in one embodiment , compound i ( or one or both of its enantiomers ) is administered to a patient to treat chronic pain at a dose that results in a sleepiness score of no more than 1 on the stanford sleepiness scale . in another embodiment , compound i ( or one or both of its enantiomers ) is administered to a patient to treat chronic pain at a dose that results in a sleepiness score of no more than 2 on the stanford sleepiness scale . in another embodiment , compound i ( or one or both of its enantiomers ) is administered to a patient to treat chronic pain at a dose that results in a sleepiness score of no more than 3 on the stanford sleepiness scale . at high doses the compounds of the invention are sedating . hence , in another embodiment , compound i ( or one or both of its enantiomers ) is administered to a patient to treat chronic pain at a dose that results in a sleepiness score of four or greater on the stanford sleepiness scale . compound i ( racemic mixture ) was assayed for its ability to alleviate sulprostone - induced tactile hypersensitivity and for sedating activity at various doses . the tactile hypersensitivity of 5 - 6 mice ( weighing approx . 25 g ) per group was scored every five minutes between 15 and 50 minutes following intraperitoneal dosing with 300 ng / kg ( in a 1 ml / kg volume ) sulprostone ( cayman chemical company , ann arbor , mich .). compound i or vehicle was administered intraperitoneally 15 minutes prior to sulprostone . tactile hypersensitivity was quantified by scoring the response of mice to light stroking of their flanks with a small paintbrush , which is not normally painful . the mice were rated on the following scale : a score of “ 2 ” was given to animals showing aggressive escape responses along with squeaking and biting at the brush ; a score of “ 1 ” was given to animals exhibiting mild squeaking with attempts to escape ; and a score of “ 0 ” was given if the animal showed no response to the light stroking of the paintbrush . the scores were summed to generate a cumulative score of 0 to 16 as described in minami et al ., pain 57 : 217 - 223 ( 1994 ). sulprostone - treated mice typically have a score of 14 and vehicle - treated mice typically have a score of 5 - 6 . chronic pain compounds including gabapentin and amitriptyline are active in this model consistent with effects in other chronic pain models and chronic pain patients , as described in gil d w , cheevers c v and donello j e , br j pharmacol 153 : 769 - 74 ( 2008 ). in addition , the locomotor activity of 5 - 6 mice per group was measured in a five minute period 30 minutes following intraperitoneal dosing with compound i . the activity is determined automatically by placing the mice in an exploratory chamber ( omnitech electronic ) that has photocell beams criss - crossing the box that are interrupted as the animal moves around . the computer analyses this movement and records total activity . locomotor activity relative to vehicle - treated animals was expressed as a percentage ; percentage sedation was calculated as 100 % minus the percent locomotor activity . statistical calculations of significance for in vivo studies were done using a two - tailed student &# 39 ; s t - test . as shown in fig1 and 2 , compound i administered at a dose of 1 mg / kg was minimally sedating and at a dose of 3 mg / kg was highly sedating . this was 10 fold - greater than the dose ( 0 . 3 mg / kg ) that produced a reduction in sulprostone induced hypersensitivity back to control levels . thus , compound i reduces pain at doses that are not sedating . studies with compound i and dexmedetomidine show that there is a & gt ; 10 - fold margin of safety for pain reduction vs . sedation with compound i ( fig3 ), but no margin for dexmedetomidine ( fig4 ). they further show that compound i is advantageous as an agent for relieving pain and can be taken systemically without the need for intravenous delivery . compounds of the invention were evaluated in a flipr assay in order to determine their specificity for five alpha adrenergic receptors . the flipr assay measures release of intracellular calcium in response to receptor activation . cells are preloaded with a calcium sensitive dye that fluoresces in response to calcium . receptors that activate the g protein , gq , elicit the response . alpha adrenergic receptors , which normally couple to gi , trigger the increase in intracellular calcium when coexpressed with a hybrid gq protein containing a gi receptor recognition domain , designated gq / i5 ( conklin et al ., nature 363 : 274 - 6 ( 1993 )) or with the promiscuous g protein g a16 . the assay was performed essentially as follows . hek 293 cells stably expressing an alpha - 2 receptor and either the chimeric g - protein gqi5 or the promiscuous g protein g16 were plated in poly - d - lysine coated 384 - well plates at 20 , 000 - 25 , 000 cells per well and grown overnight in dmem supplemented with 10 % fbs . cells were washed twice with hbss / hepes buffer ( 1 × hanks buffered salt solution , 20 mm hepes , ph 7 . 4 ) prior to the addition of fluo - 4 - am ( 4 μm fluo - 4 - am , 0 . 04 % pluronic acid in hbss / hepes buffer ), a calcium - sensitive dye . cells were loaded with dye for 60 minutes at 37 ° c ., then washed 4 times with hbss / hepes buffer . the reaction was initiated by the addition of the appropriate dilutions of compounds ( final concentration between 0 . 64 nm - 10 , 000 nm ) and the transient calcium signal captured . the peak height of the calcium curve was determined and utilized for calculation of ec 50 and efficacy using activity base . table 2 , below , shows agonist and antagonist activity at the alpha - 1a , alpha - 1b , alpha - 2a , alpha - 2b , and alpha - 2c adrenergic receptors . data in the first line in each column shows agonism ; the first number is the ec 50 , with the relative efficacy as compared to norepinephrine in parenthesis . data in the second line , when present , shows antagonism ; the first number is the ic 50 , with the percent antagonism in parenthesis . as shown in table 2 , the ( r ) enantiomer of compound 1 is an alpha - 2a and alpha - 2b agonist , and an alpha - 2a antagonist . the ( s ) enantiomer is a an alpha - 2 pan agonist having some alpha - 1a antagonist activity . the racemate ( compound i ) is an alpha - 2 pan agonist having some alpha - 1a agonist activity .
disclosed herein is a pharmaceutical composition comprising ethyl )- 2 - methylphenyl ) methanol and methods of using the composition to treat chronic pain .