topical formulations useful in this invention are 
described in the following U.S. Patent Applications, relating to specific 
capsaicin analogs and methods of treatment, which are incorporated by 
reference herein: U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 
30, 1983; and European patent application No. 0089710; LaHann, et al, 
published Sept. 28, 1983; European patent application No. 0068590, 
Buckwalter, et al, published Jan. 5, 1983; and European patent application 
No. 0068592, Buckwalter, et al, published Jan. 5, 1983. Topical vehicles, 
useful herein, are disclosed in the following U.S. patent applications, 
incorporated by reference herein: "Improved Penetrating Topical 
Pharmaceutical Compositions Combining 1-dodecylazacycloheptan-2-one", Ser. 
No. 506,275, Cooper, filed June 21, 1983, now U.S. Pat. No. 4,557,934, 
issued Dec. 10, 1985; "Penetrating Topical Pharmaceutical Compositions 
Containing N-(1-hydroxyethyl)-pyrrolidone", Ser. No. 506,273, Cooper, 
filed June 21, 1983, now U.S. Pat. No. 4,537,776, issued Aug. 27, 1985; 
and "Compounds Useful for Producing Analgesia", Ser. No. 514,206, LaHann 
and Buckwalter, filed July 14, 1983, now U.S. Pat No. 4,498,848, issued 
Jan. 15, 1985. 
Methods for Producing Analgesia 
The present invention also encompasses methods for providing analgesia in 
humans or lower animals by administering concurrently to the human or 
lower animal in need of such treatment a safe and effective amount of a 
capsaicinoid/non-steroidal combination or a composition containing the 
same. Dosages required, as well as methods of administration, are 
dependent on the type of non-steroidal employed, the physical condition of 
the patient, the severity of the pain which must be prevented or 
alleviated, the relative severity and importance of adverse side effects, 
and other factors within the judgment of the physician. The preferred 
method of administration in most cases will be orally. 
The maximum dosage of the preferred capsaicin analogue vanillyloleamide 
(VO) which would normally be administered orally to an average adult 
without unacceptable side effects is about 2000 mg (35.4 mg/kg). The 
minimum effective dosage is about 50 mg (0.85 mg/kg). The maximum dosage 
of a non-steroidal which can be administered to the average adult is also 
about 2000 mg (35.4 mg/kg). Thus, the maximum allowable dosage of the 
combination will be about 2000 mg (35.4 mg/kg). It should be noted that a 
sub-effective dosage of one compound may effectively potentiate the other 
compound; therefore, less-than-minimum dosages of each component may be 
utilized in some cases. Thus, when dealing with safe and effective dosage 
levels of the present invention, it is more appropriate to speak of safe 
and effective dosages of the combination rather than of the individual 
components. 
The compositions and combinations of this invention can be used to treat 
and prevent pain and inflammation associated with certain diseases, 
particularly muscularskeletal disorders, and to provide analgesia in 
various disorders at the deeper structures, muscles, tendons, bursa and 
joints associated with disease and trauma, and in various other conditions 
in which capsaicinoids and/or non-steroidals have heretofore been used to 
alleviate pain and discomfort. 
The compositions of the instant invention are normally administered either 
topically or orally.

The following non-limiting Examples illustrate the compositions, methods of 
treatment, and uses of the present invention. 
EXAMPLE I 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--Vanillyl-9Z-octadecenamide 
120 mg 
Aspirin 60 mg 
Methylcellulose 30 mg 
Saline 6.0 ml 
______________________________________ 
The composition was prepared by dissolving the methylcellulose in the 
saline to yield a 0.5% solution, after which the solid aspirin and 
N-vanillyl-9Z-octadecenamide were added and uniformly suspended in the 
solution by exposure to sonication. Male mice weighing approximately 25 g 
were orally dosed with a volume of this suspension sufficient to deliver 
200 mg/kg of the octadecenamide and 100 mg/kg of the aspirin. Identical 
groups of mice were dosed orally with similarly prepared formulations 
which lacked either the aspirin, the octadecenamide, or both. Analgesic 
activity was demonstrated using the phenylquinone writhing test. 
EXAMPLE II 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
120 mg 
Ibuprofen 30 mg 
Methylcellulose 30 mg 
Saline 6.0 ml 
______________________________________ 
The methylcellulose suspending agent was dissolved in the saline to yield a 
0.5% solution, to which the two drugs were added. A homogeneous suspension 
was achieved by the aid of sonication. Male mice weighing approximately 25 
g were dosed by gavage with 250 mg/kg of the mixture. Analgesic activity 
was demonstrated using the phenylquinone writhing test. 
EXAMPLE III 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
120 mg 
Ibuprofen 30 mg 
Ethyl oleate 6.0 ml 
______________________________________ 
The two analgesic agents were suspended in the ethyl oleate with the aid of 
sonication, and analgesic activity was demonstrated using the 
phenylquinone writhing test. 
EXAMPLE IV 
An analgesic composition for oral administration is made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
100 g 
Acetylsalicylic acid 100 g 
Ethyl oleate 300 g 
______________________________________ 
The composition is made by simple dissolution of the octadecenamide in the 
ethyl oleate, followed by suspension of the finely divided acetylsalicylic 
acid in the resulting solution by vigorous mechanical blending under an 
inert atmosphere of argon or dry nitrogen. The creamy suspension is then 
loaded into soft gelatin capsules to deliver 325 mg acetylsalicylic acid 
and 325 mg N-vanillyl-9Z-octadecenamide per capsule. One such capsule is 
administered orally to a 60 kg human, producing analgesia. 
Substantially similar results are produced when the octadecenamide is 
replaced, in whole or in part, by capsaicin; N-vanillyl-9E-octadecenamide; 
N-[(4-acetoxy-3-methoxyphenyl)methyl]-9-Z-octadecenamide; 
N-vanillyl-(Z,Z)-9,12-octadecadienamide; 
N-vanillyl-(E,E)-9,12-octadecadienamide; 
N-[(4-acetoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide; 
N-vanillyl-(E,E)-10,13-nonadecadienamide; N-vanillyl-9-octadecyanamide; 
9-methylene-N-octadecan-amide; 
9-methylene-N-[(4-acetoxy-3-methoryphenyl)-methyl]octadecanamide; 
4-acetoxy-3-methoxy-benzyl nonamide, or octyl 
3,4-dehydroxyphenylacetamide. 
Substantially similar results are also obtained when the acetylsalicylic 
acid is replaced, in whole or in part, by the sodium, calcium, or lysine 
salts of aspirin, ibuprofen, diflunisal, naproxen, mefenamic acid, 
fenoprofen, indomethacin, ketoprofen, suprofen, perprofen, carprofen, or 
an aspirin-phenacetin-caffeine combination (APC). 
EXAMPLE V 
A composition for oral administration is made with the following 
components: 
______________________________________ 
Individual 
Bulk Tablet 
______________________________________ 
N--vanillyl-9,12-octadecadienamide 
140 g 350 mg 
Ibuprofen 35 g 90 mg 
Starch 12 g 30 mg 
Magnesium stearate 2 g 5 mg 
Microcrystalline cellulose 
40 g 100 mg 
Colloidal silicon dioxide 
1 g 2.5 mg 
Povidone 5 g 12.5 mg 
______________________________________ 
The above ingredients are admixed in bulk and formed into compressed 
tablets, using tabletting methods known in the art, each containing 590 mg 
of the mixture. One such tablet is administered orally to a 60 kg human, 
producing analgesia. 
EXAMPLE VI 
A composition for oral administration is made with the following 
ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
225 g 
Aspirin 125 g 
Phenacetin 83 g 
Caffeine 17 g 
Mannitol 487 g 
Acacia 29.3 g 
Starch 48.1 g 
Talc 15 g 
Calcium stearate 2 g 
______________________________________ 
The above ingredients are admixed in bulk and formed into tablets weighing 
100 mg each using tabletting methods known in the art. Two such tablets 
are administered orally to a 70 kg human, producing analgesia. 
EXAMPLE VII 
A composition for transdermal topical delivery is made by admixing the 
following components: 
______________________________________ 
N--vanillyl-9,12,15[E,E,E]-octadecatrienamide 
4.0% 
Ibuprofen 1.0% 
Myristyl alcohol 1.0% 
Propylene glycol 94.0% 
______________________________________ 
Approximately 4.0 ml of the lotion is applied to an 80 sq. cm. portion of 
the skin of a 60 kg human, producing analgesia. 
Effectiveness in Providing Analgesia Phenylquinone Writhing Tests 
The extent of analgesia obtained was determined using the phenylquinone 
writhing test model. Groups of eight male mice weighing between 
approximately 25 and 30g were dosed orally by gavage with the analgesic 
composition to be tested. Identical groups of mice were dosed with control 
compositions. Three hours after this initial administration, the mice were 
injected intraperitoneally with a 0.2% solution of phenylbenzoquinone in 
aqueous ethanol. The ability of the analgesic compositions tested to 
relieve the discomfort induced was measured by counting the number of 
abdominal contractions, or "writhes", occurring in each mouse during a 10 
minute period beginning 10 minutes after injection of the 
phenylbenzoquinone solution. The results are expressed as a percent of the 
"writhing" response observed in the vehicle control group. 
EXAMPLE VIII 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9-octadecenamide 
120 mg 
Aspirin 60 mg 
Methylcellulose 30 mg 
Saline 6.0 ml 
______________________________________ 
The composition was prepared by dissolving the methylcellulose in the 
saline to yield a 0.5% solution, after which the solid aspirin and 
N-vanillyl-9Z-octadecenamide were added and uniformly suspended in the 
solution by exposure to sonication. 
Male mice weighing approximately 25 g were orally dosed with a volume of 
this suspension sufficient to deliver 200 mg/kg of the octadecenamide and 
100 mg/kg of the aspirin. Identical groups of mice were dosed orally with 
similarly prepared formulations which lacked either the aspirin, the 
octadecenamide, or both. The mouse "writhing" method for assessing pain 
response described above was used. The data, summarized in the following 
table, were normalized based on the vehicle control taken as 100. 
______________________________________ 
Treatment % Writhing Response 
______________________________________ 
Methylcellulose alone 100 
Octadecenamide (200 mg/kg) 
54 
Aspirin (100 mg/kg) 78 
Aspirin (100 mg/kg) + octadecenamide 
10 
(200 mg/kg) 
______________________________________ 
The response of the group given aspirin alone was not statistically 
distinguishable from that of the control group. The 90% inhibition of the 
writhing response resulting from the combination treatment (aspirin plus 
octadecenamide) is greater than that expected from the sum of the aspirin 
treatment (22% inhibition) and octadecenamide treatment (45% inhibition) 
when given separately. 
EXAMPLE IX 
An analgesic combination for oral administration was prepared in a manner 
similar to that described for Example I, the only difference being the 
ratio of aspirin to N-vanillyl-9Z-octadecenamide: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
120 mg 
Aspirin 120 mg 
Methylcellulose 30 mg 
Saline 6.0 ml 
______________________________________ 
A solution was prepared as described in Example I. The analgesic activity 
of the combination was assessed in mice using the "writhing" method 
described above. The activity of the combination was contrasted with those 
of similar formulations lacking the aspiring component, the octadecenamide 
component or both: 
______________________________________ 
Treatment % Writhing Response 
______________________________________ 
Methylcellulose alone 100 
Aspirin (200 mg/kg) 15 
Octadecenamide (200 mg/kg) 
33 
Aspirin (200 mg/kg + octadecenamide 
1.5 
(200 mg/kg) 
______________________________________ 
The analgesic efficacy obtained from the combination is significantly 
greater than that from either component alone. 
EXAMPLE X 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
120 mg 
Ibuprofen 30 mg 
Methylcellulose 30 mg 
Saline 6.0 ml 
______________________________________ 
The methylcellulose suspending agent was dissolved in the saline to yield a 
0.5% solution, to which the two drugs were added. A homogeneous suspension 
was achieved by the aid of sonication. The analgesic efficacy of this 
formulation was evaluated by dosing the mice by gavage with a sufficient 
dosage to provide 250 mg/kg of the mixture. The analgesic strength of the 
treatment was assessed using the "writhing" method described above. The 
efficacy of the combination was compared with that of similar formulations 
lacking the octadecenamide, the ibuprofen, or both. 
______________________________________ 
Treatment % Writhing Response 
______________________________________ 
Methylcellulose alone 100 
Ibuprofen (50 mg/kg) 114 
Octadecenamide (200 mg/kg) 
48 
Octadecenamide (200 mg/kg) + ibuprofen 
2 
(50 mg/kg) 
______________________________________ 
In this case, the addition of an ineffective dose of ibuprofen to a 
moderately effective dose of octadecenamide resulted in a greatly 
potentiated analgesic effect. 
EXAMPLE XI 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
120 mg 
Ibuprofen 30 mg 
Ethyl oleate 6.0 ml 
______________________________________ 
The two analgesics were suspended in ethyl oleate with the aid of 
sonification, and evaluated for analgesic efficacy exactly as described in 
Example X. 
______________________________________ 
Treatment % Writhing Response 
______________________________________ 
Ethyl oleate alone 100 
Octadecenamide (200 mg/kg) 
36 
Ibuprofen (50 mg/kg) 154 
Octadecenamide (200 mg/kg) + ibuprofen 
5 
(50 mg/kg) 
______________________________________ 
Although the response of the group receiving 50 mg/kg of ibuprofen alone 
did not vary significantly from that of the control group, the addition of 
this sub-effect amount of ibuprofen to the octadecenamide greatly 
potentiated its analgesic effect. Further, the combination of ibuprofen 
with the octadecenamide can provide anti-inflammatory/anti-arthritis 
efficacy lacking in N-vanillyl-9Z-octadecenamide and related capsaicin 
analogs. 
EXAMPLE XII 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
120 mg 
3-(2',4'-diflurophenyl)-salicylic acid 
60 mg 
(diflunisal) 
Ethyl oleate 6.0 ml 
______________________________________ 
The two analgesics were suspended in ethyl oleate with the aid of 
sonication and were evaluated for analgesic efficacy as described in 
EXAMPLE X. 
______________________________________ 
TREATMENT % WRITHING RESPONSE 
______________________________________ 
Ethyl oleate alone 
100 
Diflunisal (100 mg/kg) 
121 
Octadecenamide (200 mg/kg) 
50 
Diflunisal (100 mg/kg) + 
15 
Octadecenamide (200 mg/kg) 
______________________________________ 
In this case, the addition of an ineffective dose of diflunisal to a 
moderately effective dose of octadecenamide resulted in a greatly 
potentiated analgesic effect. Additionally, diflunisal provides 
anti-inflammatory activity not possessed by the octadecenamide alone. 
Example XIII 
An analgesic composition for oral administration was made using the 
following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
75 mg 
Acetaminophen 75 mg 
Ethyl oleate/benzyl alcohol 
5 ml 
(98:2 vol/vol) 
______________________________________ 
The two analgesics were suspended in the ethyl oleate solution with the aid 
of sonication and were evaluated as in Example X. 
______________________________________ 
TREATMENT % WRITHING RESPONSE 
______________________________________ 
Ethyl oleate solution alone 
100 
Acetaminophen (150 mg/kg) 
127 
Octadecenamide (150 mg/kg) 
57 
Acetaminaphen (150 mg/kg + 
17 
octadecenamide (150 mg/kg) 
______________________________________ 
In this case, the addition of an ineffective dose of acetaminophen to a 
marginally effective dose of octadecenamide resulted in a greatly 
potentiated analgesic effect. 
EXAMPLE XIV 
In order to determine the preferred capsaicinoid: non-steroidal ratios, an 
analgesic combination for oral administration was made using the following 
ingredients: 
______________________________________ 
1:1 Octadecenamide:aspirin Combination 
N--vanillyl-9Z-octadecenamide 
75 mg 
Aspirin 75 mg 
Ethyl oleate 10 ml 
1:2 Octadecenamide:aspirin Combination 
N--vanillyl-9Z-octadecenamide 
50 mg 
Aspirin 100 mg 
Ethyl oleate 10 ml 
1:5 Octadecenamide:aspirin Combination 
N--vanillyl-9Z-octadecenamide 
25 g 
Aspirin 125 mg 
Ethyl oleate 10 ml 
______________________________________ 
The two analgesics were suspended in ethyl oleate with the aid of 
sonication and were evaluated for analgesic efficacy as described in 
Example X. 
______________________________________ 
% WRITHING 
TREATMENT RESPONSE 
______________________________________ 
Ethyl oleate alone 100 
150 mg/kg aspirin 92 
150 mg/kg Octadecenamide 
43 
150 mg/kg Octadecenamide:Aspirin (1:1) 
48 
150 mg/kg Octadecenamide:Aspirin (1:2) 
28 
150 mg/kg Octadeceaamide:Aspirin (1:5) 
77 
______________________________________ 
The responses of the ethyl oleate control group, the 1:5 combination group 
(25 mg/kg octadecenamide +125 mg/kg aspirin) and the group receiving 150 
mg/kg aspirin were not significantly different. The groups receiving the 
octadecenamide alone and the 1:1 combination (75 mg/kg aspirin +75 mg/kg 
octadecenamide) displayed a moderate analgesic effect. The group receiving 
the 1:2 combination (50 mg/kg octadecenamide +100 mg/kg aspirin) displayed 
an analgesic effect unexpectedly superior to that of any of the other 
groups. 
Since the aspirin component of this combination provides an 
anti-inflammatory benefit not possessed by the octadecenamide or the other 
capsaidin analogs, and the octadecenamide provides greater analgesia than 
is obtainable using aspirin alone without many of the limitative side 
effects of aspirin, including gastrointestinal effects, the combination 
clearly provides benefits not attainable using either compound alone. 
EXAMPLE XV 
In order to determine the preferred dosages of the 
capsaicinoid/non-steroidal combination in the rat, a 2:1 
octadecenamide:ibuprofen analgesic composition for oral administration was 
made using the following ingredients: 
______________________________________ 
N--vanillyl-9Z-octadecenamide 
100 mg 
Ibuprofen 50 mg 
Ethyl oleate/benzyl alcohol 
5 ml 
(98:2 vol/vol) 
______________________________________ 
The two analgesics were suspended in the ethyl oleate solution with the aid 
of sonication, and varying dosages of the combination, as well as the 
individual components, were evaluated for analgesic efficacy as described 
in Example X. 
______________________________________ 
TREATMENT % WRITHING RESPONSE 
______________________________________ 
Ethyl oleate solution alone 
100 
50 mg/kg ibuprofen 
150 
100 mg/kg octadecenamide 
83 
400 mg/kg octadecenamide 
21 
75 mg/kg 2:1 octadecenamide: 
40 
ibuprofen combination 
150 mg/kg 2:1 octadecenamide: 
6 
300 mg/kg 2:1 octadecenamide: 
0.5 
ibuprofen combination 
______________________________________ 
All three dosage levels of the combination produced a significant analgesic 
effect, although the 75 mg/kg dosage produced less analgesia than the 
other two dosages. Preferred dosage levels will depend on the severity of 
the pain to be treated, the relative severity of adverse side effects, and 
other factors within the judgment of the physician. 
Although neither 50 mg/kg ibuprofen nor 100 mg/kg octadecenamide provided 
significant analgesia by themselves, the 150 mg/kg combination (100 mg/kg 
octadecenamide +50 mg/kg ibuprofen) demonstrated an extremely strong 
analgesic effect. Furthermore, only 150 mg/kg of the 2:1 combination 
produced a greater analgesic effect than 400 mg/kg of octadecenamide 
alone, and only 75 mg/kg of the 2:1 combination (sub-effective amounts of 
both components) produced a greater analgesic effect than 100 mg/kg of 
octadecenamide alone. These results indicate a synergistic increase in 
analgesia when the two analgesics are combined.