Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced peripheral neuropathy

Duloxetine helps reduce painful chemotherapy-induced peripheral neuropathy

Among patients with painful chemotherapy-induced peripheral neuropathy, use of the anti-depressant drug duloxetine for 5 weeks resulted in a greater reduction in pain compared with placebo, according to a study in the April 3, 2013 issue of JAMA.

Approximately 20-40% of patients with cancer who receive neurotoxic chemotherapy (e.g., taxanes, platinum, vinca alkaloids, bortezomib) will develop painful chemotherapy-induced peripheral neuropathy, which can persist from months to years beyond chemotherapy completion, causing significant challenges due to its negative influence on function and quality of life (QoL). It is difficult for management, and most randomised controlled trials testing a variety of drugs with diverse mechanisms of action revealed no effective treatment, according to background information in the article.

There is evidence that serotonin and norepinephrine dual reuptake inhibitors are effective in treating neuropathy-related pain. Several phase III studies show that duloxetine is an effective treatment for painful diabetic neuropathy. Based on these trials, the hypothesis in the current study was that duloxetine would ameliorate chemotherapy-induced peripheral neuropathic pain as well.

Ellen Lavoie Smith, PhD, of the University of Michigan School of Nursing, Ann Arbor, and colleagues within the Cancer and Leukaemia Group B (CALGB/Alliance) conducted a randomized phase III double-blind, placebo-controlled crossover trial to assess whether duloxetine taken orally once daily decreases the severity of chemotherapy-induced peripheral neuropathy. The primary hypothesis was that duloxetine would be more effective than placebo in decreasing the average pain score after a 5-week treatment period. Secondary aims were to assess duloxetine's effect on QoL and function and on adverse events.

The study included 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. The study follow-up was completed in July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment.

The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks.

The researchers found that at the end of the initial treatment period, patients in the duloxetine-first group reported a larger decrease in average pain (average change score 1.06) than those in the placebo-first group (average change score 0.34). The observed average difference in the average pain score between the duloxetine-first and placebo-first groups was 0.73. Of the patients treated with duloxetine first, 59% reported any decrease in pain vs. 38% of patients treated with placebo first. Thirty percent of duloxetine-treated patients reported no change in pain and 10% reported increased pain.

The authors noted that their results suggest that patients who received platinums (oxaliplatin) may have experienced more benefit from duloxetine than those who received taxanes.
Pain-related quality-of-life improved to a greater degree for those treated with duloxetine during the initial treatment than for those treated with placebo.

"In conclusion, 5 weeks of duloxetine treatment was associated with a statistically and clinically significant improvement in pain compared with placebo. Exploratory analyses raise the possibility that duloxetine may work better for oxaliplatin-induced rather than taxane-induced painful chemotherapy-induced peripheral neuropathy," the researchers wrote in their conclusion.

Strengths and limitations of the study

The current study is the first large phase III trial to elucidate an effective intervention for painful chemotherapy-induced peripheral neuropathy caused by platinum and taxane agents (mainly paclitaxel or oxaliplatin). The current trial has several strengths and limitations. The strengths include the prospective, randomized, placebo-controlled trial design and the geographically diverse sample. Regarding limitations, first, there was an imbalance in the dropout rate due to adverse effects in patients treated with duloxetine vs. placebo (11% vs. 1%, respectively). One reason for this differential in the dropout rate may be the higher proportion of grade 3 adverse events reported by patients treated with duloxetine.
During initial treatment, the mean change in average pain score reported by patients treated with duloxetine was 1.06, an improvement of approximately 10% that is consistent with the IMMPACT definition of a minimal clinically important difference. In addition, results of the exploratory responder analysis suggest that the relative risk of experiencing a 30% and 50% improvement in pain severity statistically favoured duloxetine.

Other factors to consider when judging clinical significance include how quickly the drug takes effect, tolerability, and the drug's influence on other efficacy end points such as function and QoL. In the current study, pain scores decreased in patients treated with duloxetine relatively quickly, within the first week of therapy. Furthermore, duloxetine is associated with improved function and QoL.

Duloxetine-related clinically meaningful improvement in other painful conditions may not be directly comparable with painful chemotherapy-induced peripheral neuropathy. Results from the exploratory subgroup analysis in this study lend support to the premise that differences in pathophysiologic mechanisms may help to explain duloxetine response rate variations across neuropathic pain conditions. Just as response rates may vary when duloxetine is used to treat diabetic vs. chemotherapy-induced peripheral neuropathy due to differences in nerve injury mechanisms. The mechanisms of taxane- vs. platinum-induced peripheral nerve injury are quite different, possibly explaining why patients treated with platinum reported less pain in the current study.

Despite its everyday use in oncology clinical settings, the CTCAE is known for its suboptimal interrater reliability and poor sensitivity to detect subtle changes. Other study limitations are that changes in concurrent ancillary analgesic dosage were not assessed, study findings may not be applicable to patients with painful chemotherapy-induced peripheral neuropathy caused by other neurotoxic agents, and the study did not address long-term duloxetine treatment (beyond 5 weeks).

Duloxetine should not be used with other drugs that inhibit serotonin reuptake due to the associated increased risk of serotonin syndrome. Also, because duloxetine is a moderate cytochrome (CYP) P450 2D6 enzyme-inhibiter, co-administration with CYP P450 2D6 substrates can lead to increased substrate drug serum concentrations and associated toxicities. Concurrent use of duloxetine with warfarin, non-steroidal anti-inflammatory drugs, or both may also increase bleeding risk. If duloxetine and tamoxifen are taken together, duloxetine-induced CYP P450 2D6 enzyme inhibition could inhibit tamoxifen conversion to its active metabolite, endoxifen.

This study was supported by a grant from the USA NCI Division of Cancer Prevention, the Alliance Statistics and Data Center, and the Alliance Chairman. Drug and placebo were supplied by Eli Lilly. The NCI provided funding for data management and statistical analysis.