Context. Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails.Objectives. We investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy.Methods. A multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]eItem 5) $ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases.Results. Seventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P ¼ 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P ¼ 0.048). Clinically meaningful pain improvement ($30%) was reported by 44.1% (n ¼ 15) of patients in Group D vs. 18.2% (n ¼ 6) in Group P (P ¼ 0.02); 32.4% (n ¼ 11) vs. 3.0% (n ¼ 1) of patients in Groups D and P, respectively, reported pain reduction $ 50% (P ¼ 0.002).Conclusion. Adding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine. J Pain Symptom

The use of chemotherapy drugs that penetrate the BBB may be a risk factor for delirium. This information may allow palliative care doctors and medical oncologists to predict which patients are at increased risk for delirium.

Background: Early palliative intervention in advanced cancer patients with metastatic nonsmall-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time.Objective: We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. Methods: Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for ,7 days (late referral group, 64 patients) and those who experienced outpatient services for 7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. Results: Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P , 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P ¼ 0.010) and 16.5 and 20.9 months (P ¼ 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P ¼ 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P ¼ 0.018) in non-small-cell lung cancer. Conclusions: The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted.

Abstract. Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the mRNA expression levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRM1 and morphine treatment; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a predictive biomarker of the response to morphine treatment.

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