Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial

Abstract

Importance: There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy.

Objective: To determine the effect of duloxetine, 60 mg daily, on average pain severity.

Design, setting, and patients: Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was completed 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 and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment.

Interventions: 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.

Main outcome measures: The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assessed using the Brief Pain Inventory-Short Form "average pain" item with 0 representing no pain and 10 representing as bad as can be imagined.

Results: Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95% CI, 0.01-0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount.

Conclusion and relevance: Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain.

Trial registration: clinicaltrials.gov Identifier: NCT00489411.

Figure 1

CONSORT Diagram (Initial and Crossover Periods)* * Number screened and number offered participation but declined is not captured.

Figure 2

Duloxetine and Placebo Effects on Average Pain Severity During the Initial and Crossover Treatment Periods Figure 2 illustrates duloxetine- and placebo-associated changes in the mean average pain score measured on Day 1 of each week in the initial and crossover treatment periods. Week 1 (Day 1) begins the initial treatment period (one capsule of duloxetine/placebo). Week 6 (Day 1) ends the initial treatment period (the start of the washout period when patients receive one capsule of duloxetine/placebo). Patients took no drug during Week 7. Error bars reflect 95% CIs.

Figure 3

Responder Analysis – Percent Decrease in Pain Score Due to Duloxetine Versus Placebo Plot showing the proportion of patients achieving various levels of pain reduction at the completion of the initial treatment period. Sample excludes patients whose pain worsened despite duloxetine/placebo treatment. N = 87 (Duloxetine); N = 94 (Placebo).

Figure 4

Comparison of Mean Differences in Average Pain Scores Across Duloxetine Chronic Pain Studies [95% CI] This forest plot provides a comparison of the observed mean difference [95% CI] in the average pain scores between the duloxetine and placebo groups reported in randomized controlled trials testing duloxetine for painful diabetic neuropathy (Goldstein 2005), fibromyalgia (Russell 2008), osteoarthritis (Chappell 2011) and the current trial (Smith 2013). The observed average pain scores between the duloxetine and placebo groups for the current study’s subgroup analysis based on the neurotoxic agent received (platinums versus taxanes) are presented below the double line.