Administration media for analgesic, anti-inflammatory and anti-pyretic drugs containing nitrous oxide and pharmaceutical compositions containing such media and drugs

Administration mediums comprising solutions of nitrous oxide in water, alcohols, ethers or oils, and optionally including essential fatty acids or C.sub.1 -C.sub.6 alkyl esters thereof enhance the action of analgesic, anti-inflammatory and anti-pyretic drugs. The drugs may be combined with the medium into a pharmaceutical composition or may be taken orally by swallowing the drug with the aid of the medium.

FIELD OF THE INVENTION
 THIS invention relates to novel preparations of analgesic,
 anti-inflammatory and anti-pyretic agents. More particularly, this
 invention relates to the enhancement of the efficacy of such agents.
 BACKGROUND TO THE INVENTION
 [a] Analgesic, Anti-inflammatory and Anti-pyretic Drugs
 Non-narcotic analgesics, most of which are also known as non-steroidal
 anti-inflammatory drugs [NSAID], are widely administered orally in the
 treatment of mild to severe pain. Within this class, the compounds vary
 widely in their chemical structure and in their biological profiles as
 analgesics, anti-inflammatory agents and anti-pyretic agents. Aspirin,
 acetaminophen and phenacetin have long been among the most commonly used
 members of this group; more recently, however, a large number of
 alternative non-narcotic agents offering a variety of advantages over the
 earlier drugs have been developed. Tolerance or addiction to these drugs
 is not generally a problem with their continuous use in the treatment of
 pain or in the treatment of acute or chronic inflammatory states [notably,
 rheumatoid arthritis and osteoarthritis]; nevertheless, these drugs
 generally have a higher potential for adverse side-effects at the upper
 limits of their effective dose ranges. Moreover, above each drug's upper
 limit or ceiling, administration of additional drugs does not usually
 increase the analgesic or anti-inflammatory effect. Among the newer
 compounds in the non-narcotic analgesic/non-steroidal anti-inflammatory
 group are compounds such as diflunisal [Dolobid.RTM.], ibuprofen
 [Brufen.RTM.], naproxen [Naprosyn.RTM.], fenoprofen [Fenopron.RTM.],
 piroxicam [Feldene.RTM.], flurbiprofen, mefenamic acid [Ponstan.RTM.] and
 sulindac [Clinoril.RTM.]. See also Physicans' Desk Reference, 35th
 edition, 1981, and The Merck Index, ninth edition, Merck & Co., Rahway,
 New Jersey (1976), for information on specific non-steroidal
 anti-inflammatory agents. Also see, generally, Wiseman, "Pharmacological
 Studies with a New Class of Non-steroidal Anti-Inflammatory Agents--Tbe
 Oxicams--With Special Reference to Piroxicam (Feldene.RTM.)", The American
 Journal of Medicine, Feb. 16, 1982:2-8; Foley et al, The Management of
 Cancer Pain, Volume II--The Rational Use of Analgesics in the Management
 of Cancer Pain, Hoffman-La Roche Inc., 1981; and Cutting's Handbook of
 Pharmacology, sixth edition, ed. T. Z. Czaky, M.D.
 Appleton-Century-Crofts, New York, 1979, Chapter 49: 538-550.
 The exact mechanism of action of this group of compounds and the
 relationship between chemical structure and analgesic, anti-inflammatory
 and anti-pyretic effect of these compounds are not yet fully understood
 despite the fact that some of these products, like aspirin and
 acetaminophen have been in use for many years. The recent contributions of
 John Vane in "Towards a better aspirin", Nature Volume 367, Jan. 20, 1993,
 pages 215 to 216 and of the authors referred to therein, which links such
 activities to the ability of these compounds to inhibit the enzyme known
 as cyclooxygenase [COX] of which two, and possibly three, isoforms exist,
 will no doubt play an important role in the future understanding of the
 mode of action and properties of this group of compounds.
 Narcotic analgesics are often used when pain control with non-narcotic
 analgesics is ineffective. While the drugs in this group vary considerably
 in their chemical structures and pharmacological properties, almost all
 suffer the disadvantages of tolerance and possible addiction with
 continued usage. Within the narcotic analgesic group, the drugs can be
 classified as narcotic agonists or narcotic antagonists. Narcotic agonists
 include the morphine group, the pethidine group and the methadone group.
 While some narcotic antagonists are pure antagonists [which are not
 analgesics], other narcotic antagonists are agonist-antagonists [i.e.
 antagonists with analgesic properties]; the agonist-antagonists are
 generally categorised as morphine-like or nalorphine-like]. Many of the
 narcotic analgesics are not effective orally, but are rather used
 parenterally. The orally active narcotic analgesics include such compounds
 as codeine, oxycodone, pethidine, dextro-propoxyphene [Doloxene.RTM.],
 methadone, propiram, buprenorphine, pentazocine [Sosegon.RTM.] and
 nalbuphine [Nubain.RTM.]. For more specific information on these
 compounds, see Physicians' Desk Reference, 35th edition, 1981, and The
 Merck Index, ninth edition, Merck & Co., Inc., Rahway, New Jersey 1976).
 Also see, generally, the Foley et al reference cited hereinabove and
 Cutting's Handbook of Pharacology, sixth edition, ed. T. Z. Czaky, M.D.,
 Appleton-Century-Crofts, New York, 1979, Chapter 50: 551-566.
 [b] Potentiation of Analgesic, Anti-inflammatory and Anti-pyretic Drugs
 It has been suggested in South African Patent 83/5324 in the name of
 Sunshine, Laska and Siegel that caffeine may be used to hasten the onset
 and to enhance the analgesic response of the analgesic, anti-inflammatory
 and anti-pyretic agents referred to above.
 [c] Nitrous Oxide Gas
 Nitrous oxide [N.sub.2 O] is a natural gas which is also produced
 synthetically. It is also known by the trivial name "laughing gas". It has
 been in use for many years as an inhalation anaesthetic and analgesic,
 particularly in dentistry.
 Nitrous oxide has been reported to have a synergistic or potentiating
 effect on halothane and other gaseous anaesthetics [See Goodman & Gilman's
 The Pharmacological Basis of Therapeutics 8th Ed. 1990 pp. 298-300].
 Since such known synergism or potentiation is based on the use of nitrous
 oxide administered by inhalation, and since the use of nitrous oxide on
 its own as an anaesthetic and analgesic has likewise been in the form of
 an inhalation agent, the use of nitrous oxide for all these purposes have
 been confined to hospitalised patients or, at best, to treatments carried
 out by medical practitioners in their consulting rooms, or treatments
 carried out by or under supervision of a nurse in charge of a home-care
 patient.
 [d] Nitrous Oxide in Solution
 Nitrous oxide is known to be soluble in water and it has been reported that
 at 20.degree. C. and 2 atm pressure one litre of the gas dissolves in 1,5
 litres of water, see The Merck Index 10th Ed. p. 6499.
 In the applicant's PCT patent application PCT/EP93/01405 published under
 number WO 93/25213 and co-pending patent applications derived therefrom
 and its South African counterpart Patent 94/3895 it disclosed
 dermatological compositions comprising nitrous oxide as an active
 ingredient in compositions which also include one or more essential fatty
 acids or lower alkyl esters thereof, and, optionally, one or more
 supplementary active ingredients selected from the group consisting of
 coal tar solution, collagen, lanolin, nicotinamide, nicotinic acid,
 lanolin, vitamin E, methyl salicylate, arnica and an H-antagonist
 antihistamine such as diphenylhydramine hydrochloride. In those
 compositions nitrous oxide is dissolved in water.
 Nitrous oxide is also known for its use as a propellant gas, mainly as a
 substitute for propellant gases such as chlorofluorocarbons, and more
 particularly to produce a food product mousse such as whipped cream or
 chocolate mousse or quick-breaking foams for hair treatment preparations.
 See in this regard U.K. Patent 1033299, U.K. Patent 1105919 and European
 Patent Application EPA-0123827. None of these prior publications suggest
 that the nitrous oxide gas, plays any other role than a physical one, i.e.
 to expand on being depressurised and thereby to create a mousse or a foam.
 In fact it is typically regarded as an inert in these applications and
 useful due to the fact that it is colourless, odourless and tasteless but
 soluble in water and oils.
 There appears to be no suggestion in the literature that aqueous solutions
 of nitrous oxide might have any analgesic or anaesthetic effect on man or
 animals. As far as the present inventors know it has also never been
 suggested that nitrous oxide may be used in conjunction with analgesic,
 anti-inflammatory or anti-pyretic substances to contribute to, or to
 hasten or to enhance their pharmacological action.
 SUMMARY OF THE INVENTION
 It has now unexpectedly been found that there is a surprisingly simple
 manner for utilising nitrous oxide to enhance the efficacy of analgesic,
 anti-inflammatory and/or anti-pyretic substances.
 According to the present invention there is provided an administration
 medium for use in conjunction with a medicament selected from the group
 consisting of the analgesic, anti-inflammatory and anti-pyretic substances
 to enhance the pharmacological action of such substances, the medium
 comprising a solution of nitrous oxide in a pharmaceutically acceptable
 carrier solvent.
 The carrier solvent may be water or any of the pharmaceutically acceptable
 alcohols, ethers or oils. The oil may be an organic or mineral oil. The
 organic oil may be an essential oil based on long chain fatty acids having
 between 14 and 20 carbon atoms in the fatty acid. The oil may also be of
 either natural or synthetic origin and, if of natural origin, it may be
 either a plant oil or an animal oil. As plant oils those rich in gamma
 linolenic acid [GLA] are preferred and as animal oil dairy cream may be
 used.
 In the preferred form of the invention the administration medium comprises
 water which is saturated with nitrous oxide.
 When used in conjunction with a medicament which is to be administered to a
 patient in a solid oral dosage form such as powders, tablets or capsules,
 the potentiating or synergistic administration medium may simply comprise
 a quantity of water charged with nitrous oxide gas used to swallow the
 medicament. In this form the water may, of course, include dissolved salts
 of the type conventionally found in potable water. Preferably, however,
 the water is deionised water.
 When the medicament to be potentiated or synergised by means of the nitrous
 oxide is in a liquid formulation, such formulation may incorporate water
 or acceptable other liquid solvent into which the nitrous oxide had been
 dissolved. Likewise, where the medicament is to be administered to the
 patient by being applied as a topical, buccal or vaginal cream or ointment
 or as an intravenous, intramuscular or subcutaneous injection or as a
 suppository the formulation used in making up such cream, ointment,
 injectable formulation or suppository may incorporate water containing,
 and preferably saturated with, nitrous oxide and such additional
 excipients and carriers as are conventionally used in the pharmaceutical
 trade in making up such dosage forms. Alternatively in this form of
 medicament the nitrous oxide may be dissolved in an oil forming part of
 the formulation. The oil may in this form be either liquid or semi-solid.
 Thus, the oil may be one which has a creamy or butter-like consistency at
 room temperature.
 In accordance with a further feature of the present invention the
 administration medium is preferably nitrous oxide saturated water which
 further includes at least one essential fatty acid or ester thereof
 selected from the group consisting of oleic acid, linoleic acid,
 alpha-linolenic acid, gamma-linolenic acid, arachidonic acid and any of
 the C.sub.1 to C.sub.6 alkyl esters thereof. The administration medium may
 further include eicosapentanoic acid [C20:5.omega.3] and/or
 decosahexaenoic acid [C22:5.omega.3] as additional long chain fatty acids.
 Surprisingly, the present inventors now find that both narcotic analgesics
 and non-narcotic analgesics, also known as non-steroidal anti-inflammatory
 drugs can advantageously be formulated into novel pharmaceutical
 compositions with nitrous oxide in solution and administered to mammals,
 especially humans, or used concomitantly therewith, not only to elicit a
 more potent analgesic, anti-inflammatory or anti-pyretic response, each
 according to its own inherent properties, but also to evoke such response
 more rapidly than possible by administration of the agent alone.
 In a further aspect, the present invention provides a novel pharmaceutical
 composition of matter for use in eliciting an analgesic or
 anti-inflammatory or anti-pyretic response, said composition comprising an
 effective analgesic, anti-inflammatory or anti-pyretic amount of a
 non-narcotic analgesic/non-steroidal anti-inflammatory or anti-pyretic
 drug or of a narcotic analgesic and an amount of nitrous oxide in solution
 sufficient to hasten the onset of the analgesic, anti-inflammatory and/or
 anti-pyretic response or to enhance the analgesic, anti-inflammatory
 and/or anti-pyretic response.
 In yet another aspect, the present invention provides a novel composition
 of matter for use in eliciting an analgesic response, said composition
 comprising an effective analgesic amount of an orally analgesically active
 narcotic agonist or agonist-antagonist and an amount of nitrous oxide in
 aqueous solution sufficient to hasten the onset of the analgesic response
 or to enhance the analgesic response.
 In another aspect, the present invention provides a novel pharmaceutical
 composition of matter for use in eliciting an analgesic response, said
 composition comprising an effective analgesic amount of an orally
 analgesically active narcotic agonist or agonist-antagonist, an amount of
 a selected non-narcotic analgesic as defined hereinafter sufficient to
 enhance analgesia, and an amount of nitrous oxide in aqueous solution
 sufficient to further enhance analgesia or to hasten its onset.
 In all the above aspects the provision of essential fatty acids or esters
 thereof as set out above as part of such formulations provide yet further
 aspects of the invention.
 Typically, the active ingredients of the compositions of the invention are
 further associated with a non-toxic pharmaceutically acceptable inert
 carrier therefor.
 In other aspects, the invention provides methods of hastening the onset of
 an analgesic or anti-inflammatory response and methods of eliciting an
 enhanced analgesic, anti-inflammatory or anti-pyretic response in a
 mammal.
 DETAILED DESCRIPTION OF THE INVENTION
 The non-narcotic analgesics or non-steroidal anti-inflammatory drugs for
 use in the compositions and methods of the present invention can be
 selected from the following categories:
 [1] the propionic acid derivatives;
 [2] the acetic acid derivatives;
 [3] the fenamic acid derivatives;
 [4] the oxicams;
 [5] the salicylic acid derivatives; and
 [6] the pyrazolones
 which has analgesic, anti-inflammatory or anti-pyretic activity.
 While some of these compounds are primarily used at the present time as
 anti-inflammatory agents and others are primarily used as analgesics, it
 has been suggested that in fact most of the contemplated compounds have
 both analgesic and anti-inflammatory activity and that many of them also
 have anti-pyretic activity and can be used at appropriate dosage levels
 for any one or all of these purposes in the compositions and methods of
 the present invention. The compounds in groups [1] through [4] above
 typically contain a carboxylic acid function; however, those acids are
 sometimes administered in the form of their pharmaceutically acceptable
 salts, e.g. sodium salts.
 Irrespective of the chemical structural nature of the analgesic,
 anti-inflammatory or anti-pyretic drug it is preferred to utilise
 anti-inflammatory drugs having a high selectivity for inhibiting COX-2,
 that is, having a COX-2:COX-1 inhibition activity as close as possible to,
 or preferably below 1. See in this regard the article by John Vane
 entitled "Towards a better aspirin", Nature Volume 367, Jan. 20, 1994,
 pages 215 to 216 in which he reports that there is support for the
 hypothesis that the unwanted side effects such as irritation of the
 stomach lining and toxic effects on the kidneys of NSAIDs are due to their
 ability to inhibit COX-1 whereas their anti-inflammatory [therapeutic]
 effects are due to inhibition of COX-2. Diclofenac, which is reported to
 have a COX-2:COX-1 activity ratio of 2.2 and meloxicam with a ratio of
 0.33 are thus clearly the products of choice for this invention.
 The propionic acid derivatives for use herein include, but are not limited
 to, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen
 [sometimes regarded as a butyric acid derivative], ketoprofen, indoprofen,
 pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen,
 tiaprofenic acid and bucloxic acid. Structurally related propionic acid
 derivatives having similar analgesic and anti-inflammatory properties are
 also intended to be encompassed by this group. Presently preferred members
 of the propionic acid group include ibuprofen, naproxen, flurbiprofen,
 fenoprofen, ketoprofen and fenbufen.
 Thus, "propionic acid derivatives" as defined herein are non-narcotic
 analgesics/non-steroidal anti-inflammatory drugs having a free
 --CH(CH.sub.3)COOH or --CH.sub.2 CH.sub.2 COOH group [which optionally can
 be in the form of a pharmaceutically acceptable salt group, e.g.
 --CH(CH.sub.3)COO.sup.- Na.sup.+ or --CH.sub.2 CH.sub.2 COO.sup.-
 Na.sup.+), typically attached directly or via a carbonyl function to a
 ring system, preferably to an aromatic ring system.
 The acetic acid derivatives for use herein include, but are not limited to,
 indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac,
 ibufenac, isoxepac, acemetacin, fentiazac and clidanac. Structurally
 related acetic acid derivatives having similar analgesic and
 anti-inflammatory properties are also intended to be encompassed by this
 group. Presently preferred members of the acetic acid group include
 tolmetin sodium, zomepirac sodium, sulindac, indomethacin and, in
 particular, diclofenac sodium.
 Thus, "acetic acid derivatives" as defined herein are non-narcotic
 analgesics/non-steroidal anti-inflammatory drugs having a free --CH.sub.2
 COOH group [which optionally can be in the form of a pharmaceutically
 acceptable salt group, e.g. --CH.sub.2 COO.sup.- Na.sup.+ ], typically
 attached directly to a ring system, preferably to an aromatic or
 heteroaromatic ring system.
 The fenamic acid derivatives for use herein include, but are not limited
 to, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and
 tolfenamic acid. Structurally related fenamic acid derivatives having
 similar analgesic and anti-inflammatory properties are also intended to be
 encompassed by this group. Presently preferred members of the fenamic acid
 group include mefenamic acid and meclofenamate sodium, in particular
 meclofenamic acid, sodium salt.
 Thus, "fenamic acid derivatives" as defined herein are non-narcotic
 analgesics/non-steroidal anti-inflammatory drugs which contain the basic
 structure
 ##STR1##
 which can bear a variety of substituents and in which the free --COOH group
 can be in the form of a pharmaceutically acceptable salt group, e.g.
 --COO.sup.- NA.sup.+.
 The oxicams for use herein include, but are not limited to, meloxicam,
 piroxicam and isoxicam. Structurally related oxicams having similar
 analgesic and anti-inflammatory properties are also intended to be
 encompassed by this group. A preferred member of this group is piroxicam.
 Thus, "oxicams" as defined herein are non-narcotic analgesics/non-steroidal
 anti-inflammatory drugs which have the general formula
 ##STR2##
 wherein R is an aryl or heteroaryl ring system.
 The salicylic acid derivatives for use herein include, but are not limited
 to, aspirin, diflusinal, salacetamide, salicylamide.
 The pyrazolones for use herein include but are not limited to
 phenylbutazone.
 Also according to the present invention there are provided pharmaceutical
 compositions of matter adapted to elicit an onset hastened and enhanced
 analgesic and anti-inflammatory response in a mammalian organism in need
 of such treatment, said composition comprising a unit dosage analgesically
 and anti-inflammatorily effective amount of an active drug component and
 an active drug potentiating adjuvant thereof, said active drug comprising
 a narcotic analgesic or an NSAID selected from the group consisting of the
 propionic, acetic, fenamic, and salicylic acid derivatives, the oxicams,
 the pyrazolones and pharmaceutically acceptable salts thereof, and said
 adjuvant consisting essentially of an active drug analgesic and
 anti-inflammatory onset hastening and enhancing amount of nitrous oxide in
 solution in a pharmaceutically acceptable liquid or solid or semi-solid
 solvent.
 Also provided consistent herewith is an advantageous method of eliciting an
 onset hastened and enhanced analgesic and anti-inflammatory response in a
 mammalian organism in need of such treatment, comprising administering to
 such organism a unit dosage analgesically and anti-inflammatorily
 effective amount of a pharmaceutical composition of matter comprising an
 active drug component and an active potentiating adjuvant therefor, said
 active drug comprising a narcotic analgesic or an NSAID selected from the
 group consisting of the propionic, acetic, fenamic and salicylic acid
 derivatives, the oxicams, the pyrazolones and pharmaceutically acceptable
 salts thereof, said adjuvant consisting essentially of an active drug
 analgesic and anti-inflammatory onset hastening and enhancing amount of
 nitrous oxide in solution in a pharmaceutically acceptable liquid or solid
 or semi-solid solvent.
 The anti-inflammatory agent may also comprise a glucocorticoid, for
 example, prednisole.
 The narcotic analgesics for use in the present invention are orally active
 narcotic agonists and narcotic agonist-antagonists [i.e. antagonists with
 analgesic properties]. Suitable narcotic agonists for use herein include
 orally analgesically active members of the morphine group, the meperidine
 group and the methadone group, notably codeine, oxycodone,
 hydromorphone,levorphanol, meperidine,propoxyphene andmethadone. Suitable
 agonist-antagonists for use herein include orally analgesically active
 antagonists of the morphine type, notably propiram and buprenorphine; and
 orally analgesically active antagonists of the nalorphine type, notably
 pentazocine, nalbuphine and butorphanol. Another suitable
 agonist-antagonist is meptazinol. In many instances, the narcotic
 analgesics for use herein are administered in the form of their
 pharmaceutically acceptable acid addition salts, e.g. codeine sulfate,
 codeine phosphate, oxycodone hydrochloride, oxycodone terephthalate,
 hydromorphone hydrochloride, levorphanol tartrate, meperidine
 hydrochloride, propoxyphene napsylate, methadone hydrochloride, propiram
 fumarate, buprenorphine hydrochloride, nalbuphine hydrochloride and
 meptazinol hydrochloride. Further narcotic analgesics which may be used
 according to this invention include dipipanone, fentanyl, hydrocodone,
 papaveretum and tilidine.
 Further non-narcotic analgesics, not mentioned as anti-inflammatory agents
 above, which may be used in accordance with the present invention comprise
 acetaminophen [also known as paracetamol], bufexamac, phenacetin.
 Some of the products mentioned above are also anti-pyretics, such as
 acetaminophen and indomethacin and may be used for that purpose according
 to the invention as may other anti-pyretics such as phenacetin.
 The term "selected NSAID" as used herein is intended to mean any
 non-narcotic analgesic/non-steroidal anti-inflammatory compound falling
 within one of the six structural categories indicated hereinabove.
 Similarly, the term "selected narcotic analgesic" as used herein is
 intended to mean any orally analgesically active narcotic agonist or a
 narcotic antagonist having oral analgesic activity. The terms "selected
 NSAID" and "selected narcotic analgesic" are used for the sake of
 simplicity in the discussion which follows.
 When a selected NSAID [or selected narcotic or non-narcotic analgesic or
 anti-pyretic] is combined with nitrous oxide in accordance with the
 present invention, the following unexpected results are produced:
 [1] the analgesic or anti-inflammatory effect of the selected NSAID [or
 selected narcotic or non-narcotic analgesic or anti-pyretic] on the mammal
 is brought on more quickly;
 [2] lower amounts of the selected NSAID [or selected narcotic or
 non-narcotic analgesic or anti-pyretic] are required for the same
 analgesic or anti-pyretic anti-inflammatory effect; and
 [3] across all doses, a greater analgesic, anti-inflammatory or
 anti-pyretic response is achieved.
 For patients suffering pain, the time from administration of medication to
 the onset of effective relief is clearly of paramount importance. The
 present inventors' discovery that nitrous oxide in solution substantially
 shortens the onset time [i.e. substantially hastens the onset] of
 analgesia is therefore very significant; moreover, it is completely
 unexpected. Likewise, in patients suffering inflammation, e.g. from
 rheumatoid arthritis or osteoarthritis, the substantial shortening of
 onset time provided by this invention is extremely important, not only
 because it provides faster relief from pain but also because it provides
 more rapid relief from other aspects of the inflammatory disease, e.g.
 morning stiffness.
 Further, the ability of nitrous oxide to enhance analgesia or to enhance
 the anti-inflammnatory response, i.e. to substantially reduce the amount
 of the selected NSAID [or selected narcotic or non-narcotic analgesic or
 anti-pyretic] which is required to elicit a given analgesic,
 anti-inflammatory or anti-pyretic response, is also an unexpected and very
 important aspect of this invention. This unexpected and important finding
 permits the use of the selected NSAID [or selected narcotic or
 non-narcotic analgesic or anti-pyretic] in quantities substantially less
 than the dosages presently suggested as an analgesic, anti-inflammatory or
 anti-pyretic agent in humans. Use of lower doses should in turn lower the
 incidence and/or severity of undesirable side effects. Moreover, at a
 given dosage level, greater analgesic, anti-inflammatory or anti-pyretic
 response can be achieved.
 While the compositions of the invention are preferably for oral use, they
 may also be formulated for and administered by other methods which are
 known for administering analgesics, e.g. as suppositories, creams,
 ointments, transdermal pads, buccal pads, or nasally.
 The compositions of the present invention are very conveniently
 administered to mammals by any route of administration suitable for the
 selected NSAID and/or selected narcotic analgesic component, e.g. oral,
 rectal or transdermal. Preferably, the combination is formulated with any
 suitable non-toxic pharmaceutically acceptable inert carrier material.
 Such carrier materials are well known to those skilled in the art of
 pharmaceutical formulations. For those not skilled in the art, reference
 is made to the test entitled "REMINGTON'S PHARMACEUTICAL SCIENCES"
 [Fourteenth Edition], 1970. In a typical preparation for oral
 administration, e.g. tablet or capsule, the selected NSAID in an effective
 analgesic or anti-inflammatory amount and nitrous oxide in an amount
 sufficient to enhance the analgesic or anti-inflammatory response or to
 hasten its onset, or the selected narcotic or non-narcotic analgesic in an
 effective analgesic amount and nitrous oxide in an amount sufficient to
 enhance the analgesic response or to hasten its onset, or the selected
 narcotic analgesic in an effective analgesic amount together with a
 selected NSAID in an amount sufficient to enhance the analgesic response
 and nitrous oxide in an amount sufficient to further enhance the analgesic
 response or to hasten its onset, are combined with any oral non-toxic
 pharmaceutically acceptable inert carrier such as lactose, starch
 [pharmaceutical grade], dicalcium phosphate, calcium sulfate, kaolin,
 mannitol and powdered sugar. Additionally, when required, suitable
 binders, lubricants, disintegrating agents and colouring, flavouring and
 fragrance agents can also be included. Typical binders include starch,
 gelatin, sugars such as sucrose, molasses and lactose, natural and
 synthetic gums such as acacia, sodium alginate, extract of Irish moss,
 carboxymethyl-cellulose, methylcellulose, polyvinylpyrrolidone,
 polyethylene glycol, ethylcellulose and waxes. Typical lubricants for use
 in these dosage forms can include, without limitation, boric acid, sodium
 benzoate, sodium acetate, sodium chloride, leucine and polyethylene
 glycol. Suitable disintegrators can include, without limitation, starch,
 methylcellulose, agar, bentonite, cellulose, wood products, alginic acid,
 guar gum, citrus pulp, carboxymethylcellulose and sodium lauryl sulfate.
 If desired, a conventional pharmaceutically acceptable dye can be
 incorporated into the dosage unit form, i.e. any of the standard FD&C
 dyes. Sweetening and flavouring agents and preservatives can also be
 included, particularly when a liquid dosage form is formulated, e.g. an
 elixir, suspension or syrup. Also, when the dosage form is a capsule, it
 may contain, in addition to materials of the above type, a liquid carrier
 such as a fatty oil. Various other materials may be present as coatings or
 to otherwise modify the physical form of the dosage unit. For instance,
 tablets, pills or capsules may be coated with shellac, sugar or both. Such
 active components; generally, the active ingredients will be between about
 2% to about 60% of the weight of the unit.
 According to the present invention there is particularly provided a topical
 application formulation comprising a mixture of at least one non-steroidal
 anti-inflammatory agent, at least one essential fatty acid or ester
 thereof consisting of oleic acid, linoleic acid, alpha-linolenic acid,
 gamma-linolenic acid, arachidonic acid and the lower alkyl esters thereof,
 and nitrous oxide dissolved in a dermatologically acceptable carrier.
 In this regard it has surprisingly been found that the compound diclofenac
 sodium, which is known to be relatively inactive in a topical application
 form, can be used in this formulation to bring rapid and long-lasting
 relief to a large variety of painful conditions by the application of a
 relatively low dosage of the active ingredient.
 The term lower alkyl esters as used herein is intended to denote esters in
 which the alcohol moiety has up to six carbon atoms.
 In the preferred form of the invention the composition is saturated with
 nitrous oxide.
 Also, in the preferred form of the invention the essential fatty acid
 component of the composition comprises a mixture of esters of the fatty
 acids listed above. Thus, in the most preferred form of the invention the
 fatty acid component of the composition is constituted by the complex
 known as Vitamin F and in this regard it is preferred to make use of the
 ester form of Vitamin F known as Vitamin F Ethyl Ester. This product is
 commercially available under the trade description of Vitamin F Ethyl
 Ester CLR 110 000 Sh.L. U./g from CLR Chemicals Laboratorium Dr. Kurt
 Richter GmbH of Berlin, Germany. The typical fatty acid distribution of
 this product is as follows:

&lt;C.sub.16 : 0%
 C.sub.16-0 : 8,3%
 C.sub.18-0 : 3,5%
 C.sub.18-1 : 21,7%
 C.sub.18-2 : 34,8%
 C.sub.18-3 : 28,0%
 &gt;C.sub.18 : 1,6%
 unknown : 2,1%
 It is further preferred to add to the formulation the long chain fatty
 acids known as eicosapentanoic acid [C20:5.omega.3] and decosahexaenoic
 acid [C22:5.omega.3]. Such a product combination is available from Roche
 Lipid Technology under the trade name "Ropzifa `30` n-3 oil".

EXAMPLES OF THE INVENTION
 Without thereby limiting the scope of the invention some examples will now
 be described to illustrate the invention.
 Example 1
 Preparing a Nitrous Oxide Solution
 A pressure vessel is charged to its operating volume with water at
 20.degree. C. [ambient temperature]. The vessel is connected to a supply
 of nitrous oxide via a flow control valve and pressure regulator. The
 closed vessel is supplied with nitrous oxide at a pressure of 2 bar for a
 period of 48 hours, it having been determined that at the aforementioned
 temperature the water is saturated with nitrous oxide over such period of
 time under the above-mentioned pressure.
 A resultant solution is bottled as stock solution for use in the
 formulations and applications set out below.
 Example 2
 Preparation of Nitrous Oxide/Vitamin F Emulsion
 30 g Vitamin F ethyl ester as described above was mixed with 10 g
 chremaphor, 2,2 g methyl paraben, 0,08 g butyl hydroxyanisole, 0,23 g
 butyl hydroxytoluene with stirring at 80.degree. C.
 Into 942,5 g of the stock nitrous oxide solution was dissolved 2,5 g sodium
 propyl paraben and 2,5 g Gennall 115 [Imidurea] with stirring at room
 temperature.
 The oily composition first described was emulsified into the aqueous
 solution with stirring to constitute a stock nitrous oxide/Vitamin F
 emulsion.
 Example 3
 Preparation of an Indomethacin-containing Topical Lotion
 One gram indomethacin was included in the stock nitrous oxide/Vitamin F
 emulsion as described in Example 2 above by the addition thereof to the
 oily composition before the latter was emulsified into the aqueous
 solution. Keltrol [about 9 g] was added to the final composition as a
 thixotropic agent to obtain the desired thickness of the emulsion.
 The amounts of the other ingredients were recalculated for a final
 formulation having a concentration of 0,1% indomethacin, that is 1 mg/g.
 Example 4
 Preparation of an Ibuprofen-containing Formulation
 An ibuprofen-containing formulation was prepared in the same manner as
 described in Example 3 by introducing 8 g of ibuprofen instead of 1 g
 indomethacin and using 935,5 g of stock nitrous oxide solution.
 This resulted in a formulation containing 8 mg/g ibuprofen.
 Example 5
 Preparation of a Diclophenac Sodium Formulation
 A diclophenac preparation was prepared in the same manner as described in
 Example 3, save that 10.8 g diclophenac sodium was added to the aqueous
 nitrous oxide solution rather than indomethacin to the oil. Quantities of
 other ingredients were again adjusted to yield a resultant preparation
 containing 10.8 mg/g diclophenac sodium, that is 1 g/100 g diclofenac
 expressed as base.
 Example 6
 Preparation of a Dental Pad
 The indomethacin-containing emulsion as prepared according to Example 3 but
 without any Keltrol was impregnated onto strips cut from a woven cotton
 pad of the type used as a cosmetic cleansing pad. Each strip was 50 mm
 long and 10 mm high and was impregnated with 0,5 ml of the emulsion of
 Example 3 sans Keltrol. The strips thus each contained 0,5 mg of
 indomethacin. The impregnated pad was packaged in a sealed PVC sachet.
 CLINICAL EVALUATIONS
 CASE 1
 NITROUS OXIDE WITH ASPIRIN AND CODEINE PHOSPHATE IN THE TREATMENT OF
 MIGRAINE
 A Caucasian woman, aged 25, presenting with recurrent migraine attacks was
 given two commercially available aspirin tablets [i.e. 1000 mg aspirin+16
 mg codeine phosphate] which were crushed and suspended in a glass of stock
 nitrous oxide solution [as described in Example 1] at the onset of what
 was expected to be a migraine attack as experienced by dots before the
 eyes and a mild headache. The headache abated within 10 minutes and no
 migraine ensued.
 Previous attempts to prevent migraine attacks by taking the same aspirin
 tablets alone in plain water at the same stage of onset proved fruitless
 for this patient. Likewise, the administration of a nitrous oxide solution
 alone previously did not prevent an attack.
 CASE 2
 NITROUS OXIDE, VITAMIN F AND INDOMETHACIN IN A TOPICAL APPLICATION FOR THE
 TREATMENT OF PSORIATIC ARTHRITIS
 A 50 year old Caucasian female patient suffering from psoriatic arthritis
 had previously been treated with gold injections, diclophenac sodium
 injections, cortisone injection, and hospitalisation. She had very little
 relief from these treatments and had great difficulty in walking.
 The formulation of Example 3 above was applied 4 hourly to the affected
 joints and after two days of such treatment there was a visible reduction
 of the swelling of the joints and she managed to undertake walks in excess
 of 1 kilometre with a natural gait.
 The relief was transient and treatment had to continue to maintain her
 improved condition. She reported that the formulation was clearly much
 more efficient than commercially available ointments containing
 indomethacin in a quantity of 10 mg/g, i.e. 10 times that of the
 preparation of the invention.
 CASE 3
 NITROUS OXIDE, VITAMIN F AND IBUPROFEN IN A TOPICAL APPLICATION FOR THE
 TREATMENT OF ARTHITIS AND BACKACHE
 A Caucasian male in his late 40's who had undergone four knee operations as
 a result of being afflicted with arthritis was also suffering from such
 severe backache that he seldom enjoyed more than 1 to 2 hours sleep at
 night.
 The formulation of Example 4 above was applied to his back as a lotion once
 every four hours and he reported a measure of relief within a day. He
 managed to go for a week without the need of further treatment after
 treatment on the first day.
 He had previously not experienced the same or even a comparable measure of
 relief when using commercially available diclophenac formulation of much
 higher [typically 116 mg/g] concentration of diclophenac, i.e. more than
 10 times the concentration found in the preparation of the invention.
 CASE 4
 NITROUS OXIDE, VITAMIN F AND IBUPROFEN IN BUCCAL APPLICATION FOR TREATMENT
 OF PERIODONTAL PAIN
 A male Caucasian in his early 40's suffered severe pain following
 periodontal surgery. The pad of the type described in Example 6 but
 containing 8 mg ibuprofen rather than 0,5 mg indomethacin was applied to
 the gums at the affected area and the pain subsided within minutes.
 This result is particularly remarkable in view of the fact that the patient
 had 4 hours before this treatment taken 2 tablets of a commercially
 available oral preparation each containing ibuprofen 200 mg, paracetamol
 250 mg and codeine phosphate 10 mg and had not experienced significant
 pain reduction.
 CASE 5
 NITROUS OXIDE, VITAMIN F AND INDOMETHACIN IN BUCCAL APPLICATION FOR
 TREATMENT OF INFLAMMATION OF GUMS
 A random sample of 10 volunteers experiencing simple inflammation of the
 gums post dental treatment were selected. Each patient was handed six [6]
 impregnated strips as described in Example 6 above with the following
 instructions:
 [1] Place strip against inflamed area and retain until pain subsides.
 [2] Measure and record the exact time taken to experience complete pain
 relief.
 [3] Measure and record the duration of analgesic effect after each single
 application.
 [4] Record any untoward effects.
 [5] Record any effects other than reduction of pain.
 [6] Assess and record effect on swelling.
 [7] Repeat if pain recurs.
 Findings
 The result of the trial are recorded in Tables 1 and 2.
 From Table 1 below the following are apparent:
 [1] The average time required for full analgesia was 53 seconds.
 [2] The effective time of full analgesia reduced progressively with
 succeeding applications.
 [3] Only three patients required a sixth application.
 [4] The average total drug delivery was 2,5 mg per patient.
 TABLE 1
 Patient Time Required for Analgesic Effect (Seconds)
 Number 1st 2nd 3rd 4th 5th 6th
 1 45 50 45
 2 55 45 65 55 40
 3 65 60 65 55 45 45
 4 35 40 35 45
 5 95 80 85 90 75
 6 50 45 40 40 35
 7 45 50 45 45 40 40
 8 70 70 65 70 60 65
 9 45 50 45 40 35
 10 50 60 75 50 45
 Average 55.5 55 56.5 54.44 46.88 50
 From table 2 below the following are apparent:
 [1] The average period of duration of analgesia was 7.2 hours per
 application.
 [2] The average period of duration of analgesic effect increased by 41%
 from 5.78 hours at first application to 8.17 hours for the last
 application.
 [3] On average, the total period of treatment required was 36.6 hours which
 translates into 1.5 days in treatment.
 [4] The total daily requirement of indomethacin per patient was therefore
 1,67 mg.
 TABLE 2
 Patient Duration of Analgesic Effect (Hours)
 Number 1st 2nd 3rd 4th 5th 6th
 1 5.5 7 10
 2 4 5 5.5 6.75 7.25
 3 6.5 5 7.5 7.25 8 9.5
 4 6 6.5 7.5 10.5
 5 4 4 5.5 7 9.5
 6 6.75 7.25 7.25 8.5 8.75
 7 6.5 6 7 7.25 6.5 7.5
 8 4.5 6 5.5 7 7.25 7.5
 9 6.5 5 7 7.5 7.75
 10 7.5 8.5 8 9.5 10
 Average 5.78 6.03 7.08 7.92 8.13 8.17
 In general, the following patient observations have been made:
 [1] No side-effects have been experienced.
 [2] A slight numbness was experienced by 7 of the patients. The duration
 thereof was limited to a few minutes. This was, however, considered to be
 an acceptable side-effect as it contributed to the feeling of comfort.
 [3] In all patients there was a considerable reduction of inflammation and
 only 2 patients required treatment in excess of the experimental six
 applications.
 Conclusions
 From the above the following are apparent:
 [1] There is every reason to believe that this modality of treatment
 provides an effective lower dose alternative to the oral administration of
 NSAID's in the treatment of inflammation of the buccal area.
 [2] Although no control group using conventional treatment has been used in
 this experiment, experience has led us to believe that the efficacy of
 this treatment is considerably superior to the conventional.
 CASE 6
 NITROUS OXIDE, VITAMIN F AND DICLOFENAC SODIUM IN TOPICAL APPLICATION FOR
 THE TREATMENT OF MIGRAINE
 A 48 year old female Caucasian who had a long history of migraine attacks
 which had been quite severe and quite often associated with visual
 disturbances as well as photo- and phonophobia was seen by a specialist
 neurologist when she had an attack of migraine and was in considerable
 distress. The attack was associated with her period and some
 dysmenorrhoea. She was given the diclofenac sodium formulation of Example
 5 from which she applied about 5 cc over the temples, over the frontal
 areas and over the upper nuchal and occipital areas. The formulation was
 re-applied over the same areas ten minutes later and within fifteen
 minutes thereafter and with some surprise, she indicated that the pain had
 completely disappeared.
 On previous occasions she had taken 2 Disprins.RTM. [each containing 300 mg
 aspirin] at the onset of migraine symptoms and mostly this would result in
 relief after about thirty minutes. This treatment had not always been
 successful.
 CASE 7
 NITROUS OXIDE, VITAMIN F AND DICLOFENAC SODIUM IN TOPICAL APPLICATION FOR
 THE TREAT OF MIGRAINE
 Another female Caucasian patient aged 53 of the same specialist neurologist
 referred to in case 6 above has suffered from typical migraine headaches
 since her early 20's and over the past 2 to 3 years these had occurred at
 irregular intervals, from about 3 or 4 to 1 per month. There were no
 obvious precipitating factors and at the onset she would have nausea and
 mild visual disturbances with photophobia.
 During a typical migraine attack with the pain mainly over the R-nuchal and
 occipital region, but also the R-temple and frontal areas, and after these
 had already been present for about 20 minutes, she applied the diclofenac
 formulation of Example 5 to these areas and within twenty minutes her pain
 had completely subsided.
 Previously she had found that Migril.RTM. with Voltaren.RTM. suppository
 provided her with the best relief and on average it took about half an
 hour for the pain to subside. On this occasion such medication was not
 required.
 CASE 8
 NITROUS OXIDE, VITAMIN F AND DICLOFENAC SODIUM IN TOPICAL ADMINISTRATION
 FOR TREADED OF POLYMORPHIC RASH AND INAON FOLLOWING SUNBURN
 A 9 year old blond girl with a very pale skin started developing a rash
 over her chest and shoulders during the summer. This only occurred with
 sun exposure. The condition was diagnosed as a Polymorphic rash. The
 condition developed again on exposure, and the following day after she had
 again been in the sun for a short time this became much more inflamed,
 very itchy and painful. The diclofenac formulation of Example was applied
 over the affected areas and within five minutes the itchiness and pain had
 completely disappeared. By the following day the rash had completely
 disappeared.
 CASE 9
 NITROUS OXIDE, VITAMIN F AND DICLOFENAC IN THE TOPICAL TREATMENT OF PAIN
 RESULTING FROM KNEE SURGERY
 A gentleman in his seventies underwent a knee replacement operation and for
 five weeks thereafter he was still in pain and on crutches, but his main
 complaint was the discomfort experienced at night. During this period it
 was necessary to take pain relieving tablets on a regular basis. His
 sleeping pattern was severely affected resulting in the patient also
 having to resort to the taking of sleeping tablets. He reported that he
 experienced very little relief from the use of a commercially available
 gel formulation containing diclofenac diethylammonniumin a concentration
 of 1.16 g/100 g, i.e. about 1 g/100 g diclofenac expressed as base.
 Within minutes after a first application of the diclofenac sodium
 preparation of Example 5 he experienced substantial relief and that night,
 after further application he was able to sleep for periods of two to three
 hours which was for him a great improvement. This was obtained by merely
 rubbing a little of the lotion over the knee. After about 3 weeks it was
 possible to get much longer periods of relief at nights using just the
 formulation. Since using that formulation he has not had any need to
 resort to any other sort of medication.
 CASE 10
 PILOT STUDY ON NITROUS OXIDE, VITAMIN F AND DICLOFENAC SODIUM IN THE
 TREATMENT OF ARTHROPATHY
 A pilot, uncontrolled study on the effects of the diclofenac sodium
 formulation of Example 5 on patients suffering from arthropathy resulting
 from various causes was conducted by a rheumatologist of many years
 standing. The patients were selected from his extensive practice and most
 of these have over a period of years tried various preparations.
 The formulation of Example 5 was applied in 5 to 15 ml quantities 3 to 4
 times per day over the affected parts of the body.
 Measurement of effect was by simple patient and physician global assessment
 and hence had an element of subjectivity. However, the fact that 70% of
 the patients reported a positive result [33% being "much better" and 37%
 being "better"] attributed to the treatment is highly significant bearing
 in mind that most of these patients had the symptoms for many years. Some
 of the patients reported a dramatic improvement while only two patients
 reported being worse after the treatment.
 The investigating rheumatologist noted that side effects were minimal and
 remarked that a particular impression of the product was its apparent
 rapid onset of action--a particular advantage in the treatment of patients
 with the conditions in issue.
 These positive results had lead to the applicant's current planning a full
 scale properly controlled trial of the preparation on patients suffering
 from osteoarthritis and rheumatoid arthritis.
 CASE 11
 NITROUS OXIDE, VITAMIN F AND MEFENAMIC ACID IN ORAL FORMULATON FOR THE
 TEATMENT OF FEVER AND PAIN
 A suspension for oral administration comprising mefenamic acid in the stock
 nitrous oxide/Vitamin F emulsion of Example 2 was made up so that the
 concentration was just 15 mg/5 ml, i.e. substantially less than the 50
 mg/5 ml present in commercially available mefenamic acid preparations.
 The preparation was administered to three children aged from 9 to 12 years
 instead of the proprietary brand containing Mefenamic acid that they
 normally used. The conditions for which the medicine was given ranged from
 fever to pain and headache and the dose was given as if it were the higher
 concentration proprietary product.
 In all cases the onset of pain relief and reduction of fever was shorter
 than that experienced with the proprietary preparation.
 The duration of action was of the same order as the proprietary brand.
 In one case only the subject required more than two administrations during
 a 24 hour period, however the total drug delivery was still lower than
 that normally given with the proprietary brand.
 This provides a strong indication that the drug is more highly absorbed and
 therefore a lower dose can be given for the same or better effects.
 CASE 12
 NITROUS OXIDE, VITAMIN F AND NAPROXEN IN A TOPICAL APPLICATION FOR THE
 TREATMNT OF JOINT ACHES AND SPORT INJURIES
 A topical preparation containing 5% naproxen in the emulsion of Example 2
 was made up and used on 3 patients who suffered from rheumatic joint
 problems and also on two patients who had suffered low grade sport
 injuries, one to the knee and one to the shoulder. All of the patients
 with rheumatic joint problems reported an increase in mobility of the
 affected joints, reduction of pain and a marked reduction of swelling.
 One of the patients felt that this treatment gave better effects than that
 after intra-articular steroid injections. The other two patients felt that
 the effects were equal to their normally orally administered
 anti-inflammatories.
 Compliance was better with all these patients who normally received orally
 administered NSAID's as they did not experience the gastric side effects
 with the topical product.
 Both the patients with the sports injuries were able to resume their normal
 activities within two days from starting application of product. The
 relief of pain was achieved within the first 15 minutes and sustained for
 approximately six hours.
 The first patient, who had suffered a knee injury [from bicycling] was able
 to walk without a limp on the second day, but felt unready to resume
 bicycling at that time.
 The second patient, who suffered an exacerbation of a shoulder injury [from
 archery] was able to resume his sport within a week. He reported that
 previously in such a situation neither oral or topical NSAID's or other
 medications or procedures other than total inactivity would allow this
 resumption, and then only after some weeks.
 CASE 13
 NITROUS OXIDE, VITAMIN F AND SULINDAC IN A TOPICAL PREATION FOR THE
 TREATMENT OF PSORIATIC ARTHROPATHY
 A topical preparation containing 5% sulindac in the emulsion of Example 2
 was made up and used on patients that suffered from psoriatic arthropathy.
 These patients, having already had experience of topically applied NSAID's
 as well as orally administered NSAID's, felt that the effects of the above
 test material were similar to that of the orally administered products,
 better than that of the topically administered products and quicker in
 onset of action than any of the previously tried products.
 Duration of action was considerably longer than that of other topically
 applied NSAID's. Duration of action as compared to orally administered
 medications was difficult to ascertain as their normal oral medication
 included long acting once a day preparations. The total drug delivery of
 the test material per day on a comparative basis with the long acting oral
 preparations was much lower and the patients felt that this lower systemic
 dose would help them comply with treatment.
 CASE 14
 NITROUS OXIDE, VITAMIN F AND DIFLUSINAL IN A TOPICAL PREATION FOR USE IN
 THE TREATMENT OF PSORIATIC ARTHROPATHY, RHEUMATOID ARTHRITIS AND SUNBURN
 INFLAMMATION
 A topical preparation containing 3% diflusinal in the suspension of Example
 2 was made up and used on patients that suffered from psoriatic
 arthropathy, rheumatoid arthritis and inflammation due to sunburn.
 One patient with rheumatoid arthritis of both hands reported a lessening of
 pain and a visible increase in mobility of both wrist joints within two
 minutes of application. She was able to resume her job of collating
 paperwork at a printing firm without pain the same day. Previously she
 required intra-articular corticosteroid injections to her wrist joint and
 to the joint between the first and second fingers. The pain of these
 injections made her reluctant to continue therapy.
 Two patients with inflammation due to severe sunburn reported a total
 cession of pain with a single application of this composition. There was
 no need for re-application until awakening the next day, and then only as
 a measure "just in case", as the redness was not totally removed. None of
 the patients developed blisters.
 Patients with psoriatic arthropathy experienced similar effects to that
 experienced with the sulindac test material, with no discernible
 differences.
 CASE 15
 NITROUS OXIDE, VITAMIN F AND MELOXICAM IN ORAL ADMINISTRATION FOR THE
 TREATMENT OF ABDOMINAL PAIN
 A patient suffering abdominal pain resulting from post-operative abdominal
 adhesions regularly took two commercially available tablets containing
 meloxicam as active ingredient for pain relief. This patient experienced
 much more rapid onset of the pain relief when these tablets were crushed
 as swallowed down with 15 ml of the nitrous oxide/Vitamin F emulsion of
 Example 2, than when swallowed with ordinary water, even using crushed
 tablets. This was also his experience when swallowing the crushed
 meloxicam tablets with a saturated solution of nitrous oxide in water.
 EXPERIMENTAL
 In Vitro Release of Diclofenac Sodium from the Preparation of Example 5
 The in vitro release of diclofenac sodium from the lotion of the
 preparation made as described in Example 5 was measured with a set-up
 related to USP dissolution apparatus. The reservoir of the dissolution
 cell [enhancer cell] was filled according to the prescribed procedure with
 the lotion and the lotion was covered with the membrane [cellulose
 acetate; 0.4 .mu.m pore size], taking care to exclude air bubbles between
 the lotion and the membrane. The cell was capped and placed in the
 dissolution vessel containing the receptor medium [pH 6.8 phosphate
 buffer; 190 ml]. The paddle speed was 100 rpm. Samples of 250 .mu.l were
 withdrawn with a micropipette at 30, 60, 120, 240 and 360 minutes. The
 samples were analysed for diclofenac by means of HPLC.
 RESULTS
 The release experiment was done six fold and the average release was
 calculated for each analysis point.
 The release rate [or flux] of diclofenac sodium from the formulation was
 determined to be 122 .mu.g/cm.sup.2 /min.sup.0.5 which is considered to be
 very high since the release rate of active ingredients from most creams,
 irrespective of the active ingredient typically about 10 times lower, i.e.
 about 10 .mu.g/cm.sup.2 /min.sup.0.5. This high release rate may well
 contribute to the reported rapid onset of relief referred to above. The
 mechanism of absorption is however not yet understood but it is clear that
 the formulation of the invention allows rapid release of the active
 ingredient and hence rapid availability for absorption through the skin.