a total of 38 patients with chronic painful dpn ( neuropathy total symptom score 6   > 4 and < 16 ) for at least 6 months with stable glycemic control ( a1c < 11% ) were assessed . those with persistent pain , despite an adequate trial of tricyclic antidepressants , were recruited . three modalities of pain ( superficial , deep , and muscular pain ) were assessed daily using a 100-mm visual analog scale ( vas ) . the dose of study medication was titrated over 2 weeks , followed by a 10-week maintenance phase . at baseline , depression was assessed using the seven - item depression subscale of the hospital anxiety and depression scale ( hads - d ) ( 3 ) . improvement in pain , as assessed by the pain diary and neuropathic pain scale ( nps ) questionnaire , was used as the primary outcome measure . study end point was the final week mean pain and nps score while taking the maximum tolerated dose of study medication . a total pain score ( tps ) ( average score of all three pain modalities ) was also calculated . secondary outcome measure was quality of life ( qol ) , assessed by mcgill pain and qol ( 5 ) , sf-36 health survey ( 6 ) , and euroqol ( 7 ) questionnaires . sativex ( tetrahydrocannabinol [ 27 mg / ml ] and cannabidiol [ 25 mg / ml ] ) and its matching placebo were presented as a pump - action spray . doses were administered sublingually in divided doses up to four times a day . an intent - to - treat analysis was undertaken . differences in subgroup baseline characteristics were correlated to the outcome and adjustments performed at a coefficient > 0.50 . multiple linear regression was used for a normal distribution , while skewed distribution was initially transformed . hoc analysis , patients were divided into individuals with depression ( hads - d score 10 ) and no depression ( hads - d score < 10 ) . using ancova , we compared mean change in tps from baseline between these groups . the interaction between depression and treatment each treatment arm was divided into patients with and without depression , and outcomes were compared using an independent sample t test . differences in subgroup baseline characteristics were correlated to the outcome and adjustments performed at a coefficient > 0.50 . multiple linear regression was used for a normal distribution , while skewed distribution was initially transformed . hoc analysis , patients were divided into individuals with depression ( hads - d score 10 ) and no depression ( hads - d score < 10 ) . using ancova , each treatment arm was divided into patients with and without depression , and outcomes were compared using an independent sample t test . we excluded one placebo - treated patient from the intent - to - treat analysis ( n = 29 ) because of a protocol violation . covariates used in the analysis were duration of diabetes , baseline scores , age , and sex . there was no significant difference in mean change tps between sativex and placebo ( p = 0.40 ; sem 9.5 ; 95% ci 11.3 to 27.8 ) at end point . similarly , there was no difference in mean change in superficial ( p = 0.72 ; 9.1 ; 15.3 to 21.93 ) , deep ( p = 0.38 ; 10.5 ; 12.2 to 30.8 ) , and muscular ( p = 0.26 ; 10.3 ; 9.15 to 33.0 ) pain vas . differences in nps did not reach statistical significance ( p = 0.62 ; 7.8 ; 20.1 to 12.1 ) . eight ( 53% ) sativex - treated patients responded ( defined as 30% total pain vas improvement ) versus nine ( 64% ) placebo patients ( p = 0.55 , odds ratio 0.63 , 95% ci 0.142.82 ) ( table 1 ) . demographics and primary and secondary outcome measures data are n or means  sd unless otherwise indicated . the mcgill pain questionnaire showed no difference in sensory scale ( p = 0.65 ; sem 3.3 ; 95% ci 5.39 to 8.44 ) , affective scale ( p = 0.81 ; 1.3 ; 3.0 to 2.4 ) , vas ( p = 0.24 ; 1.0 ; 0.91 to 3.4 ) , and present pain intensity ( p = 0.57 ; 0.53 ; 0.79 to 1.4 ) between study cohorts . euroqol and sf-36 questionnaires showed improvement in both groups , but differences between groups were not statistically significant ( table 1 ) . mean hads - d for patients with depression ( n = 10 ) and no depression ( n = 18 ) were 13.4  3.5 ( means  sd ) and 5.94  2.2 , respectively . patients with depression had significantly higher baseline tps ( 62.3  22.1 vs. 43.4  24.3 ; p = 0.05 ) and greater tps improvement ( 31.6  24.2 vs. 10.7  25.0 ; p = 0.04 , sem 9.8 , 95% ci 0.5441.1 ) compared with those without depression . however , there was a significant main effect of depression on tps ( p = 0.05 ) , suggesting that in both treatment arms , patients who were depressed were more likely to respond to intervention : sativex arm , depressed ( 36.7  28.6 ) vs. nondepressed ( 4.9  14.4 ) , p = 0.02 , 56.5 to 7.2 ; placebo arm , 26.5  20.7 vs. 17.3  33.1 , p = 0.60 , 45.9 to 27.6 . covariates used in the analysis were duration of diabetes , baseline scores , age , and sex . there was no significant difference in mean change tps between sativex and placebo ( p = 0.40 ; sem 9.5 ; 95% ci 11.3 to 27.8 ) at end point . similarly , there was no difference in mean change in superficial ( p = 0.72 ; 9.1 ; 15.3 to 21.93 ) , deep ( p = 0.38 ; 10.5 ; 12.2 to 30.8 ) , and muscular ( p = 0.26 ; 10.3 ; 9.15 to 33.0 ) pain vas . differences in nps did not reach statistical significance ( p = 0.62 ; 7.8 ; 20.1 to 12.1 ) . eight ( 53% ) sativex - treated patients responded ( defined as 30% total pain vas improvement ) versus nine ( 64% ) placebo patients ( p = 0.55 , odds ratio 0.63 , 95% ci 0.142.82 ) ( table 1 ) . demographics and primary and secondary outcome measures data are n or means  sd unless otherwise indicated . the mcgill pain questionnaire showed no difference in sensory scale ( p = 0.65 ; sem 3.3 ; 95% ci 5.39 to 8.44 ) , affective scale ( p = 0.81 ; 1.3 ; 3.0 to 2.4 ) , vas ( p = 0.24 ; 1.0 ; 0.91 to 3.4 ) , and present pain intensity ( p = 0.57 ; 0.53 ; 0.79 to 1.4 ) between study cohorts . euroqol and sf-36 questionnaires showed improvement in both groups , but differences between groups were not statistically significant ( table 1 ) . mean hads - d for patients with depression ( n = 10 ) and no depression ( n = 18 ) were 13.4  3.5 ( means  sd ) and 5.94  2.2 , respectively . patients with depression had significantly higher baseline tps ( 62.3  22.1 vs. 43.4  24.3 ; p = 0.05 ) and greater tps improvement ( 31.6  24.2 vs. 10.7  25.0 ; p = 0.04 , sem 9.8 , 95% ci 0.5441.1 ) compared with those without depression . however , there was a significant main effect of depression on tps ( p = 0.05 ) , suggesting that in both treatment arms , patients who were depressed were more likely to respond to intervention : sativex arm , depressed ( 36.7  28.6 ) vs. nondepressed ( 4.9  14.4 ) , p = 0.02 , 56.5 to 7.2 ; placebo arm , 26.5  20.7 vs. 17.3  33.1 , p = 0.60 , 45.9 to 27.6 . despite being common , there are few effective treatments that provide symptomatic relief for painful dpn ( 8) . for centuries , cannabinoids have been consumed for their analgesic properties and more recently studied in other neuropathic conditions ( 9 ) . in this study , when compared with placebo , sativex failed to show statistically significant improvements in primary and secondary outcome measures . patients with depression had higher baseline pain scores and were also more likely to respond favorably to intervention , regardless if sativex or placebo . most painful dpn trials to date either have not screened for depression or exclude individuals who have it ( 10,11 ) . as in a number of recent studies , there was a large placebo effect that may have led to a failure to show differences in outcome measures ( 12 ) . this may provide an insight into the nature of pain in dpn and the placebo effect . there is a need for more robust and objective end points for use in clinical trials of painful dpn . also , it was felt ethically inappropriate to discontinue treatments from which patients may be benefiting . the use of specific painful dpn qol questionnaires ( 13 ) may have captured subtle changes missed by the generic ones used in this study . finally , while the search for therapeutic agents to halt or reverse the neuropathic process continues , more effective treatments are required that provide better symptom control with fewer side effects . the assessment of depression may be important when designing future clinical trials into painful dpn .