according to the invention , inhibitors of trpv1 are administered to a patient suffering from dry eye . the compounds suitable for use in the present invention inhibit the activity of trpv1 by binding to trpv1 at the ocular surface of a patient , thereby reducing the pro - inflammatory effects of trpv1 signaling associated with dry eye . the use of trpv1 antagonists for treating dry eye provides an advantage over current therapies that involve anesthetics , because local treatment of trpv1 antagonists will not cause loss of ocular sensations associated with anesthesia or have a central analgesic effect . as shown in the examples herein , trpv1 antagonists are beneficial in treating various ocular pain states and other conditions that have a neurogenic inflammatory component . in particular , trpv1 antagonists can inhibit endogenous agonists acting on trpv1 that provide a major contribution to certain ocular pain conditions . the examples herein also show that trpv1 antagonists have significant topical analgesic activity without topical anesthetic activity , thus making them very useful for treating symptoms of dry eye and for treating ocular pain . according to the invention , trpv1 antagonists are administered to a patient to prevent or ameliorate ocular pain associated with various stimuli . for example , the trpv1 antagonists and compositions of the present invention may be used in treating pain arising from allergens , inflammation , trauma , dry eye , and / or foreign body sensation , such as from contact lenses and surgery . the compounds of the present invention may be used for the treatment of pain following ocular surgery , such as prk surgery . with such treatment , the trpv1 antagonists can be individually dosed , or in combination with other pharmaceutical agents such as by methods disclosed in u . s . pat . nos . 4 , 939 , 135 and 5 , 401 , 510 ( robertson et al . ), the entire contents of which are incorporated herein by reference . the compounds will be utilized in a concentration effective to prevent or ameliorate ocular pain . the term “ trpv1 antagonist ” and “ trpv1 inhibitor ” includes any agent that can inhibit the activity of trpv1 ( i . e . block trpv1 - mediated signaling cascade ) at an ophthalmically relevant concentration . as used herein , an “ ophthalmically relevant concentration ” is less than 5 . 0 % ( w / v ). trpv1 antagonists useful in the methods of the invention include , but are not limited to , fused azabicyclic , heterocyclic , and amide compounds as described , for example , in u . s . patent application no . 2004 / 0157849 , u . s . patent application no . 2004 / 0209884 , u . s . patent application no . 2005 / 0113576 , international patent application no . wo 05 / 016890 , u . s . patent application no . 2004 / 0254188 , u . s . patent application no . 2005 / 0043351 , international patent application no . wo 05 / 040121 , u . s . patent application no . 2005 / 0085512 , and gomtsyan et al ., 2005 , j . med . chem . 48 : 744 - 752 ; fused pyridine derivatives as described , for example , in u . s . patent application no . 2004 / 0138454 ; pyridyl piperazinyl ureas as described , for example , in swanson et al ., 2005 , j . med . chem . 48 : 1857 - 1872 and u . s . patent application no . 2005 / 0049241 , as well as amg8163 ( bannon et al ., 2005 , 11 th world congress on pain ) and bctc ( sun et al ., 2003 , chem . lett . 13 : 3611 - 3616 ); 2 -( piperazine - 1 - yl )- 1h - benzimidazole ; pyridazinylpiperazines ; urea derivatives as describe , for example , in u . s . patent application no . 2005 / 0107388 , u . s . patent application no . 2005 / 0187291 , and u . s . patent application no . 2005 / 0154230 , as well as a - 425619 ( el kouhen et al ., 2005 , j . pharmacol . exp . ther . 314 : 400 - 409 ); cinnamides , including sb - 366791 ( gunthorpe et al ., 2004 , neuropharmacology 46 : 133 - 149 ) and amg 9810 ( gavva et al ., 2005 , j . pharmacol . exp . ther . 313 : 474 - 484 ); each of which is incorporated by reference . particular trpv1 antagonists useful in the methods of the invention include amg - 517 and amg - 628 ( amgen inc ., thousand oaks , calif .). trpv1 antagonists useful in the methods of the invention are also described , for example , in international patent application no . wo 2006065484 ; international patent application no . wo 2003070247 ; u . s . patent application no . us 2005080095 ; international patent application no . wo 2005007642 ; international patent application no . wo 2003080578 ; international patent application no . wo 2004007459 ; international patent application no . wo 2006063178 ; international patent application no . wo 2006062981 ; international patent application no . wo 2006065646 ; international patent application no . wo 2006122250 ; international patent application no . wo 2007050732 ; international patent application no . wo 2005077938 ; international patent application no . wo 2005077944 ; international 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2007010138 ; international patent application no . wo 2007010144 ; and international patent application no . wo 2007088277 ; the disclosure of each of which is incorporated herein by reference . according to the methods of the present invention , a composition comprising one or more of the specified trpv1 antagonists and a pharmaceutically acceptable carrier for topical ophthalmic administration or implantation into the conjunctival sac or anterior chamber of the eye is administered to a mammal in need thereof . the compositions are formulated in accordance with methods known in the art for the particular route of administration desired . the compositions administered according to the present invention comprise a pharmaceutically effective amount of one or more of the specified trpv1 antagonists . as used herein , a “ pharmaceutically effective amount ” refers to that amount of one or more trpv1 antagonists that prevents or alleviates ocular pain and / or is sufficient to reduce or eliminate symptoms of dry eye . preferably , compositions are intended to be administered topically to the eye in the form of eye drops or eye ointments , wherein the total amount of trpv1 antagonist will be about 0 . 001 to 5 . 0 % ( w / v ). preferably , the amount of trpv1 antagonists is about 0 . 01 to about 5 . 0 % ( w / v ). preferably , the compositions administered according to the present invention will be formulated as solutions , suspensions and other dosage forms for topical administration . aqueous solutions are generally preferred , based on ease of formulation , as well as a patient &# 39 ; s ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes . however , the compositions may also be suspensions , viscous or semi - viscous gels , or other types of solid or semi - solid compositions . suspensions may be preferred for cytokine synthesis inhibitors which are sparingly soluble in water . the compositions administered according to the present invention may also include various other ingredients , including but not limited to surfactants , tonicity agents , buffers , preservatives , co - solvents and viscosity building agents . various tonicity agents may be employed to adjust the tonicity of the composition , preferably to that of natural tears for ophthalmic compositions . for example , sodium chloride , potassium chloride , magnesium chloride , calcium chloride , dextrose and / or mannitol may be added to the composition to approximate physiological tonicity . such an amount of tonicity agent will vary , depending on the particular agent to be added . in general , however , the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality ( generally about 150 - 450 mosm , preferably 250 - 350 mosm ). an appropriate buffer system ( e . g ., sodium phosphate , sodium acetate , sodium citrate , sodium borate or boric acid ) may be added to the compositions to prevent ph drift under storage conditions . the particular concentration will vary , depending on the agent employed . preferably , however , the buffer will be chosen to maintain a target ph within the range of ph 6 . 0 - 7 . 5 . topical ophthalmic products may also be packaged in multidose form . preservatives may thus be required to prevent microbial contamination during use . suitable preservatives include : chlorobutanol , methyl paraben , propyl paraben , phenylethyl alcohol , edetate disodium , sorbic acid , polyquaternium - 1 , or other agents known to those skilled in the art . such preservatives are typically employed at a level of from 0 . 001 to 5 . 0 % w / v . unit dose compositions of the present invention will be sterile , but typically unpreserved . such compositions , therefore , generally will not contain preservatives . the ophthalmic compositions of the present invention may also be provided preservative free and packaged in unit dose form . the preferred compositions of the present invention are intended for administration to a human patient suffering from ocular pain or dry eye or symptoms of dry eye . preferably , such compositions will be administered topically . in general , the doses used for the above described purposes will vary , but will be in an effective amount to reduce or eliminate ocular pain and / or eliminate or improve dry eye conditions . generally , 1 - 2 drops of such compositions will be administered one or more times per day . for example , the composition can be administered 2 to 3 times a day or as directed by an eye care provider . a representative eye drop formulation is provided in table 1 below . the above composition is prepared by the following method . the batch quantities of boric acid , sodium chloride , disodium edetate , and polyquaternium - 1 are weighed and dissolved by stirring in 90 % of the batch quantity of purified water . the ph is adjusted to 7 . 4 .±. 0 . 1 with naoh and / or hcl . the batch quantity of the trpv1 antagonist as a stock solution is measured and added . purified water is added to q . s . to 100 %. the mixture is stirred for five minutes to homogenize and then filtered through a sterilizing filter membrane into a sterile recipient . all references cited in this application are expressly incorporated by reference herein for any purpose . unless otherwise required by context , singular terms used herein shall include pluralities and plural terms shall include the singular . the following examples , including the experiments conducted and results achieved are provided for illustrative purposes only and are not to be construed as limiting the invention . the effects of two transient receptor potential vanilloid receptor subfamily , member 1 ( trpv1 ) antagonists on ocular pain in rats were tested using a formalin - induced blink response assay . sprague - dawley rats were treated topical ocular with 20 μl of vehicle ( maxidex vehicle ), n -{ 4 -[ 6 -( 4 - trifluoromethyl - phenyl )- pyrimidin - 4 - yloxy ]- benzothiazol - 2 - yl }- acetamide ( al - 49975 , also known as amg - 517 , amgen inc ., thousand oaks , calif . ), or ( r )— n -( 4 -( 6 -( 4 -( 1 -( 4 - fluorophenyl ) ethyl ) piperazin - 1 - yl ) pyrimidin - 4 - yloxy ) benzo [ d ] thiazol - 2 - yl ) acetamide ( al - 49976 , also known as amg - 628 , amgen inc ., thousand oaks , calif .) to one eye only . after the appropriate pretreatment time of about 5 minutes , 5 μl of 0 . 1 % formalin was applied topical ocular . each rat was placed in a clear plastic box , and the number of blinks was counted for 1 minute immediately following the formalin challenge . the results of the blink response assay indicated that al - 49975 inhibited the formalin - induced blink response in a dose - dependent fashion , achieving significant inhibition at the highest concentration tested ( table 1 ), and that al - 49976 also significantly inhibited the pain response at the highest concentration tested ( table 1 ). corneal anesthetic effects of trpv1 antagonists were examined by analyzing suppression of blinks induced by mechanical touch . a cochet - bonnet esthesiometer was used to determine corneal anesthetic activities of the trpv1 antagonist , amg - 517 ( al - 49975 ), in normal rats . male sprague dawley rats (˜ 500 g ) were divided into groups of 6 each , restrained in a decapicone rat restraint , and secured at the posterior with tape . a hole was cut into the cone to expose the right eye . twenty - four hours prior to the experiment the eyelashes and whiskers were trimmed with scissors . the right eye was dosed with 20 μl of drug or maxidex vehicle , and the timer was set for 5 minutes to allow the rat time to acclimate . the cochet - bonnet esthesiometer fiber was set at 30 mm and perpendicularly touched by a masked observer to the center of the cornea 10 times with a 3 second delay between counts . blinks were counted with each touch of the fiber , and a total score out of 10 was recorded . if more than one blink occurred in response to a single touch , this event was counted as one blink response . the topical anesthetic , 0 . 5 % proparacaine ( alcaine ), inhibited the mechanical blink response by 95 %, providing a reference for the study ( table 2 ). al - 49975 did not significantly inhibit the blink response at a 1 % concentration . thus , the trpv1 antagonist , amg - 517 , which displayed significant topical analgesic activity as a 1 % suspension , did not have topical anesthetic activity at that same concentration . it should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that all modifications or alternatives equivalent thereto are within the spirit and scope of the invention as set forth in the appended claims .
methods of treating symptoms of dry eye by administering inhibitors of transient receptor potential cation channel , subfamily v , member 1 are disclosed . methods of preventing or alleviating ocular pain by administering trpv1 inhibitors are also disclosed .