Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated.

CONTEXT: Cancer patients with dyspnea may be able to have the symptom pharmacologically controlled while its underlying cause is sought or treated. OBJECTIVES: This study was done to determine whether symptom control can be achieved while the cause is evaluated or treated and whether morphine or midazolam would be more suitable in this setting. METHODS: Sixty-three ambulatory patients with advanced cancer and dyspnea were clinically characterized and then randomized to receive either oral morphine or oral midazolam. A fast in-clinic drug titration scheme was implemented followed by an ambulatory five-day period in which the patients received the effective dose that relieved their dyspnea. During this period, the patients were followed daily while the underlying causes of dyspnea were sought out or treated. RESULTS: Thirty-one patients with dyspnea entered the morphine arm and 32 patients entered the midazolam one. During the initial in-clinic phase, dyspnea was alleviated by at least 50% in all patients, whether they received morphine or midazolam. During the ambulatory phase, midazolam was superior to morphine in controlling baseline and breakthrough dyspnea. Both treatments were well tolerated, with mild somnolence being the most common adverse event. Neither morphine nor midazolam affected the outcome and/or implementation of additional diagnostic and/or therapeutic interventions. CONCLUSION: Our results suggest that cancer-related dyspnea in ambulatory patients can be pharmacologically treated while its most probable specific cause is sought and/or while an etiology-oriented intervention is implemented. In this setting, midazolam appeared to be a better option than morphine for the immediate and long-term relief of the symptom.

Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer.

Under the common denomination of Systemic Immune-Metabolic Syndrome (SIMS), we grouped many symptoms that share a similar pathophysiologic background. SIMS is the result of the dysfunctional interaction of tumor cells, stroma cells, and the immune system, leading to the release of cytokines and other systemic mediators such as eicosanoids. SIMS includes systemic syndromes such as paraneoplastic hemopathies, hypercalcemia, coagulopathies, fatigue, weakness, cachexia, chronic nausea, anorexia, and early satiety among others. Eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil can help in the management of persistent chronic inflammatory states, but treatment's compliance is generally poor. Preferentially, Cox-2 inhibition can create a favorable pattern of cytokines by decreasing the production of certain eicosanoids, although their role in SIMS is unknown. The aim of this study was to test the hypothesis that by modulating systemic inflammation through an eicosanoid-targeted approach, some of the symptoms of the SIMS could be controlled. We exclusively evaluated 12 patients for compliance. Patients were assigned 1 of the 4 treatment groups (15-, 12-, 9-, or 6-g dose, fractionated every 8 h). For patients assigned to 15 and 12 doses, the overall compliance was very poor and unsatisfactory for patients receiving the 9-g dose. The maximum tolerable dose was calculated to be around 2 capsules tid (6 g of fish oil per day). A second cohort of 22 patients with advanced lung cancer and SIMS were randomly assigned to receive either fish oil, 2 g tid, plus placebo capsules bid (n = 12) or fish oil, 2 g tid, plus celecoxib 200 mg bid (n = 10). All patients in both groups received oral food supplementation. After 6 wk of treatment, patients receiving fish oil + placebo or fish oil + celecoxib showed significantly more appetite, less fatigue, and lower C-reactive protein (C-RP) values than their respective baselines values (P < 0.02 for all the comparisons). Additionally, patients in the fish oil + celecoxib group also improved their body weight and muscle strength compared to baseline values (P < 0.02 for all the comparisons). Comparing both groups, patients receiving fish oil + celecoxib showed significantly lower C-RP levels (P = 0.005, t-test), higher muscle strength (P = 0.002, t-test) and body weight (P = 0.05, t-test) than patients receiving fish oil + placebo. The addition of celecoxib improved the control of the acute phase protein response, total body weight, and muscle strength. Additionally, the consistent nutritional support used in our patients could have helped to maximize the pharmacological effects of fish oil and/or celecoxib. This study shows that by modulating the eicosanoid metabolism using a combination of n-3 fatty acids and cyclooxygenase-2 inhibitor, some of the signs and symptoms associated with a SIMS could be ameliorated.

Double-blinded, placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer.

PURPOSE: We performed this double-blinded, placebo-controlled study to determine the safety and efficacy of L-alanyl-L-glutamine in the prevention of mucositis in patients with head-and-neck cancer. METHODS AND MATERIALS: Thirty-two patients with head-and-neck cancer were treated with chemoradiotherapy (CRT) (radiotherapy daily up to 70 Gy plus cisplatin/5-fluoruracil once a week) and were asked to participate. Twenty-nine patients received the CRT schedule and were double-blindly assigned to receive either intravenous L-alanyl-L-glutamine 0.4 g/kg weight/day or an equal volume of saline (placebo) during chemotherapy days. RESULTS: Fourteen patients received L-alanyl-L-glutamine and 15 received placebo. Mucositis was assessed by the Objective Mucositis Score (OMS) and the World Health Organization (WHO) grading system. There was a significant difference in incidence of mucositis developed in patients receiving placebo compared with those who received L-alanyl-L-glutamine (p = 0.035). The number of patients with severe objective mucositis (OMS >1.49) was higher in the placebo group compared with the L-alanyl-L-glutamine group (67% vs. 14%, p = 0.007). L-alanyl-L-glutamine patients experienced less pain (three highest Numeric Rating Scale scores of 1.3/10 vs. 6.3/10 respectively, p = 0.008) and need for feeding tubes (14% vs. 60% respectively, p = 0.020) compared with placebo patients. No adverse effects related to the drug or the infusions were noted in either group. CONCLUSION: For patients with head-and-neck cancer receiving CRT, intravenous L-alanyl-L-glutamine may be an effective preventive measure to decrease the severity of mucositis.

Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer.

The mainstay of dyspnea palliation remains altering its central perception. Morphine is the main drug and anxiolytics have a less established role. This trial assessed the role of midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in terminally ill cancer patients. One hundred and one patients with severe dyspnea were randomized to receive around-the-clock morphine (2.5 mg every 4 hours for opioid-naïve patients or a 25% increment over the daily dose for those receiving baseline opioids) with midazolam rescue doses (5 mg) in case of breakthrough dyspnea (BD) (Group Mo); around-the-clock midazolam (5 mg every 4 hours) with morphine rescues (2.5 mg) in case of BD (Group Mi); or around-the-clock morphine (2.5 mg every 4 hours for opioid-naïve patients or a 25% increment over the daily dose for those receiving baseline opioids) plus midazolam (5 mg every 4 hours) with morphine rescue doses (2.5 mg) in case of BD (Group MM). All drugs were given subcutaneously in a single-blinded way. Thirty-five patients were entered in Group Mo, 33 entered in Mi, and 33 entered in MM. At 24 hours, patients who experienced dyspnea relief were 69%, 46%, and 92% in the Mo, Mi, and MM groups, respectively (P = 0.0004 and P = 0.03 for MM vs. Mi and MM vs. Mo, respectively). At 48 hours, those with no dyspnea relief (no controlled dyspnea) were 12.5%, 26%, and 4% for the Mo, Mi, and MM groups, respectively (P = 0.04 for MM vs. Mi). During the first day, patients with BD for the groups Mo, Mi, and MM were 34.3%, 36.4%, and 21.2%, respectively (P = NS or not significant), whereas during the second day, these percentages were 38%, 38.5%, and 24%, respectively (P = NS). The data demonstrate that the beneficial effects of morphine in controlling baseline levels of dyspnea could be improved with the addition of midazolam to the treatment.

Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as a radiation sensitizer in patients with unresectable brain metastases.

PURPOSE: The primary goal of this phase I/II study was to evaluate the feasibility, safety and efficacy of celecoxib administered concomitant to radiotherapy to treat unresectable BM. PATIENTS AND METHODS: Patients with measurable BM by CT or MRI, unresectability criteria by a neurosurgeon and RPA-RTOG class II were eligible. Celecoxib was administered at 400 mg/day during the entire course of radiotherapy. All patients were irradiated with 60Co beams to whole-brain dose of 32 Gy (20 fractions of 1.6 Gy each two times a day with a 6 h interval between treatments) followed by a 22.4 Gy boost (same fractionation schedule) over evident lesions. RESULTS: Twenty-seven patients were treated. The concurrent regimen was well tolerated with 15 cases of mild dyspepsia. Alopecia (NCI grades 1-2) was the most important side effect. Three patients presented rash/desquamation of moderate intensity. Radiological responses occurred in 18 of 25 valuable patients (72), with five complete responses (CR). Symptomatic responses were reported in 25 of 27 patients (92.6), with 20 CR. The overall response rate (considering complete plus partial responses) was 66.7. Percentile 50 for time-to-progression, time-to-neurological-progression and functional-independence-time were 3, 6.25 and 6.7 months, respectively. Median survival time was 8.7 months. CONCLUSION: Our initial results suggest that radiotherapy plus celecoxib is safe and a possible active treatment for patients with BM. Further investigation in a randomized trial is warranted to validate its clinical utility.

Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study.

Systemic syndromes characterized by a persistent activity of circulating mediators (cytokines) are frequently present with advanced cancer. We grouped under the general heading of "Systemic Immune-Metabolic Syndrome (SIMS)" a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis, with overlapping clinical manifestations. SIMS may include cachexia, anorexia, nausea, early satiety, fatigue, tumor fever, cognitive changes and superinfection. The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy. Fifteen patients with evidence of SIMS were studied. SIMS was defined as the presence of weight loss, anorexia, fatigue performance status>/=2 and acute-phase protein response. Patients received medroxyprogesterone (MPA) (500 mg twice daily), celecoxib (200 mg twice daily), plus oral food supplementation for 6 weeks. After treatment, 13 patients either had stable weight (+/- 1%) or had gained weight. There were significant differences in improvement of body-weight-change rate, nausea, early satiety, fatigue, appetite and performance status. Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients (P=0.039). Our results suggest that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and dietary intervention, might have considerable improvement in certain SIMS outcomes. This multitargeted symptomatic approach deserves further study.

Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study.

To determine the potential clinical utility of peripheral opioid action using a clinical model of cancer treatment-induced inflammation and pain that allowed for topical application of morphine in the damaged tissue (oral mucosa). This pilot study followed a two blocks design. Ten patients with painful oral mucositis were enrolled in the first block (dose-response relationship finding) and randomized in two groups to receive oral rinses with 15 ml of either 1 per thousand or 2 per thousand morphine solution. Twenty-two patients were enrolled into the second block (efficacy and safety determination). Additionally, serum concentrations of morphine were measured in five representative patients. In the first block (n=10) a dose-response relationship for topical morphine was found. Rinses with 2 per thousand -morphine solution showed better pain relief (median 80%, range 70-80%) than those with 1 per thousand (median 60%, range 55-70%; P=0.0238). Therefore, subsequent patients enrolled for the second block (n=22) received oral rinses with 2 per thousand -morphine solution. In these patients the time to good (>or=50%) or to complete (100%) pain relief was 28 (+/-12)min after the first mouthwash, and the duration of relief was on average 216 (+/-25)min. Twenty patients (90%) received the successive mouthwashes every 3 h and 10% of them every 2 h. The duration of severe pain at the moment of swallowing was 5.17 (+/-1.47) days. Only six patients needed supplementary analgesia, and the time elapsed before the first supplemental analgesic was 1.18 (+/-0.8) days. The duration of severe functional impairment was 1.52 (+/-1.31) days, thus allowing us to feed the patient by mouth with liquid-food supplementation. During our experiment no systemically active detectable concentrations of morphine were found (GC-MS analysis). The most important side effect attributable to morphine mouthwashes was burning/itching sensation (very mild to mild intensity). Patients with painful chemoradiotherapy-induced stomatitis could be alleviated using topical morphine mouthwashes.

Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma.

BACKGROUND: Oral mucositis is the dose-limiting toxicity for patients receiving concurrent chemoradiotherapy regimens for tumors of the head and neck area. Currently, the management of established mucositis includes the use of topical anesthetics and systemic analgesics. Based on the clinical evidence of pain alleviation by topical morphine in patients with some inflammatory and painful conditions, a clinical study was undertaken to determine this effect on mucositis-associated pain. METHODS: Twenty-six patients with head and neck malignancies treated with concomitant chemoradiotherapy for head and neck carcinoma who had severe painful mucositis (World Health Organization Grade 2 or higher) were enrolled. Patients were randomly assigned to morphine mouthwash (MO; 14 patients) or magic mouthwash (MG), a mixture of equal parts of lidocaine, diphenhydramine, and magnesium aluminum hydroxide (12 patients). RESULTS: The duration of severe pain was 3.5 days less in the MO group compared with the MG group (P = 0.032). The intensity of oral pain was also significantly lower in the MO group compared with the MG group (P = 0.038). No patient in the MO group required third-step opiates for alleviation of the mouth pain. There was a significant difference in duration of severe functional impairment (P = 0.017). Five patients in the MG group complained of local side effects and only one in the MO group (P = 0.007). CONCLUSIONS: For patients with head and neck carcinomas receiving concomitant chemoradiotherapy, MO is a simple and effective treatment to decrease the severity and duration of pain and the duration of functional impairment.