primary outcome:
Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia
The primary outcome was short‐term (up to and including 12 weeks) improvement of pain compared with baseline using validated scales of pain intensity or pain relief. We accepted both visual analogue and categorical scales. Where reports expressed pain relief as none, minor, moderate, major or complete, we considered only moderate, major or complete as improvement. Where studies measured pain with a continuous scale, we took improvement to be an improvement of 50% or more from baseline on that scale. If studies reported results only as improvement on a continuous scale, we planned to try to obtain results from the authors to provide this dichotomous analysis.Five trials in painful diabetic neuropathy reported data on the primary outcome measure of ≥ 50% improvement of pain compared with baseline at less than 12 weeks (Goldstein 2005; Raskin 2005; Wernicke 2006; Gao 2010; Yasuda 2010). Participants received duloxetine 20 mg, 40 mg, 60 mg or 120 mg per day. Combining data from all doses from the five trials together (1655 participants), the RR of ≥ 50% improvement with any dose was 1.53 (95% CI, 1.21 to 1.92) compared with placebo (see Figure 2, Analysis 1.1). The RR of improvement was significantly greater than placebo for the 40 mg, 60 mg and 120 mg daily doses but not the 20 mg daily dose, for which it was 1.43 (95% CI 0.98 to 2.09; the CIs for 20 mg were wide as only one study with few participants provided data). There was no significant difference nor a dose effect in the RR of improvement with increasing doses of duloxetine from 40 mg to 120 mg. Significant heterogeneity in the 'all doses' and the 120 mg dose analysis is explained by the inclusion of Gao 2010. As it was not clear how many participants completed that trial on doses of 60 mg or 120 mg daily, we assumed for the purposes of the analysis that the higher dose was reached by all. Removing Gao 2010 removed the heterogeneity and slightly increased the RR of benefit for 'all doses' (RR 1.68, 95% CI 1.41 to 2.02).The mean improvement in pain at 12 weeks or less on an 11‐point Likert scale was significantly greater than placebo with the 60 mg dose of duloxetine (MD ‐0.96, 95% CI ‐1.26 to ‐0.65; 4 trials, 722 participants) and the 120 mg dose (MD ‐0.93, 95% CI ‐1.21 to ‐0.65; 4 trials, 828 participants), but not with the 20 mg dose (see Figure 3, Analysis 1.2, 1 trial, 179 participants, wide CIs from the single study). Removal of the Gao 2010 data removed the heterogeneity contributed by this study and the data then indicated a dose effect (MD ‐1.16, 95% CI ‐1.49 to ‐0.83; 3 trials, 612 participants) (see Analysis 1.2, Figure 3).The quality of the evidence available for this outcome remains moderate, mainly as a result of relatively high dropout rates. Lilly sponsored and performed all of these studies but there is no significant suspicion of publication bias despite a number of trials remaining without an identified publication in ClinicalTrials.gov.FIve trials reported data corresponding to the primary outcome for this review (Arnold 2004; Arnold 2005; Russell 2008; Arnold 2010; Arnold 2012) and the sixth reported data for the same outcome at more than 12 weeks (Chappell 2008). The studies used two scales; in Arnold 2004, the Fibromyalgia Impact Questionnaire pain score (Burckhardt 1991), and in the remainder, the BPI modified SF‐36 average pain severity score. The 20 mg dose of duloxetine in Russell 2008 (223 participants) did not show significant differences in any of the reported measures. The 30 mg dose, used only in Arnold 2012 (308 participants), was also negative on all measures of outcome except for a statistically significant benefit on the Patient Global Impression of Improvement (PGI‐I) (interchangeable with the Patient Global Impression of Change (PGI‐C)) and the mental component ot the SF‐36, neither of which were of a magnitude to be clinically significant. Both of these studies had wide CIs because of the small number of participants (Analysis 3.1). Five studies reported short‐term (up to and including 12 weeks) ≥ 50% improvement of pain compared with baseline. The RR of improvement was significantly greater with duloxetine 60 mg (1.57, 95% CI 1.20 to 2.06; 2 trials, 528 participants) and with 120 mg daily (1.69, 95% CI 1.40 to 2.03; 4 trials, 1234 participants) than with placebo (see Analysis 3.1). The RR of improvement compared with placebo for all doses in all five short‐term trials, which had a total of 1887 participants, was 1.50 (95% CI 1.29 to 1.75). Exclusion of the data for 111 participants in the Arnold 2012 study, which was responsible for the heterogeneity in the analysis, gave an RR of 1.68 (95% CI 1.41 to 2.01).Painful physical symptoms associated with major depressive disorder have been assessed in three studies each lasting eight weeks that used a duloxetine dose of 60 mg daily (Brecht 2007; Gaynor 2011a; Gaynor 2011b). The proportion of participants achieving ≥ 50% pain relief was greater with duloxetine than placebo in two studies (1023 participants) for which adequate information was available (RR 1.37, 95% CI 1.19 to 1.59) (see Analysis 4.1) and the magnitude of improvement was greater in those two studies (MD ‐0.55, 95% CI ‐0.75 to ‐0.35) (see Analysis 4.3). No data were available for Brecht 2007 in the comparison of magnitude as the report does not provide SDs, although the absolute magnitude of improvement was similar to the two studies of Gaynor.