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Abstract
Introduction Duloxetine has previously been reported to be promising in the setting of chemotherapy-induced peripheral neuropathy (CIPN). The aim of this study was to conduct a comprehensive systematic review and meta-analysis, on the use of duloxetine in prevention and treatment of CIPN.
Methods PubMed, Embase and Cochrane CENTRAL were searched from database inception up until April 2022. Articles were included in this review if they reported on duloxetine use in the setting of CIPN, in a multiarm comparative human trial. A random effects DerSimonian-Laird model was used to calculate summary risk ratios (RR) and corresponding 95% CIs, comparing duloxetine to placebo. This review was registered on.
Results Seven randomised controlled trials that included 645 patients were identified. Five reported on duloxetine for treatment of CIPN, and two for prevention of CIPN. Two studies had some concern for bias. Duloxetine was statistically similar to placebo in its efficacy, both in the treatment (RR 0.92, 95% CI 0.84 to 1.01) and prevention (RR 1.02, 95% CI 0.87 to 1.19) of CIPN. Safety profile was similar, in the treatment (RR 1.31, 95% CI 0.90 to 1.89) and prevention (RR 1.52, 95% CI 0.98 to 2.38) setting.
Conclusion There is currently limited evidence supporting duloxetine’s use for CIPN. There is a need for more comprehensive and higher-quality trials assessing duloxetine in the setting of CIPN, before further clinical practice recommendations.
Trial registration number PROSPERO (CRD42022327487).
- Symptoms and symptom management
- Supportive care
Data availability statement
No data are available.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Duloxetine has been reported to be promising in the setting of chemotherapy-induced peripheral neuropathy (CIPN), and even recommended for certain indications. But, there is no comprehensive systematic review and meta-analysis to-date.
WHAT THIS STUDY ADDS
There is currently limited evidence supporting duloxetine's use for CIPN. It is statistically similar to placebo, in treatment and prevention settings.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
There is a need for more comprehensive and higher-quality trials assessing duloxetine in the setting of CIPN, before further clinical practice recommendations
Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neuropathic chemotherapy, with 68% of patients reporting CIPN at 1 month after chemotherapy, 60% within 3 months and 30% within 6 months.1 Patients commonly describe CIPN as tingling or pins-and-needles sensation, pain, burning, numbness, temperature sensitivity and/or difficulty with fine motor skills.2 Several chemotherapy drugs have been well documented as risk factors for CIPN, including platinum-based agents such as cisplatin, carboplatin and oxaliplatin; and taxanes, such as paclitaxel and docetaxel.3 Severe CIPN may ultimately lead to treatment discontinuation.
Duloxetine has previously been reported to be effective for the treatment of painful diabetic neuropathy,4 and recently also been reported to be promising for CIPN treatment. In a landmark study by Smith et al,5 231 patients were randomised to either duloxetine or placebo, with patients in the duloxetine arm ultimately reporting significantly reduced average pain—59% reported pain reduction, as opposed to only 38% in those receiving placebo. A systematic review searching up to January 2018 reported on several other observational studies, and suggested that duloxetine may be effective in the treatment of CIPN, but overall data remain sparse.6
Recently, there has also been increasing interest in duloxetine for CIPN prevention. In one of the first studies by Rokhsareh et al,7 40 patients were randomised to duloxetine or placebo for the placebo of CIPN. Patients receiving duloxetine reported less peripheral sensory pain, less tingling and discomfort in extremities, and less temperature-induced pain. Several other trials are currently underway and are registered on ClinicalTrials.gov.8 9
Currently, there is no comprehensive systematic review and meta-analysis reporting on the prevention and treatment of CIPN using duloxetine. In order to develop a better understanding and appreciation of duloxetine’s true effect estimate and provide valuable insight into whether duloxetine should be recommended for routine standard of practice. The aim of this review was to report on duloxetine use for the prevention and treatment of CIPN.
Methods
This review was registered on PROSPERO (CRD42022327487). PubMed, Embase and Cochrane CENTRAL were searched from database inception up until April 2022 (online supplemental appendix 1). The search concepts were duloxetine and CIPN. No restrictions were applied. The search strategy is presented in online supplemental appendix 1.
Supplemental material
After duplication removal and a calibration exercise, two review authors (RC and MN) independently screened articles to assess eligibility for this review. Discrepancies were resolved by discussion and consensus, or if needed, the involvement of a third and senior author (EP). Articles were eligible after level 1 title and abstract screening if they reported on human trials of duloxetine, in the setting of CIPN. Articles were eligible after level 2 full-text screening if they reported on duloxetine in a multiarm comparative trial, employing either a randomised controlled trial design or an observational study design with a multivariable or propensity-score matched analysis. Finally, articles were included in this review if they had extractable data—either efficacy or safety data, pertaining to duloxetine.
For each included study, patient demographics and chemotherapy treatment characteristics were noted. The setting of duloxetine use, whether prevention or treatment and its comparator arm was also noted. Quantitative endpoints of CIPN in the format of event data, as reported by authors, were extracted—number of patients reporting cold-induced dysesthesia, cranial neuropathy, motor neuropathy, neuropathic pain, no response numbness, paresthesia, sensory neuropathy, <30% reduction and <50% reduction. Data extraction was conducted independently and in-duplicate by two study authors (RC and MN), and discrepancies resolved via consensus or involvement of a third and senior author (EP). Where clarification was needed for an article, corresponding author(s) of the paper was contacted via email for clarification/data and followed up 1 week later if no response was provided. If still no response was provided, the data in question wee omitted from this review. Study quality was assessed using the Risk of Bias V.2 for randomised controlled trials, and Risk of Bias in Non-Randomised Studies of Interventions for observational studies.10 11 Study quality assessment was conducted independently and in-duplicate by two study authors (RC and OS); discrepancies were resolved by consensus or involvement of a third and senior author (EP).
A random effects DerSimonian-Laird model was used to calculate summary risk ratios (RR) and corresponding 95% CIs, comparing duloxetine to placebo. Due to the paucity of data, no meta-analysis could be conducted comparing duloxetine to other comparator drugs of pregabalin or venlafaxine. Studies were analysed separately by duloxetine setting—treatment and prevention. For studies that reported an endpoint at multiple timepoints, event and sample size data were summed by treatment arm, to account for all endpoints in the analysis. Publication bias was assessed using a funnel plot and Egger’s test. Type I error was set at 0.05. All analyses were conducted using StataBE 17.0.
Results
Of the 149 articles identified through the search strategy, 136 underwent level 1 screening, 77 underwent level 2 screening and a total of 8 papers reporting on 7 trials were included (figure 1).5 7 12–17 Six of the seven studies were double-blind randomised controlled trials.5 7 12–15 17 Four studies enrolled patients with any cancer diagnosis.5 15–17 Sample size ranged from 34 to 231 patients, and trials were published between 2013 and 2022. Two studies investigated duloxetine in the setting of prevention,7 12 while five studies investigated duloxetine for the treatment of CIPN.5 13–17 Duloxetine doses ranged from 20 mg to 60 mg by mouth daily. Of the six two-arm trials, five compared duloxetine to placebo7 8 12 16 17 and one compared duloxetine to pregabalin.13 14 One three-arm trial compared duloxetine to venlafaxine to placebo.15 Individual study characteristics are presented in table 1.
PRISMA flow diagram.
Study characteristics
Of the seven trials, five had overall low risk of bias (figure 2). Hirayama et al employed an open-label cross-over design, and Matsuoka et al’s intervention arm involved re-evaluation and possible redosing of duloxetine after 2 days, and thereby possibly making participants and research personnel aware of their assignment; both studies were evaluated as having some concern for bias.16 17
Study quality assessment.
Three studies reported on the efficacy of duloxetine relative to placebo, in the treatment setting (figure 3A).5 15 16 Patients receiving duloxetine were more likely to experience a reduction in CIPN; patients receiving duloxetine were less likely to not experience <30% (RR 0.76, 95% CI 0.45 to 1.29) and <50% (RR 0.89, 95% CI 0.71 to 1.12) reduction in CIPN, although not statistically significant. Furthermore, patients treated with duloxetine were less likely to experience neuropathic pain, but again, this was not statistically significant (RR 0.88, 95% CI 0.67 to 1.15). Across all 8 subgroups and 11 datapoints, patients treated with duloxetine were favoured to experience less CIPN, although just failing to reach statistical significance (RR 0.92, 95% CI 0.84 to 1.01). There was little concern for heterogeneity (p=0.63) or publication bias (online supplemental appendix 2.1; p=0.45). One study compared duloxetine to pregabalin, and reported duloxetine to be inferior to pregabalin (RR 8.25, 95% CI 2.71 to 25.1).13 14
Efficacy of duloxetine, compared with placebo (A) treatment setting (B) prevention setting.
Two studies reported on the efficacy of duloxetine relative to placebo, in the prevention setting (figure 3B).7 12 Across all six subgroups and eight datapoints, duloxetine was similar to placebo (RR 1.02, 95% CI 0.87 to 1.19). There was no significant concern for heterogeneity (p=0.46), but significant concern for publication bias (online supplemental appendix 2.2; p=0.02).
Two studies reported on the safety of duloxetine compared with placebo, when used for treatment. Across the 10 subgroups and three datapoints, duloxetine may be associated with greater risk of drug-related toxicities, although was found to be statistically insignificant (figure 4; RR 1.31, 95% CI 0.90 to 1.89). There was no significant concern for heterogeneity (p=0.40) or publication bias (online supplemental appendix 3; p=0.57). In the one study reporting on duloxetine relative to pregabalin, duloxetine was associated with a lower risk of drug-related toxicities (RR 0.40, 95% CI 0.18 to 0.90).13 14
Safety of duloxetine, compared with placebo in the treatment setting.
One study reported on the safety of duloxetine relative to placebo used in the preventative setting. Duloxetine was associated with higher risk for drug-related toxicities compared with placebo, although statistically insignificant (RR 1.52, 95% CI 0.98 to 2.38).
Discussion
To our knowledge, this is the first systematic review and meta-analysis reporting on the efficacy and safety of duloxetine for the prevention and treatment of CIPN. Seven randomised trials were identified, with a total amalgamated sample size of 645 patients. Relative to placebo, duloxetine in CIPN treatment showed a favourable trend that was not statistically significant. There was also a trend to greater adverse effects with duloxetine, which was also not statistically significant.
There are minimal data on the use of duloxetine for CIPN prevention. Duloxetine was similar to placebo when used for CIPN prevention, summarising data across two studies. One study reported duloxetine to have a poorer safety profile than placebo, although results were not statistically significant. These results should be interpreted with caution, as they are based largely on results of single trials. As expected, there is significant concern for publication bias in this result. We look forward to the forthcoming phase 2 and 3 studies, which are currently in progress.8 9
It is important to note that the dosing of duloxetine was quite heterogeneous across studies, ranging from 20 mg to 60 mg. This heterogeneity may explain the wide and imprecise CIs of this meta-analysis. Furthermore, this heterogeneity may not accurately represent duloxetine’s efficacy for CIPN, as duloxetine may be administered at doses that are below the therapeutic dose of 60–120 mg. As well, duloxetine may take several weeks to have an effect, which may not be within the follow-up time frame of some included studies.
One study that compared duloxetine to pregabalin for CIPN treatment, and reported pregabalin to be superior to duloxetine in its efficacy for the treatment of CIPN. This study also reported significantly higher risk of drug-related toxicities for pregabalin, and may lead to clinical reassessment of benefits of improved CIPN in the setting of increased toxicities.13 14 Akin to pregabalin, duloxetine was originally postulated to be a good option for treating CIPN in case studies,18 19 but subsequent double-blind randomised controlled trials showed pregabalin to be similar to placebo.20 21
While previous review articles22–26 and guideline articles27–29 expressed promise surrounding duloxetine, our review found that there was a modest trend for pain reduction and a trend in increased adverse effects is also present. It is not clear from the data thus far that duloxetine should be routinely recommended in practice for CIPN treatment, and there are limited available data on its use for CIPN. The initial landmark trial by Smith et al was very promising,5 but the addition of subsequent smaller trials have led to a summary effect estimate and wide CI indicating similarity between duloxetine and placebo. Future publications of even 1–2 additional trials could strongly change our understanding of duloxetine’s effect. Again, we eagerly await the results of ongoing clinical trials, for a better understanding of duloxetine’s true effect.8 9
This study was not without limitations. As is inherent in the study design of systematic reviews and meta-analyses, the validity of the results relies on the validity of the underlying studies. Of the seven trials reporting on duloxetine overall, two trials had some concern for bias. Within the three trials reporting on duloxetine efficacy in CIPN treatment, one trial had some concern for bias. There is a need for more and higher-quality trials reporting on duloxetine use in CIPN treatment and prevention before definitive conclusions can be drawn. Additionally, despite no heterogeneity in datapoints, there is significant heterogeneity in CIPN endpoints. Most of the included studies had different CIPN endpoints, which creates a challenge for the meta-analysis of duloxetine efficacy. Future guidelines and clinical trials should include standardised guidelines for CIPN reporting, to allow for comparison between trials. Nevertheless, because of the sparse data and heterogeneous endpoints, this review and its results should be interpreted with caution, and considered to be hypothesis-generating rather than practice changing.
In conclusion, this review reports on the relative efficacy and safety of duloxetine in the treatment and prevention of CIPN. We cannot conclude that duloxetine is more effective than placebo for either for the treatment or prevention of CIPN. Increased adverse effects with duloxetine compared with placebo were likely, but not statistically proven. There is a need for larger trials to clarify more precisely the benefits of duloxetine for CIPN, before routine clinical use for this purpose is widely endorsed.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @ElizabethPrsic
Contributors All authors contributed significantly, and are accountable for the published work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.