Predictors of duloxetine response in patients with neuropathic cancer pain: a secondary analysis of a randomized controlled trial-JORTC-PAL08 (DIRECT) study.

PURPOSE: Duloxetine has some effect against cancer neuropathic pain (CNP); however, predictors of duloxetine response are unclear. This study sought to identify predictors of duloxetine response in patients with CNP. METHODS: Patients (N = 70) with CNP unresponsive to or intolerant of opioid-pregabalin combination therapy, with a brief pain inventory-short form (BPI-SF) Item 5 score (average pain) ≥ 4, and with a total hospital anxiety and depression scale score < 20, were randomized to a duloxetine or a placebo group. Multiple linear regression analysis was conducted to identify predictors of duloxetine response as a secondary analysis with the change in the average pain score on day 10 from day 0 as the dependent variable, and the following five covariates; baseline (day 0) average pain score, baseline opioid dose, continuation/discontinuation of pregabalin, and items 20 and 21 score of the short-form McGill pain questionnaire 2 (SF-MPQ-2) as independent variables. RESULTS: Of the four domains (continuous pain, intermittent pain, neuropathic pain, and affective descriptors) score of SF-MPQ-2 on day 0, significant differences were observed in the neuropathic pain domain (p = 0.040) in change on the average pain between day 10 and day 0 in the duloxetine group. Multiple linear regression analysis revealed that patients with a high score for SF-MPQ-2 Item 21 (tingling pain) on day 0 had a significantly greater change in average pain between day 10 and day 0 (p = 0.046). CONCLUSION: Patients with a high score for SF-MPQ-2 Item 21 might benefit more from duloxetine.

Chemotherapeutic drugs that penetrate the blood-brain barrier affect the development of hyperactive delirium in cancer patients.

OBJECTIVE: Delirium is a frequently encountered psychiatric disease in terminal cancer patients. However, the mechanism of delirium is unclear. The aim of our study was to investigate the relationship between administration of chemotherapy drugs that penetrate the blood-brain barrier (BBB) and the development of delirium in cancer patients. METHOD: We retrospectively analyzed 166 cancer patients (97 males, 69 females) continuously who died between September of 2007 and January of 2010 using a review of medical charts. Multiple logistic regression analysis was employed to investigate the effects of antineoplastic drugs penetrating the BBB on development of delirium in cancer patients with control for other risk factors. RESULTS: In multivariate analysis, antineoplastic drugs that penetrated the BBB were significantly associated with development of delirium (OR = 18.92, CI 95 = 1.08-333.04, p < 0.001). SIGNIFICANCE OF RESULTS: 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.

Early palliative intervention for patients with advanced cancer.

BACKGROUND: Early palliative intervention in advanced cancer patients with metastatic non-small-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 = 0.010) and 16.5 and 20.9 months (P = 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P = 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P = 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.

[The role of psychosomatic medicine doctors in palliative care medicine--two case reports].

Palliative care medicine deals with the issue of death by listening to the story of patient's lives. There are several problems such as stress overload or burnout due to the difficulty in responding to all demands from patients and the shortness of time. These problems sometimes make doctors specializing in palliative care have less interest in patients, negative feelings or an indifferent attitude to them. In this report, two cases in which a psychosomatic medical doctor intervened were analyzed. The satisfaction of patients and the stress overload of doctors engaged in palliative care were examined retrospectively by investigation of patients' charts. Both factors were improved by such interventions, thus underscoring the possible contributions by these doctors in cancer medicine. Psychosomatic medicine is based on a biopsychosocial model and related to both physical and psychosocial factors. There are many similar viewpoints between psychosomatic medicine and palliative care medicine. Psychosomatic medical doctors have an advantage in that they can contribute to palliative care without stress overload or burnout because of their special training in communication skills to deal with patients from the standpoints of both mind and body. However, these doctors have not received psychiatric training so as to be able to diagnose precisely and treat psychiatric problems such as adjustment disorders, depression and delirium. Therefore, their further training in psychiatry for several months or years is an issue to be addressed in future.

[Cancer pain management using opioid together with NSAIDs at Sakai Kinki University Hospital].

The basic cancer pain management at our hospitalis based on WHO Cancer Pain Treatment Method-Opioid together with NSAIDs. We investigated 48 patients who were administered an opioid as management of cancer pain for three (3) months from May to July in 2008. Consequently, we found that 20 out of the 48 patients (41.7%) used an opioid together with NSAIDs. Meanwhile, we also investigated constipation and digestive impediment as side effects caused from opioid and NSAIDs, respectively. Of the 20 patients, 12 patients (60%) used laxative for constipation, and 18 patients (90%) used a digestive ulcer treatment drug for digestive impediment. Ten (20.8%) of the 48 patients used all 4 drugs-opioid, NSAIDs, laxative and digestive ulcer treatment drugs. As a result, we decided to further examine cancer pain management at our hospital.

Additive Duloxetine for Cancer-Related Neuropathic Pain Nonresponsive or Intolerant to Opioid-Pregabalin Therapy: A Randomized Controlled Trial (JORTC-PAL08).

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]-Item 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 = 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 = 0.048). Clinically meaningful pain improvement (≥30%) was reported by 44.1% (n = 15) of patients in Group D vs. 18.2% (n = 6) in Group P (P = 0.02); 32.4% (n = 11) vs. 3.0% (n = 1) of patients in Groups D and P, respectively, reported pain reduction ≥ 50% (P = 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.

Factors Associated with Length of Stay at Home in the Final Month of Life among Advanced Cancer Patients: A Retrospective Chart Review.

BACKGROUND: Living at home is an important factor for maintaining high quality of life among patients. Many studies have discussed parameters associated with place of death, but no studies have yet clarified which factors influence the length of stay at home during the end of life. OBJECTIVE: The aim of this study was to identify factors influencing the amount of time spent at home during the final month of life among patients with advanced cancer. METHODS: A retrospective chart review was conducted for 415 patients with advanced cancer. Multivariate multiple linear regression analysis was used to examine relationships between the length of stay at home during the final month of life and variables measuring patient's background (four indicators), family structure (three indicators) cancer type (four types), chief complaint at initial palliative care referral (seven indicators), and medical interventions (three factors). RESULTS: The multiple linear regression predicting time spent at home in the last month of life yielded partial regression coefficients of 4.2 for past outpatient palliative care services (OPCS) (p < 0.001) and 3.3 for in-home nurse visits (p = 0.003). DISCUSSION: The most influential factor for length of stay at home in the final month of life was a history of OPCS. Many patients with advanced cancer who receive chemotherapy without OPCS spend time as inpatients after an initial period at home. Palliative care interventions for outpatients effectively enable patients with advanced cancer to adapt and continue living at home.

Incidence of carnitine deficiency in patients with cancer pain: A pilot study.

Carnitine deficiency is reportedly associated with increased pain sensation in diabetes mellitus and fibromyalgia, but the association between serum carnitine concentration and cancer pain has not been fully elucidated. We investigated the incidence of carnitine deficiency in patients with cancer pain, and examined the effect of the patients' demographic and clinical characteristics on pain intensity and carnitine deficiency. The serum carnitine concentration was measured in 50 patients with cancer pain receiving non-steroidal anti-inflammatory drugs, but not opioids. Multivariate regression analysis was used to determine the association of carnitine concentration, pain intensity, age and gender with hemoglobin and C-reactive protein (CRP) concentrations. Carnitine deficiency was detected in 9 of the patients (18.0%) and found to be significantly correlated with an elevated CRP concentration (P=0.039). In conclusion, although there does not appear to be an association between carnitine deficiency and cancer pain, it may be affected by inflammation or infection.

Pilot study of duloxetine for cancer patients with neuropathic pain non-responsive to pregabalin.

BACKGROUND: Neuropathic pain frequently occurs in cancer patients, but no drug therapy has been established for this type of disorder. The purpose of this study was to investigate the effect of duloxetine in cancer patients suffering from neuropathic pain. PATIENTS AND METHODS: The subjects of the study were 15 cancer patients with neuropathic pain who visited the Kinki University Faculty of Medicine Hospital and met the International Association for the Study of Pain diagnostic criteria for neuropathic pain. Duloxetine was administered to patients in whom pregabalin could not be administered. The influence of duloxetine was investigated retrospectively with the use of a numerical rating scale. RESULTS: Pain was reduced in 7 out of the 15 patients. Sleepiness and the light-headed feeling were improved in four patients, in whom, however, the pain was not reduced. Thus, duloxetine was judged to be effective in 11 patients. The maintenance dose of duloxetine was 20-40 mg/day. CONCLUSION: Duloxetine administration may be effective for neuropathic pain in cancer patients who cannot tolerate pregabalin administration.

Expression changes in arrestin ß 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients.

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 ß 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.

Prospective study evaluating the plasma concentrations of twenty-six cytokines and response to morphine treatment in cancer patients.

Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naïve cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GM-CSF), interferon α2 (IFN-α2), IFN-γ, interleukin 1α (IL-1α), IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1ß, tumor necrosis factor-α (TNF-α) and TNF-ß. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1α significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1α and MIP-1ß were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.