Ørnulf Paulsen

Efficacy of Methylprednisolone on Pain, Fatigue, and Appetite Loss in Patients With Advanced Cancer Using Opioids: A Randomized, Placebo-Controlled, Double-Blind Trial

PURPOSE Corticosteroids are frequently used in cancer pain management despite limited evidence. This study compares the analgesic efficacy of corticosteroid therapy with placebo. PATIENTS AND METHODS Adult patients with cancer receiving opioids with average pain intensity ≥ 4 (numeric rating scale [NRS], 0 to 10) in the last 24 hours were eligible. Patients were randomly assigned to methylprednisolone (MP) 16 mg twice daily or placebo (PL) for 7 days. Primary outcome was average pain intensity measured at day 7 (NRS, 0 to 10); secondary outcomes were analgesic consumption (oral morphine equivalents), fatigue and appetite loss (European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire C30, 0 to 100), and patient satisfaction (NRS, 0 to 10). RESULTS A total of 592 patients were screened; 50 were randomly assigned, and 47 were analyzed. Baseline opioid level was 269.9 mg in the MP arm and 160.4 mg in the PL arm. At day-7 evaluation, there was no difference between the groups in pain intensity (MP, 3.60 v PL, 3.68; P = .88) or relative analgesic consumption (MP, 1.19 v PL, 1.20; P = .95). Clinically and statistically significant improvements were found in fatigue (-17 v 3 points; P .003), appetite loss (-24 v 2 points; P = .003), and patient satisfaction (5.4 v 2.0 points; P = .001) in favor of the MP compared with the PL group, respectively. There were no differences in adverse effects between the groups. CONCLUSION MP 32 mg daily did not provide additional analgesia in patients with cancer receiving opioids, but it improved fatigue, appetite loss, and patient satisfaction. Clinical benefit beyond a short-term effect must be examined in a future study.

How to switch from morphine or oxycodone to methadone in cancer patients? a randomised clinical phase II trial.

AIM Opioid switching is a treatment strategy in cancer patients with unacceptable pain and/or adverse effects (AEs). We investigated whether patients switched to methadone by the stop and go (SAG) strategy have lower pain intensity (PI) than the patients switched over three days (3DS), and whether the SAG strategy is as safe as the 3DS strategy. METHODS In this prospective, open, parallel-group, multicentre study, 42 cancer patients on morphine or oxycodone were randomised to the SAG or 3DS switching-strategy to methadone. The methadone dose was calculated using a dose-dependent ratio. PI, AEs and serious adverse events (SAEs) were recorded daily for 14 days. Primary outcome was average PI day 3. Secondary outcomes were PI now and AEs day 3 and 14 and number of SAEs. RESULTS Twenty one patients were randomised to each group, 16 (SAG) and 19 (3DS) patients received methadone. The mean preswitch morphine doses were 900 mg/day in SAG and 1330 mg/day in 3DS. No differences between groups were found in mean average PI day 3 (mean difference 0.5 (CI -1.2-2.2); SAG 4.1 (CI 2.3-5.9) and 3DS 3.6 (CI 2.9-4.3) or in PI now. The SAG group had more dropouts and three SAEs (two deaths and one severe sedation). No SAEs were observed in the 3DS group. CONCLUSION The SAG patients reported a trend of more pain, had significantly more dropouts and three SAEs, which indicate that the SAG strategy should not replace the 3DS when switching from high doses of morphine or oxycodone to methadone.

Polypharmacy in Patients With Advanced Cancer and Pain: A European Cross-Sectional Study of 2282 Patients

CONTEXT Patients with advanced cancer need multiple drugs to control symptoms and to treat cancer and concomitant diseases. At the same time, the goal of treatment changes as life expectancy becomes limited. This results in a risk for polypharmacy, maintained use of unneeded drugs, and drug-drug interactions (DDIs). OBJECTIVES The aim of the study was to analyze the use of medications and to identify unneeded drugs, and drugs and drug combinations with a risk for DDIs in a cohort of advanced cancer pain patients, defined by a need for a World Health Organization analgesic ladder Step III opioid. METHODS All drugs taken within a study day by cancer patients receiving opioids for moderate or severe pain (Step III opioids) were analyzed. Nonopioids and adjuvants were analyzed for their use across countries. Unneeded medications and drugs and drug combinations with a risk for pharmacodynamic and pharmacokinetic DDIs were identified on the basis of published literature and electronic resources. RESULTS In total, 2282 patients from 17 centers in 11 European countries were included. They received a mean of 7.8 drugs (range 1-20). Over one-quarter used 10 or more medications. The drugs and drug classes most frequently coadministered with opioids were proton pump inhibitors, laxatives, corticosteroids, paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, metoclopramide, benzodiazepines, anticoagulants, antibiotics, anticonvulsants, diuretics, and antidepressants. The use of nonopioids and essential adjuvants varied across countries. Approximately 45% of patients received unnecessary or potentially unnecessary drugs, and about 7% were given duplicate or antagonizing agents. Exposures to DDIs were frequent and increased the risk of sedation, gastric ulcerations, bleedings, and neuropsychiatric and cardiac complications. Many patients were exposed to pharmacokinetic DDIs involving cytochrome P450, including about 58% who used a Step III opioid CYP3A4 (izoenzyme of cytochrome P450) substrate, and more than 10% who were given major CYP3A4 inhibitors or inducers. CONCLUSION Patients with cancer treated with a World Health Organization Step III opioid use a high number of drugs. Nonopioid analgesics and corticosteroids are frequently used, but different patterns of use between countries were found. Many patients receive unneeded drugs and are at risk of serious DDIs. These findings demonstrate that drug therapy in these patients needs to be evaluated continuously.

Computer-Based Assessment of Symptoms and Mobility in Palliative Care: Feasibility and Challenges

The aims of the study were to explore the ability of cancer patients who are primarily receiving palliative care to use a touchscreen computer for assessment of symptoms and mobility and to investigate which factors predicted the need for assistance during the assessment. Before the main data collection, a pilot study was conducted to explore the preferences of these patients toward using such a computerized assessment tool. Patients were recruited from nine different inpatient and outpatient palliative care and general cancer clinics in Norway. The patients responded to 60 items on symptoms and mobility directly on the computer. In the pilot study (n=20), 11 patients (55.0%) preferred computerized assessment over paper and pencil, whereas five (25.0%) had no preference. In the main data collection, 370 patients (52.7% men with mean age 62 years and mean Karnofsky Performance Status score of 70) completed the assessment. Eighty-six patients (23.2%) required assistance. Patients requiring assistance were significantly older, had worse performance status, and poorer cognitive function than those not requiring assistance. Predictors for requiring assistance were age (P<0.001) and performance status (P<0.001). Because higher age and worse performance status resulted in more need of assistance, assessment tools should be short and user-friendly to ensure good compliance in frail patients.

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

PurposeOur aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days.MethodsForty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent CSS on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3.ResultsThirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350–2000) mg/day in the SAG group and 800 (range 90–3600) mg/day in the 3DS group (p = 0.43);42% reached CSS for methadone in the SAG group on day 4 compared with 22% in the 3DS group (p = 0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p = 0.032). One SAG patient suffered from respiratory depression on day 5.ConclusionThe SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy.

The relationship between pro-inflammatory cytokines and pain, appetite and fatigue in patients with advanced cancer

Background Systemic inflammation is associated with reduced quality of life and increased symptoms in patients with advanced cancer. The aims of this study were to examine the relationships between inflammatory biomarkers and the Patient Reported Outcome Measures (PROMs) of pain, appetite and fatigue; and to explore whether levels of baseline biomarkers were associated with changes in these PROMs following treatment with corticosteroids. Material and methods An exploratory analysis was done on a trial examining the analgesic properties of corticosteroids in patients with advanced cancer. Inclusion criteria were: >18 years, taking opioids for moderate or severe cancer pain; pain ≥4 (numerical rating scale 0–10). Serum was extracted and levels of inflammatory biomarkers were assessed. PROMs of pain, appetite and fatigue were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30). The relationships between PROMs and inflammatory biomarkers were examined using Spearman Rho-Rank and multiple regression analysis. Results Data were available on 49 patients. Levels of sTNF-r1, IL-6, IL-18, MIF, MCP-1, TGF-β1, IL-1ra, and C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) were elevated; IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12(p70), interferon-γ, MIP-1α, and TNF-α were below the level of detection. The following correlations were observed: appetite and IL-6 and CRP; fatigue and IL-1ra (rs: 0.38–0.41, p< .01). There was no association between pretreatment biomarkers and effect from corticosteroid treatment. Conclusion In patients with advanced cancer and pain, some pro-inflammatory cytokines were related to appetite and fatigue. Inflammatory biomarkers were not associated with pain or with the efficacy of corticosteroid therapy. Further research examining the attenuation of the systemic inflammatory response and possible effects on symptoms would be of interest.

Reply to A. Molfino et al

We thank Molfino et al for their thoughtful comments regarding our article. Anorexia is a burdensome symptom for patients with cancer, and is significantly associated with survival. Anorexia is associated with systemic inflammatory response in cancer. Therefore, loss of appetite was chosen as a secondary outcome in our trial assessing the effects of methylprednisolone for cancer pain. Our trial showed a significant improvement of appetite loss, which coincides with the findings of Yennurajalingam et al. They also found a significant improvement in anorexia using the Functional Assessment of Anorexia/Cachexia Therapy subscale of 4.89 points on day 15 (P .013) in favor of the dexamethasone group as compared with the placebo group. As Molfino et al correctly point out, appetite is only one part of the symptom complex causing anorexia and reduced food intake. In addition to appetite, changes in taste and GI motility are important, together with secondary factors caused by the disease itself or the treatment, such as stomatitis, diarrhea, and constipation. Furthermore, food intake is an important item to measure separately, as it shows only a weak association with loss of appetite. Consequently, it is recommended to assess all these symptoms as well as food intake in cancer cachexia trials. Different assessment tools have been proposed to assess the anorexia symptom, including the Functional Assessment of Anorexia/ Cachexia Therapy, which rates the intensity of anorexia and cachexia and the related symptoms on a verbal rating scale 0 to 4. The abridged Patient-Generated Subjective Global Assessment assesses the symptoms on a yes or no basis together with nutritional and functional levels. Finally, loss of appetite can be quantitatively evaluated by a numeric rating scale like the Edmonton Symptom Assessment System, and the European Association for Palliative Care minimum data set, or health-related quality-of-life tools like the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). Loss of appetite can be measured by the EORTC QLQ-C30 in a reliable way. Indeed, the EORTC group is currently developing a lack of appetite item bank for computer-adaptive testing as a further development of this single item. Due to the risk of adverse effects in prolonged use, it is generally agreed that corticosteroids should be used to treat anorexia in the end-of-life setting. In patients with short life expectancy, the primary foci are symptom control and quality of life. Therefore, patientreported outcomes are recommended at this stage of disease, and only a minor improvement in appetite may be important to the patients. The risk of adverse effects from the use of high-dose corticosteroids is substantial. This needs to be assessed and may counterbalance the positive effects on appetite. Ornulf Paulsen Telemark Hospital Trust, Skien; Norwegian University of Science and Technology, Trondheim, Norway