WO2006012700A1

WO2006012700A1 - Method of treatment

Info

Publication number: WO2006012700A1
Application number: PCT/AU2005/001169
Authority: WO
Inventors: Peter Glyn Lewis
Original assignee: TEAM HEALTH Pty Ltd
Current assignee: TEAM HEALTH Pty Ltd
Priority date: 2004-08-04
Filing date: 2005-08-04
Publication date: 2006-02-09
Anticipated expiration: 2007-02-04

Abstract

The invention relates to a method of reducing or preventing pain associated with injection of an irritating substance comprising administering by injection, a combination of an effective amount of a local anaesthetic and an effective amount of an irritating substance and compositions and kits containing a local anaesthetic and an irritating substance for use in the method.

Description

METHOD OF TREATMENT

Field of the Invention

The present invention relates to a method of reducing or preventing pain associated with injection of an irritating substance by administration of the irritating substance in combination with a local anaesthetic. The invention also relates to compositions and kits useful in the method of the invention.

Background of the Invention

Many medicines are administered by injection. Some of these medicines cause pain upon administration and some continue to cause pain after administration. A number of injectable medicines cause soreness and redness at the site of administration for some hours and possibly days after administration. This is particularly the case with vaccines which contain toxins for eliciting an immune response.

Children around the world receive vaccinations as part of the world health standard immunisation requirements. Periodic booster injections are also required by children and adults alike. Although it is possible to apply a topical local anaesthetic to the site of administration before injection, this reduces only the pain caused at administration and does not relieve pain caused by an irritating substance after administration. There is a need for methods and compositions that reduce or prevent the pain associated with the administration of an irritating substance.

Summary of the Invention ,

In an aspect of the invention there is provided a method of reducing or preventing pain associated with injection of an irritating substance comprising administering by injection a combination of an effective amount of a local anaesthetic and an effective amount of an irritating substance. In another aspect of the invention there is provided a pharmaceutical composition comprising an irritating substance and a local anaesthetic together with a pharmaceutically acceptable carrier, adjuvant or diluent, wherein the pharmaceutical composition is formulated for injection.

In another aspect of the invention there is provided a use of a local anaesthetic in the manufacture of a medicament for reducing or preventing pain associated with injection of an irritating substance, wherein the medicament is administered by injection in combination with an irritating substance.

In yet another aspect of the invention there is provided a use of an irritating substance in the manufacture of a medicament for reducing or preventing pain associated with injection of an irritating substance, wherein the medicament is administered by injection in combination with a local anaesthetic.

In a further aspect of the invention there is provided a use of a local anaesthetic and an irritating substance in the manufacture of a medicament for reducing or preventing pain associated with injection of an irritating substance, wherein the medicament is formulated for injection.

In yet a further aspect of the invention there is provided a kit comprising an effective amount of a local anaesthetic and an irritating substance, in a container designed to keep the local anaesthetic and the irritating substance in separate chambers and allow delivery of both the local anaesthetic and irritating substance in a single injection.

Brief Description of the Figures

Figure 1 schematically depicts a two chamber syringe capable of sequential delivery of a first component followed by a second component by virtue of a hollow conduit that pierces the moveable plug. Figure 2 schematically depicts a two chamber syringe capable of sequential delivery of a first component followed by a second component by virtue of a bypass groove in the syringe barrel.

Figure 3 schematically depicts a two chamber syringe which allows the mixing of two components directly before use.

Detailed Description of Preferred Embodiments

In one aspect of the invention there is provided a method of reducing or preventing pain ., associated with injection of an irritating substance comprising administering by injection a : combination of an effective amount of a local anaesthetic and an effective amount of an irritating substance.

Suitable local anaesthetics for use in the invention include those from the amino amide class of local anaesthetics and those from the amino ester class of local anaesthetics. Local ; anaesthetics suitable for use in the present invention include, but are not limited to, ropivacaine (2S)-N-(2,6-dimethylphenyl)-l -propyl-piperidinecarboxamide), bupivacaine ( 1 -butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide), levobupivacaine

((S)- 1 -butyl-N-(2,6)-dimethylphenyl)-2-piperidinecarboxamide), mepivacaine

(N-(2,6-dimethylphenyl)-l-methyl-2-piperidinecarboxamide), etidocaine

(N-(2,6-dimethylphenyl)-2-ethylpropylamino)butamide), lignocaine (lidocaine,

2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide), prilocaine (N-(2-methylphenyl)-2-(propylamino)propanamide), procaine (4-aminobenzoic acid 2-(diethylamino)ethyl ester), chloroprocaine (4-amino-2-chlorobenzoic acid 2-(diethylamino)ethyl ester) and articaine (3-(N-propyl-2-amino-propionylamino)- 2-carbomethoxy-4-methylthiophene) or pharmaceutically acceptable salts thereof. In a preferred embodiment, the local anaesthetic is a long acting local anaesthetic. Preferred local anaesthetics are from the amino amide class of local anaesthetics, especially ropivacaine, bupivacaine, levobupivacaine, mepivacaine and etidocaine or pharmaceutically acceptable salts thereof, especially ropivacaine and bupivacaine or pharmaceutically acceptable salts thereof.

As used herein, the term "irritating substance" refers to a substance which causes pain upon administration and which continues to cause pain after administration. The irritating substance may cause redness and/or soreness at the injection site, a swelling or lump around the injection site and/or a prolonged ache in the vicinity of the injection site. The duration of the pain after the administration of the irritating substance is in the order of hours to days. Often the pain after the injection of an irritating substance will last in the order of 1 hour to 48 hours. Although the effects of the anaesthetic may last 1 to 4 hours, the long term pain associated with the injection of the irritating substance lasting longer than the local anaesthetic may be reduced and in some cases, entirely prevented by the combination of local anaesthetic and irritating substance.

Irritating substances which are suitable for use in the invention include, but are not limited to, substances which intrinsically cause pain because of an interaction with the human . body, for example, with nerve cells. Examples of suitable substances are those which contain toxins, those which contain vitamins or other dietary supplements and those in which the injection volume is high, for example, greater than 2 mLs. In a preferred embodiment of the invention, the irritating substance is a vaccine, especially a vaccine containing a toxic substance intended to elicit an immune response. An especially preferred irritating substance is a tetanus vaccine comprising tetanus toxoid and optionally one or more other immunity stimulating substances. In another preferred embodiment, the irritating substance is a vitamin composition. Examples of vitamins that may be included in a vitamin composition include Vitamin A, B-group vitamins, Vitamin C, Vitamin D, Vitamin E or Vitamin K, or mixtures thereof. An irritating substance that is particularly suitable for use in accordance with the present invention is a composition comprising B- group vitamins and Vitamin C. In a further preferred embodiment, the irritating substance is a supplement containing iron. As used herein, the term "combination" refers to administration of the local anaesthetic and irritating substance as a single composition or as two separate compositions. The combination may be administered simultaneously, separately or sequentially. When the combination is administered sequentially, it is preferred that the local anaesthetic is administered first. Administration may occur simultaneously or with an interval of seconds or minutes. Preferably the local anaesthetic and irritating substance are administered, either as a single composition or as separate compositions in a single injection.

Each of the components of the composition should be administered in an effective amount to achieve the desired effect of the irritating substance and the desired level and length of pain relief. An effective amount of local anaesthetic is an amount which, when administered according to the desired dosage regimen, is sufficient to at least partially attain the desired pain relief, delay the onset of pain, or fully attain the desired pain relief for a desired period of time. For example, suitable amounts of local anaesthetic include 0.25 - 5 mL of a 0.5 - 2 % solution. Exact amounts will vary depending on the local anaesthetic used. An effective amount of the irritating substance is an amount to attain the desired effect. For example, suitable amounts of tetanus vaccines such as ADT and Tet- Tox™ are 0.5 mL of commercially available vaccine per injection. A person skilled in the art would be able to determine suitable dosages of both local anaesthetic and irritating substance to provide the desired effect. Suitable dosage amounts and dosage regimes can be determined by the attending physician and may depend on severity of condition being treated, the amount of immunity required, the extent of vitamin or iron deficiency, as well as the general age, health and weight of the subject.

The volume ratio of local anaesthetic to irritating substance will depend on the irritating substance. In general, the volume ratio of local anaesthetic to irritating substance is in the range of 1 : 3 to 1 : 1 vol/vol. For example a 0.5 mL bolus of local anaesthetic may be used in conjunction with a 0.5 mL bolus of tetanus vaccine, a 1 mL bolus of local anaesthetic may be used in conjunction with a 2 mL bolus of vitamin composition, or a 0.5 mL to 1 mL bolus of local anaesthetic may be used in conjunction with a 2 mL bolus of iron composition.

Each of the components used in the invention may be in the form of a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. A preferred salt is a hydrochloride salt.

Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, meglumine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.

Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

The method of the invention may also be used in conjunction with conventional means of preparing a subject for injection. For example, the site of injection may be swabbed with a sterilising solution such as an alcohol. The site of injection may also be treated with a topical anaesthetic to reduce or prevent pain associated with the needle piercing the skin.

A suitable topical local anaesthetic is EMLA gel. Such methods are known by those who administer injections and are commonly used in the art. In another aspect of the invention there is provided a pharmaceutical composition comprising an irritating substance and a local anaesthetic together with a pharmaceutically acceptable carrier, adjuvant or diluent, wherein the pharmaceutical composition is formulated for injection.

The formulation of such compositions or each component separately is well known to those skilled in the art. The composition may include pharmaceutically acceptable additives such as carriers, adjuvants and/or diluents. These include all conventional solvents, isotonic and absorption agents, complexing agents, and the like. It will be understood that the compositions may also include other supplementary physiologically active agents. The compositions for use in the invention may be formulated to be water or lipid soluble.

The carrier, adjuvant and/or diluent must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. The compositions useful in the invention must be suitable for administration by injection. Administration may be by subcutaneous, intramuscular or intradermal injection.

The compositions may conveniently be presented in unit dosage form, as one composition or each component in a separate composition, and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association one or both of the active components with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association, one or both of the active components with liquid carriers to form the injectable composition. If the two components are in separate compositions, a composition containing both the components may be prepared by mixing the two separate compositions. Such mixing may be performed at any time, but preferably is performed immediately before use.

Compositions suitable for administration by injection include aqueous or non-aqueous isotonic sterile solutions which may contain antioxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient. Compositions may also be aqueous or non-aqueous sterile suspensions which may contain suspending agents or thickening agents. The compositions of the invention may be presented containing both components in a separate unit dose sealed containers or both components in a single unit dose sealed container, for example ampoules or vials. The compositions may be stored in a freeze dried form (lyophilized) requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use.

Vaccine compositions are often formulated with adjuvants that enhance the immune response to the vaccine toxin injected. The choice of adjuvants reflects a compromise between the ability of the adjuvant to stimulate or enhance the immune response and an acceptable level of adverse reaction. Common adjuvants in vaccines include oil emulsions such as Freund's emulsified oil adjuvants (complete and incomplete), Arlacel A, mineral oil, and emulsified peanut oil adjuvant (adjuvant 65); mineral compounds such as aluminium phosphate, aluminium hydroxide and calcium phosphate; bacterial products such as Bordetella pertussis, Corynebacterium granulosum derived P40 component, Mycobaterium and its components and Cholera toxin; liposomes; immunostimulating complexes (ISCOMs) and squalene.

Each component may also be obtained as a commercially available composition. For example, ropivacaine hydrochloride is available under the trade name Naropin®, bupivacaine hydrochloride monohydrate is available under the trade names Marcaine®, Carbostesin™ and Sensorcaine™, levobupivacaine hydrochloride is available under the trade name Chirocaine®, etidocaine hydrochloride is available under the trade name Duranest™, lignocaine is available under the trade name Xylocaine™, Prilocaine hydrochloride is available under the trade names Citanest™ and Xylonest™, procaine butyrate is available under the trade name Probutylin™, procaine hydrochloride is available under the trade name Anestil™, and chloroprocaine hydrochloride is available under the trade name Nesacaine™. Vaccines suitable for use in the invention include tetanus vaccines. Commercially available tetanus vaccines include Tet-Tox™ and ADT (Adult diphtheria and tetanus) vaccine. ADT contains not only tetanus toxins but also substances to elicit immune response for diphtheria. Combination vaccines comprising tetanus toxins and one or more other substances for eliciting an immune response against other diseases may also be used in the methods of the invention.

Vitamin compositions suitable for use in the invention include Vitamin B-group and ascorbic acid compositions, such as Intravite® and Neo-cytamen™. Intravite® is a composition in which each 2 mL contains ascorbic acid (50 mg), nicotinamide (50 mg), sodium pantothenate (5 mg), riboflavine (5 mg), thiamine (10 mg) and pyridoxine (2.5 mg). Neo-cytamen™ is a source of vitamin Bi₂ and is available as 1000 μg hydroxocobalamin per mL.

Dietary supplements suitable for use in the invention include iron compositions, such as Ferrum H™ and Ferrosig™. Ferrum H™ and Ferrosig™ are compositions in which each 2 mL ampoule contains iron polymaltose complex (100 mg) in an aqueous solution with a pH adjustment to approximate isotonicity with sodium hydroxide.

When the local anaesthetic and the irritating substance are administered as a single composition, it is important to ensure that the two components do not interact with one another or have decreased stability in the composition. The stability of the composition can be determined by methods known to those skilled in the art. For example, the two components may be mixed and stored at room temperature or below room temperature, preferably in accordance with the storage temperatures of each component alone. After a given time period, for example, the shortest known storage period for one of the components, the composition can be analysed for the concentration of each component. If the stability is compromised by mixing the two components, stabilisers may be included in the composition to prevent decomposition or inactivation of either component. Alternatively, the two components may be administered in separate compositions or may be mixed to form a single composition immediately before use. Similarly, interaction between the local anaesthetic and the irritating substance can be assessed by methods known to those skilled in the art. For example, after mixing of the two components, the composition can be analysed to assess the concentration of each component and the production of by-products, or the composition may be tested in a suitable model to assess the effectiveness of the anaesthetic or more importantly, the irritating substance. It is understood by those in the art that compounds that have complementary reactive groups should not be mixed in a single composition. If the local anaesthetic is found to decrease the activity of the irritating substance, the two components may be administered in separate compositions.

In yet a further aspect of the invention there is provided a kit comprising an effective amount of a local anaesthetic and an irritating substance in a container designed to keep the local anaesthetic and the irritating substance in separate chambers and allow delivery of the local anaesthetic and irritating substance in a single injection. As used herein the term "a single injection" requires that the needle pierce the skin of the subject only one time but allow the delivery of both the local anaesthetic and the irritating substance, either together, or sequentially.

In a preferred embodiment the container is a two constituent syringe which contains within the syringe barrel two horizontally disposed chambers, one chamber containing the local anaesthetic and the other chamber containing the irritating substance.

In another preferred embodiment the two constituent syringe is designed to allow sequential delivery of the local anaesthetic and the irritating substance. The local anaesthetic or the irritating substance may be delivered first but preferably the local anaesthetic is delivered to the subject first.

The sequential administration may be achieved by any means which allows the two chambers in the syringe barrel to remain separated until one component has been entirely delivered.

In one embodiment, the kit comprises a container which is a syringe, as shown in Figure IA, comprising a syringe barrel (1) which contains a moveable plug (2) between the delivery end of the syringe (3) and the plunger (4) received in the syringe barrel to form the two chambers (5) and (6). Extending into the barrel from the delivery end of the syringe is a hollow conduit (7) which contains an opening (8) near the delivery end of the syringe (3) and is adapted to pass through the moveable plug (2). The inward extension of the conduit (7) is slightly greater than the thickness of the moveable plug (2).

In use, the conduit (7) is placed or contained in a needle which is inserted into the subject. As pressure is applied to the plunger, the component in the first chamber (5) is forced through the opening (8) into the needle and then into the subject while simultaneously, the end of the hollow conduit which is adapted to pass through the moveable plug (2), moves through the moveable plug (2) as shown in Figure IB. At the time the moveable plug reaches the delivery end of the syringe barrel (3) and the contents of the first chamber have been expelled, the end of the hollow conduit adapted to pass through the moveable plug enters the second chamber allowing the contents of the second chamber to pass through the conduit and into the needle as shown in Figure 1C. An example of this type of syringe is provided in US 3,911,916.

An alternative sequential delivery syringe provides sequential delivery by the use of one or more bypassing grooves longitudinally disposed at the delivery end of the syringe. Such as the syringe shown in Figure 2. A moveable plug (11) which separates the two chambers (12) and (13) is disposed in the syringe barrel (14). As the plunger (15) places pressure on the two chambers, the component in the first chamber is expelled through a needle (16) attached to the delivery end of the syringe (17) and into the subject. As the moveable plug (11) approaches the delivery end of the syringe barrel (17), the second component is allowed to enter the bypass groove (18) and thereby bypass the moveable plug and enter the first chamber for delivery through the needle attached to the delivery end of the syringe and into the subject. An example of this type of syringe is provided in US 5,720,731.

In another embodiment, the two chambers each include a container which are separated by a means of piercing both containers to allow the local anaesthetic and irritating substance to mix before use. A suitable syringe device is shown in Figure 3. A pre-filled two constituent syringe with a dispensing end (21) which has an inwardly directed stationary piercing cannula (22). Within the syringe barrel (23) is a first, sealed, collapsible container (24) holding a first component at subatmospheric pressure. The first container is slidably disposed within the syringe barrel adjacent to the inwardly piercing cannula (22). A second, sealed, collapsible container (25) holding the second component is slidably disposed within the syringe barrel (23) spaced from the first container. A carrier (26) is slidably disposed in the syringe barrel (23) between the first container (24) and the second container (25). The carrier (26) has a double-ended, hollow, piercing needle (27) with oppositely extending first and second ends for piercing the first and second containers respectively. A plunger (28) is slidably mounted within the syringe barrel (23) for applying a force to the second container. An example of this type of syringe is provided in US 5,637,087. In use in the present invention, one of the containers holds the local anaesthetic and the other container holds the irritating substance. Upon application of force to the second container (25) by the plunger (28), the second piercing end of the double ended piercing needle (27) pierces the second container (25) and the first piercing end of the double ended piercing needle (27) pierces the first container (24) and the component in the second container is forced through the double-ended hollow needle (27) into the first container (24) and mixing with the component in the first container occurs. Upon application of further force to the plunger, the first container (24) is pierced by the inwardly directed cannula (22) and the mixture of local anaesthetic and irritating substance is able to flow out of the container, through a needle and into the subject.

In this embodiment the local anaesthetic may be contained in the first container and the irritating substance may be contained in the second container. Alternatively, the irritating substance is in the first container and the local anaesthetic is in the second container.

Advantageously this embodiment allows the two components of the kit to be stored separately and then mixed at the time of use.

The kit of the present invention may include a needle for delivery to the subject. Alternatively a needle can be added at the time of use. Preferred kits include a needle and preferably a safety cover for the needle.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope.

The invention will now be described with reference to the following examples which are included for the purpose of illustration only and are not intended to limit the generality of the invention hereinbefore described.

EXAMPLES

Example 1

Combination tetanus vaccine and local anaesthetic

One hundred subjects were treated with a combination of tetanus vaccine (ADT) and ropivacaine (Naropin®). 0.5 mL of 0.75 wt % Naropin® was drawn into a 2 mL syringe, 0.5 mL of ADT was drawn into the same syringe through a 21 gauge needle. The needle was then changed to a 25 gauge needle before injection into the subject to ensure sterility and reduce needle size.

The skin of the subject is cleaned over the distal deltoid muscle area with isopropyl alcohol and the syringe needle inserted into the muscle. The plunger of the syringe was depressed to expel the contents of the syringe into the muscle of the subject. The syringe needle was removed from the muscle and pressure applied to the injection site.

None of the subjects complained of adverse effects such as soreness, tenderness, aching or redness in the vicinity of the injection site before the effect of the local anaesthetic had worn off. Most of the subjects did not have soreness, tenderness, aching or redness in the vicinity of the injection site after the local anaesthetic had worn off. A few subjects sustained minor tenderness in the vicinity of the injection site after the local anaesthetic had worn off.

Example 2

Combination vitamin injection and local anaesthetic

50 subjects were treated with a combination of a vitamin composition Intravite® and ropivacaine (Naropin®). 1 mL of 0.75 wt % Naropin® was drawn into a 5 mL syringe, 2 mL Intravite® was drawn up followed by 1 mL Neocytamen™. The skin over the buttock area was cleaned with isopropyl alcohol and the syringe inserted into the gluteus muscle. The plunger was then depressed to expel the contents of the syringe into the muscle of the subject. The syringe needle was removed from the muscle and pressure applied to the injection site.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method of reducing or preventing pain associated with injection of an irritating substance comprising administering by injection, a combination of an effective amount of a local anaesthetic and an effective amount of an irritating substance.

2. A method according to claim 1, wherein the local anaesthetic is selected from the amino amide class of local anaesthetics or the amino ester class of local anaesthetics.

3. A method according to claim 1, wherein the local anaesthetic is a long acting local anaesthetic.

4. A method according to claim 1, wherein the local anaesthetic is selected from ropivacaine, bupivacaine, levobupivacaine, mepivacaine, etidocaine, lignocaine, prilocaine, procaine, chloroprocaine, articaine and pharmaceutically acceptable salts thereof.

5. A method according to claim 4, wherein the local anaesthetic is selected from ropivacaine, bupivacaine, levobupivacaine, mepivacaine, etidocaine and pharmaceutically acceptable salts thereof.

6. A method according to claim 1, wherein the irritating substance is a substance that contains a toxin, a substance that contains vitamins or other supplements or a substance that is injected in a volume of greater than 2 mLs.

7. A method according to claim 6, wherein the substance that contains a toxin is a vaccine.

8. A method according to claim 7, wherein the vaccine is a tetanus vaccine.

9. A method according to claim 8, wherein the tetanus vaccine comprises one or more other immunity stimulating substances.

10. A method according to claim 6, wherein the substance that contains vitamins comprises Vitamin A, B-group Vitamins, Vitamin C, Vitamin D, Vitamin E,

Vitamin K or mixtures thereof.

11. A method according to claim 10, wherein the substance that contains vitamins comprises B-group Vitamins and Vitamin C.

12. A method according to claim 1, wherein the irritating substance is a supplement that comprises iron.

13. A pharmaceutical composition comprising an irritating substance and a local anaesthetic together with a pharmaceutically acceptable carrier, adjuvant or diluent, wherein the pharmaceutical composition is formulated for injection.

14. A pharmaceutical composition according to claim 13, wherein the local anaesthetic is selected from the amino amide class of local anaesthetics or the amino ester class of local anaesthetics.

15. A pharmaceutical composition according to claim 13, wherein the local anaesthetic is a long acting local anaesthetic.

16. A pharmaceutical composition according to claim 13, wherein the local anaesthetic is selected from ropivacaine, bupivacaine, levobupivacaine, mepivacaine, etidocaine, lignocaine, prilocaine, procaine, chloroprocaine, articaine and pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition according to claim 16, wherein the local anaesthetic is selected from ropivacaine, bupivacaine, levobupivacaine, mepivacaine, etidocaine and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition according to claim 13, wherein the irritating substance is a substance that contains a toxin, a substance that contains vitamins or other supplements or a substance that is injected in a volume of greater than 2 mLs.

19. A pharmaceutical composition according to claim 18, wherein the substance that contains a toxin is a vaccine.

20. A pharmaceutical composition according to claim 19, wherein the vaccine is a tetanus vaccine.

21. A pharmaceutical composition according to claim 20, wherein the composition comprises one or more other immunity stimulating substances.

22. A pharmaceutical composition according to claim 18, wherein the substance that contains vitamins comprises Vitamin A, B-group Vitamins, Vitamin C, Vitamin D, Vitamin E, Vitamin K or mixtures thereof.

23. A pharmaceutical composition according to claim 22, wherein the substance that contains vitamins comprises B-group Vitamins and Vitamin C.

24. A pharmaceutical composition according to claim 13, wherein the irritating substance is a supplement that comprises iron.

25. Use of a local anaesthetic in the manufacture of a medicament for reducing or preventing pain associated with injection of an irritating substance, wherein the medicament is administered by injection in combination with an irritating substance.

26. Use of an irritating substance in the manufacture of a medicament for reducing or preventing pain associated with injection of an irritating substance, wherein the medicament is administered by injection in combination with a local anaesthetic.

27. Use of a local anaesthetic and an irritating substance in the manufacture of a medicament for reducing or preventing pain associated with injection of an irritating substance, wherein the medicament is formulated for injection.

28. A kit comprising an effective amount of local anaesthetic and an irritating substance in a container designed to keep the local anaesthetic and the irritating substance in separate chambers and allow delivery of the local anaesthetic and irritating substance in a single injection.

29. A kit according to claim 28, wherein the container is a two chambered syringe.