Several clinical trials have been conducted for the treatment of CIPN, but not much success has been achieved [5, 10]. Given the lack of an effective treatment, investigating prophylactic strategies might be of value; such a policy showed success in chemotherapy-induced nausea and vomiting . Most of the previous trials in the prevention of CIPN failed to find an effective neuroprotective agent [15-17], although there are a few positive studies too . Different drugs including Calcium and magnesium, Pregabalin, Metformin, Venlafaxine, and Vitamin E has been used for the prevention of OIPN, yet there is no recommendation for daily practice [19-24].
To the best of our knowledge this is the first randomized clinical trial to evaluate efficacy of duloxetine in the prevention of CIPN. Results of this study suggests potential efficacy of duloxetine.
We found three clinical trials in which duloxetine were used for treating CIPN. The first one was a pilot study in 39 colorectal cancer patients suffering from CIPN. Duloxetine was effective and tolerable and the authors suggested that “In the future, it may play a role in effectively treating chronic OIPN” . The second one was a high quality randomized clinical trial that led to 2014 American Society of Clinical Oncology’s (ASCO) moderate recommendation on duloxetine as the only drug for the treatment of CIPN. They evaluated 231 patients with CIPN (due to taxane or platinum) randomized to two groups of duloxetine (30 mg/day in the first week and then continued by 60 mg/day) and placebo. They concluded that among patients with painful CIPN, duloxetine for 5 weeks resulted in a greater reduction in pain intensity compared to placebo . The third study was held in Japan on 34 patients who had received oxaliplatin, paclitaxel, vincristine, or bortezomib. Duloxetine for 4 weeks, at the standard dose in japan (20mg/day for one week and then increased to 40 mg/day), was associated with improved neuropathy .
We planned to start duloxetine at the same dosage as the previous studies but since at the time of study, duloxetine capsule 30 mg was not easily available, we started with 60 mg/day of duloxetine. Acute OIPN occurred in 90 percent of the patients which is consistent with previous studies [5, 10, 13]. In this study some objectives were improved and some were not. Interpretation of these results should be done cautiously. Relative frequency of distal paresthesia, throat discomfort, and cold induced neuropathy in each cycle was non-significantly reduced in duloxetine arm compared to placebo arm. Proportion of chemotherapy cycles (mean) in which patients reported symptoms of neuropathy was significantly lower in two out of three measured symptoms (distal paresthesia and throat discomfort) in duloxetine arm. The study did not detect an improvement in the clinician assessment of grade of neuropathy via CTCAE perhaps due to sample size and low oxaliplatin cumulative dose. Most of the patients in this study did not receive high cumulative doses of oxaliplatin (i.e. >750-850 mg/m2), so the severity of OIPN in both groups was low (no Grade 3 of neuropathy).
In terms of objective assessment, results of the nerve conduction velocity in the tibial and deep peroneal nerves were in favor of duloxetine efficacy. Reduction in sensory nerve action potential (SNAP) amplitudes is also an expected finding of chronic CIPN due to axonal injury, but we did not find significant difference in terms of SNAP amplitude between the two arms. In an interesting study it was shown that the SNAP amplitude did not significantly change until after 21-24 weeks of oxaliplatin-based chemotherapy initiation (8/9 cycles of chemotherapy) while in our study most of the patients were examined in <21 weeks of chemotherapy initiation (4/5 cycles of chemotherapy), so one explanation may be inappropriate time interval or low oxaliplatin cumulative dose .
Adverse effects of duloxetine were tolerable. In contrast to previous studies which prescribed duloxetine continuously, we prescribed duloxetine intermittently (two weeks on and one week off) which might explain lower rate of duloxetine discontinuation in this study. None of the patients experienced serotonin syndrome, which has been mentioned as a concern due to the potential interaction of duloxetine and other drugs that inhibit serotonin reuptake (i.e., Granisetron that was used as a premedication drug before chemotherapy) .
The most common cited mechanism of acute OIPN is related to the chelation of calcium by oxalate , but this is not relevant to the known mechanism of duloxetine effects. In a recent study, duloxetine was shown to be neuroprotective in OIPN, both in vitro and in vivo. Inhibiting the MAPK signaling and consequently preventing the NF-kB activation was considered as the duloxetine mechanism of action in one study . In an animal research anti-allodynia effect of duloxetine in OIPN was shown to be mediated by the spinal alpha1-adrenergic receptors . Norepinephrine (NE) and serotonin inhibit the transmission of pain signals into Dorsal Root Ganglia (DRG) . Considering duloxetine effect on inhibition of NE and serotonin reuptake, it was thought to be useful for chronic neuropathy like diabetic peripheral neuropathy which may explains the potential efficacy of duloxetine in chronic CIPN as well.
The findings of this study have to be seen in light of some limitations. The first one is small sample size, so the study might not have enough power to demonstrate duloxetine efficacy in all endpoints. The second one is the difference in oxalipaltin cumulative dose in the two groups. The third one is relatively short duration of chemotherapy administration in this trial, so that most of the patients did not receive a high cumulative dose of oxaliplatin.