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We investigated associations between the number of pain sites (NPS) and role conflict with medically certified, pain-related sickness absence (SA) in employees of Norwegian enterprises (N = 5,654). Latent profile analyses identified exposure profiles based on 3 types of role conflict (work-role conflict, work-life conflict, and emotional dissonance). Multinomial logistic regressions estimated effects on absence (short-term absence of less than 56 days, long-term absence of more than 56 days) during 1 year after survey. Effects of the NPS on absence were compared across exposure profiles. Results suggested the NPS and all types of role conflict predicted absences separately. Mutually adjusted regressions revealed unique contributions of the NPS to the short-term and long-term absence (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.18, 1.30 and OR 1.51, 95% CI 1.37, 1.66) and of work-role conflict to the short-term absence (OR 1.18, 95% CI 1.03, 1.35). Latent profile analyses identified 4 exposure profiles ("1 unconflicted," "2 dissonant, otherwise medium," "3 conflicted, medium dissonance," "4 conflicted and dissonant"). Profiles 3 and 4 exhibited elevated risk of SA, with the strongest baseline-adjusted effects for profile 4 (short-term absence OR 1.90, 95% CI 1.40, 2.57, long-term absence OR 1.95, 95% CI 1.15, 3.31). Effects of the NPS on short-term absence were stronger for profile 4 versus profile 1 (OR 1.38 vs 1.24, P < .001). Our findings suggest that addressing role conflicts may prevent pain-related absence, possibly also for individuals already experiencing pain. PERSPECTIVE: This article elucidates the connections between role conflicts associated with work roles, the NPS, and SA due to pain. This should help organizations prevent pain-related absences from work and improve working conditions for workers who remain occupationally active in spite of pain problems., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Patients´ own perceptions and evaluations of symptoms, functioning and other health-related factors, i.e. Patient Reported Outcomes (PROs), are important elements for providing good patient care. Symptoms are subjective and best elicited by the patient orally or by using PRO measures (PROMs), be it on paper, or as electronic assessment tools. Reference values on frequently used PROMs facilitate the interpretation of scores for use in clinics and research settings, by comparing patient data with relevant samples from the general population. Study objectives were to (1) present reference values for the M.D. Anderson Symptom Inventory (MDASI) (2) examine the occurrence and intensity of symptoms assessed by the MDASI in a general Norwegian adult population sample, and (3) examine factors associated with higher symptom burden defined as the sum score of all symptoms, and factors associated with symptoms` interference on functions., Methods: In 2015, MDASI was sent by mail as part of a larger survey, to a representative sample of the general Norwegian adult population (N = 6165). Medical comorbidities were assessed by the Self-Administered Comorbidity Questionnaire. Depression was self-reported on the Patient Health Questionnaire 9 (PHQ-9). Linear multivariable regression analysis was used to examine for factors associated with MDASI sum score and factors associated with symptoms' interference on functions., Results: The response rate was 36%. More women (54%) than men (46%) responded. Mean age was 55 years (SD 14). The most frequent symptoms were fatigue (59.7%), drowsiness (56.2%) and pain (56.1%). Fatigue, pain and disturbed sleep had the highest mean scores. The presence of one or more comorbidities, increasing PHQ-9 score and lower level of education were associated with higher MDASI sum score (p < 0.001). The MDASI sum score and the PHQ-9 score were positively associated with all interference items (p < 0.001) except for walking (p = 0.22)., Conclusion: This study provides the first Norwegian reference values for MDASI. The presence of one or more comorbidities, higher level of depressive symptoms and lower level of education were significantly associated with higher MDASI sum score. These covariates must be controlled for when using the reference values.

Background: The increased pain sensitivity following reduced sleep may be related to changes in cortical processing of nociceptive stimuli. Expectations shape pain perception and can inhibit (placebo) or enhance (nocebo) pain. Sleep restriction appears to enhance placebo responses; however, whether sleep restriction also affects nocebo responses remains unknown. The aim of the present study was to determine whether sleep restriction facilitates nocebo-induced changes in pain and pain-evoked cortical potentials., Methods: In an experimental study with a crossover design, the sensitivity to electrically induced pain was determined in 53 nurses under two sleep conditions, after habitual sleep and after two consecutive nights at work. Nocebo was induced by conditioning one-third of the pain stimuli. Pain-elicited cortical event-related potentials were recorded by electroencephalography (EEG). Data were analysed both in the time domain (N2P2 amplitude) and in the time-frequency domain (ERP magnitude). Sleepiness and vigilance were also assessed., Results: Both nocebo alone and sleep restriction alone increased the sensitivity to electrically induced pain. However, no interaction effect was found. Moreover, the magnitude of the pain-elicited responses increased after sleep restriction and decreased after nocebo expectation, suggesting that nocebo is probably not an underlying mechanism for the commonly observed hyperalgesia induced by sleep restriction., Conclusions: The present work addresses whether sleep restriction, known to increase the sensitivity of the pain system, facilitates nocebo-induced hyperalgesia. Our findings suggest that this is not the case, indicating that the increased sensitivity of the pain system following nocebo and sleep restriction are mediated by different cortical mechanisms., (© 2019 European Pain Federation - EFIC®.)

Objectives: The aim of this study was to investigate the association between different working shifts (i.e. morning, evening, night shifts) and headache, musculoskeletal and abdominal pain, and the extent to which reduced sleep duration could account for these associations., Methods: Nurses (N = 679, 649 female, aged 22-53 years) were followed up for a period of 28 consecutive days, responding to a diary about sleep, shift type and pain complaints (measured on a Likert-type scale ranging from 0 to 3). Generalised structural equation modelling mediation analysis (GSEM) was performed to test whether shift type was associated with higher incidence or higher intensity of pain (headache, pain in neck/shoulders/upper back, upper extremity, low back, lower extremity and abdominal pain), and if this effect was mediated by sleep duration (continuous variable), after controlling for age, work and lifestyle factors., Results: Pain scores in lower extremities were decreased following night shifts in general. However, when night shifts were followed by short sleep duration, the risk of pain in the lower extremities and abdominal pain were increased. Headache and pain in the upper extremity were increased after night shifts, but were not associated with sleep duration. Pain in the neck/shoulder/upper back and lower back was not related to shift work., Conclusions: Among nurses in a three-shift rotating schedule, night shifts increased the risk of pain in several regions, but only pain in the lower extremities and abdomen was related to reduced sleep duration.

Objective Despite the multifactoriality of work and health, studies of psychosocial work factors with pain are typically limited to a few factors. This study examined a wide range of factors to determine (i) typical combinations of work factor levels ("work situations") and (ii) whether "work situations" predicted pain complaints of six anatomic regions. Methods Questionnaires were distributed to 6175 employees twice over a two-year period. Latent profile analysis was conducted to group employees into profiles of work factor levels. Twelve work factors were measured, reflecting six themes: demands, control, role expectations, leadership, predictability, and organizational climate. Logistic and Poisson regressions compared the groups' risk of pain of the neck, head, back, shoulders, legs and arms, as well as multi-site pain (>1 pain site). Results Four latent profiles emerged based on relative levels of work factors. Profile 1 reflected relatively "desirable" levels of all factors, demonstrating the lowest risk of pain. Profile 2 exhibited the highest, and profile 3 the lowest levels of both demands and control with similar risks of pain, suggesting high levels of control were insufficient to buffer the impact of the combination of the other factors. Profile 4 exhibited "undesirable" levels of all factors and the highest risk, most notably for multi-site pain [odds ratio (OR) 2.32, 95% confidence intervals (CI) 1.80-2.85 compared with profile 1]. Conclusions Different compositions of psychosocial exposures were differentially related to pain. Future studies should take the complexity of work into account by studying comprehensive arrays of co-occurring work factors with health.

Purpose: The purpose of this study was to examine attitudinal barriers to cancer pain management and their relationship to pain, analgesic use, clinical, and demographic variables, as well as QOL, in a large sample of patients receiving strong opioids for pain in three European countries., Methods: Participants in the present study were 555 patients with cancer, 18 years and older recruited from six centers in Germany, Iceland, and Norway. All had received strong opioids for at least 72 h. Data was collected with the Barriers Questionnaire-II, the Brief Pain Inventory, and the European Organization for Research and Treatment of Cancer QLQ-C30., Results: The mean (SD) age of patients was 61.68 (12.35) years and 53% were men. Most common diagnoses were gastrointestinal, lung, prostate, and breast cancer. The mean (SD) time from diagnosis was 32.24 (44.55) and 4.97 (9.64) months from start of opioid therapy. Mean (SD) pain severity was 3.19 (1.93) on a 0 to 10 scale, and 46.5% reported worst pain of 7 or higher. Attitudinal barriers had a mean (SD) of 1.95 (0.82) on a 0-5 scale, with fear of addiction as the strongest barrier across countries 2.85 (1.49). Barrier scores increased with age, and were higher among men than women. Higher barrier scores were associated with higher pain severity and interference, and lower performance status, but not with global health-QOL. Patients who had been on opioids for a shorter time reported higher barriers., Conclusions: Attitudinal barriers are frequent in cancer pain patients on opioids and are associated with less effective pain control.

Background and Aims: The prevalence of pain in cancer patients are relatively high and indicate inadequate pain management strategies. Therefore, it is necessary to develop new methods and to improve implementation of guidelines to assess and treat pain. The vast improvement in information technology facilitated development of a computerized symptom assessment and decision support system (CCDS) - the Combat system - which was implemented in an outpatient cancer clinic to evaluate improvement in pain management., Methods: We conducted a controlled before-and-after study between patient cohorts in two consecutive study periods: before (n=80) and after (n=134) implementation of the Combat system. Patients in the first cohort completed questionnaires with the paper-and-pencil method and this data was not shown to physicians. Patients in the latter cohort completed an electronic questionnaire by using an iPad and the data were automatically transferred and presented to physicians at point of care. Additionally, the system provided computerized decision support at point of care for the physician based on the electronic questionnaires completed by the patients, an electronic CRF completed by physicians and clinical guidelines., Results: The Combat system did not improve pain intensity and there were no significant alterations in the prescribed dose of opiates compared to the cohort of patients managed without the Combat system., Conclusion: The Combat system did not improve pain management. This may be explained by several factors, however, we consider lack of proper implementation of the CCDS in the clinic to be the most important factor. As a result, we did not manage to change the behaviour of the physicians in the clinic., Implications: There is a need to conduct larger prospective studies to evaluate the efficacy of modern information technology to improve pain management in cancer patients. Before introducing new information technology in the clinics, it is important to have a well thought out implementation strategy. The trial is registered at Clinialtrials.gov, number NCT01795157., (Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

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.

Purpose: To determine the impact of the healthy worker effect (HWE) as a bias for the external and internal validity of the follow-up assessment in prospective survey research. Specifically, the study examined (1) whether the health status of respondents at the baseline measurement influenced response at the follow-up survey (external validity) and (2) whether HWE is a threat to internal validity by differential attrition, i.e., whether associations between work and health at baseline differ between stayers and dropouts., Methods: In a two-wave questionnaire survey with a 2-year time lag comprising 6283 persons, 4392 responded at both time points (response rate 70%). Mental distress and somatic symptoms served as indicators of health. Role conflict and role clarity were indicators of work factors., Results: There were few differences in response rate at follow-up between persons with and without health complaints at the baseline measurement. As response rate increased incrementally with educational level, there seems to be a socio-educational bias, rather than a HWE bias on survey participation. Baseline relationships between work factors and health indicators were equal in magnitude among stayers and dropouts., Conclusion: The health status of participants at baseline seems to have little impact on the external and internal validity of the follow-up assessment in prospective survey research. Hence, the findings provide little support to the HWE as a potential bias in prospective studies within occupational health research. A limitation of the study is that the findings do not inform about the impact of the HWE on participation in the baseline assessment.

Purpose: Patient-reported outcomes should ideally be adapted to the individual patient while maintaining comparability of scores across patients. This is achievable using computerized adaptive testing (CAT). The aim here was to develop an item bank for CAT measurement of the pain domain as measured by the EORTC QLQ-C30 questionnaire., Methods: The development process consisted of four steps: (1) literature search, (2) formulation of new items and expert evaluations, (3) pretesting and (4) field-testing and psychometric analyses for the final selection of items., Results: In step 1, we identified 337 pain items from the literature. Twenty-nine new items fitting the QLQ-C30 item style were formulated in step 2 that were reduced to 26 items by expert evaluations. Based on interviews with 31 patients from Denmark, France and the UK, the list was further reduced to 21 items in step 3. In phase 4, responses were obtained from 1103 cancer patients from five countries. Psychometric evaluations showed that 16 items could be retained in a unidimensional item bank. Evaluations indicated that use of the CAT measure may reduce sample size requirements with 15-25% compared to using the QLQ-C30 pain scale., Conclusions: We have established an item bank of 16 items suitable for CAT measurement of pain. While being backward compatible with the QLQ-C30, the new item bank will significantly improve measurement precision of pain. We recommend initiating CAT measurement by screening for pain using the two original QLQ-C30 pain items. The EORTC pain CAT is currently available for "experimental" purposes.

Study Objectives: Sleep restriction (SR) has been hypothesized to sensitize the pain system. The current study determined whether experimental sleep restriction had an effect on experimentally induced pain and pain-elicited electroencephalographic (EEG) responses., Design: A paired crossover study., Intervention: Pain testing was performed after 2 nights of 50% SR and after 2 nights with habitual sleep (HS)., Setting: Laboratory experiment at research center., Participants: Self-reported healthy volunteers (n = 21, age range: 18-31 y)., Measurements and Results: Brief high-density electrical stimuli to the forearm skin produced pinprick-like pain. Subjective pain ratings increased after SR, but only in response to the highest stimulus intensity (P = 0.018). SR increased the magnitude of the pain-elicited EEG response analyzed in the time-frequency domain (P = 0.021). Habituation across blocks did not differ between HS and SR. Event-related desynchronization (ERD) was reduced after SR (P = 0.039). Pressure pain threshold of the trapezius muscle region also decreased after SR (P = 0.017)., Conclusion: Sleep restriction (SR) increased the sensitivity to pressure pain and to electrically induced pain of moderate, but not low, intensity. The increased electrical pain could not be explained by a difference in habituation. Increased response magnitude is possibly related to reduced processing within the somatosensory cortex after partial SR., (© 2015 Associated Professional Sleep Societies, LLC.)

Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain 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., (Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

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., (© 2014 by American Society of Clinical Oncology.)

Background and Purpose: An objective measure of pain relief may add important information to patients' self assessment, particularly after a treatment. The study aims were to determine whether measures of physical activity and/or gait can be used in characterizing cancer-induced bone pain (CIBP) and whether these biomarkers are sensitive to treatment response, in patients receiving radiotherapy (XRT) for CIBP., Materials and Methods: Patients were assessed before (baseline) and 6-8weeks after XRT (follow up). The following assessments were done: Brief Pain Inventory (BPI), activPAL™ activity meter, and GAITRite® electronic walkway (measure of gait). Wilcoxon, Mann-Whitney and Pearson statistical analyses were done., Results: Sixty patients were assessed at baseline; median worst pain was 7 and walking interference was 5. At follow up 42 patients were assessed. BPI worst pain, average pain, walking interference and total functional interference all improved (p<0.001). An improvement in functional interference correlated with aspects of physical activity (daily hours standing r=0.469, p=0.002) and gait (cadence r=0.341, p=0.03). The activPAL and GAITRite parameters did not change following XRT (p>0.05). In responder analyses there were no differences in activPAL and GAITRite parameters (p>0.05)., Conclusion: Assessment of physical activity and gait allow a characterization of the functional aspects of CIBP, but not in the evaluation of XRT., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl., Methods: CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl)., Results: Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability., Conclusion: Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl.

Unlabelled: The aim of the present study is to compare physician clinical assessment with patient-rated evaluations in the classification of cancer pain patients into groups with different pain levels, according to the presence of incident/breakthrough pain, neuropathic pain, and psychological distress. Average pain in the previous 24 hours was used as the dependent variable in multivariate linear regression models, and incident/breakthrough pain, neuropathic pain, and psychological distress were tested as regressors; in the assessment of regressors, physicians used the Edmonton Classification System for Cancer Pain, whereas patients used structured self-assessment questionnaires. The amount of variability in pain intensity scores explained by the 2 sets of regressors, physician and patient rated, was compared using R(2) values. When tested in 2 separate models, patient ratings explained 20.3% of variability (95% confidence interval [CI] = 15.2-25.3%), whereas physician ratings explained 6.1% (95% CI = 2.2-9.8%). The higher discriminative capability of patient ratings was still maintained when both regressor sets were introduced in the same model, with R(2) indices of 17.6% (95% CI = 13.0-22.2%) for patient ratings vs 3.4% (95% CI = .9-5.9%) for physician ratings. Patients' self-assessment of subjective symptoms should be integrated in future cancer pain classification systems., Perspective: Our results indicate that patient-structured assessment of incident/breakthrough pain, neuropathic pain, and psychological distress significantly contributes to the discrimination of cancer patients with different pain levels. The integration of patient self-assessment tools with more objective clinician assessments can improve the classification of cancer pain., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Context: Pain localization is an important part of pain assessment. Development of pain tools for self-report should include expert and patient input, and patient testing in large samples., Objectives: To develop a computerized pain body map (CPBM) for use in patients with advanced cancer., Methods: Three studies were conducted: 1) an international expert survey and a pilot study guiding the contents and layout of the CPBM, 2) clinical testing in an international symptom assessment study in eight countries and 17 centers (N = 533), and 3) comparing patient pain markings on computer and paper body maps (N = 92)., Results: Study 1: 22 pain experts and 28 patients participated. A CPBM with anterior and posterior whole body views was developed for marking pain locations, supplemented by pain intensity ratings for each location. Study 2: 533 patients (286 male, 247 female, mean age 62 years) participated; 80% received pain medication and 81% had metastatic disease. Eighty-five percent completed CPBM as intended. Mean ± SD number of marked pain locations was 1.8 ± 1.2. Aberrant markings (15%) were mostly related to software problems. No differences were found regarding age, gender, cognitive/physical performance, or previous computer experience. Study 3: 70% of the patients had identical markings on the computer and paper maps. Only four patients had completely different markings on the two maps., Conclusion: This first version of CPBM was well accepted by patients with advanced cancer. However, several areas for improvement were revealed, providing a basis for the development of the next version, which is subject to further international testing., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Context: Corticosteroids are frequently used in cancer patients for their analgesic properties. The evidence for analgesic effects of corticosteroids in palliative care has not been established., Objectives: To assess the evidence for the use of corticosteroids in cancer pain management., Methods: A systematic literature search was performed. The articles were evaluated according to the Grading of Recommendations Assessment, Development and Evaluations system by two independent reviewers., Results: The search provided 514 references, four of which were included. Another two trials were identified from reference lists. Two of these six studies were excluded from the qualitative review. One crossover study showed a significant reduction in pain intensity of 13 (visual analogue 0-100 scale) accompanied by significant lower analgesic consumption in favor of the steroid group. In another study, the addition of steroids did not have any effect on pain. In two studies, outcomes of pain intensity or analgesic consumption were not adequately reported. However, one of these studies showed significant pain reduction, whereas the other found no effect. Corticosteroids given in medium doses were well tolerated in studies for up to seven days. However, the studies indicated that corticosteroids may have serious toxicity and even higher mortality when administered in high doses over eight weeks., Conclusion: Corticosteroids may have a moderate analgesic effect in cancer patients. The paucity of relevant studies was striking; consequently, the evidence was graded as "very low." More studies addressing the analgesic efficacy in cancer patients are required., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Background: Population-based studies have reported conflicting findings on the relationship between physical activity and pain, and most studies reporting a relationship are cross sectional. Temporal relationships are therefore difficult to infer and associations may be subject to confounding from a variety of other factors. The aim of the current study was to investigate the association between exercise and pain longitudinally and to use within subjects analyses to remove between subjects confounding., Methods: In the population-based HUNT 3 study, participants reported both pain and level of exercise. A random sub-sample of 6419 participants was in addition invited to report their last week pain and exercise every three months over a 12 month period (five measurements in total). We used multilevel mixed effects linear regression analyses to prospectively estimate the association between regular levels of exercise (measured in HUNT 3) and subsequent longitudinal reporting of pain. We also estimated within-subjects associations (i.e. the variation in pain as a function of variation in exercise, over time, within individuals) to avoid confounding from between subject factors., Results: Among those invited to participate (N = 6419), 4219 subjects returned at least two questionnaires. Compared with subjects who reported no or light exercise, those who reported moderate levels of exercise or more at baseline, reported less pain in repeated measures over a 12 month period in analyses adjusted for age, sex,education and smoking. Adjusting for baseline level of pain distinctly attenuated the findings. Within subjects, an increase in exercise was accompanied by a concurrent reduction in intensity of pain. However, we found no indication that exercise level at one occasion was related to pain reporting three months later., Conclusion: This longitudinal population-based study indicates that exercise is associated with lower level of pain and that this association is close in time.

Background: Colonoscopies are common examinations at Norwegian hospitals. In contrast to many other countries, the majority of colonoscopies in Norway are conducted without routine sedation or analgesia. We wanted to investigate whether current Norwegian practice offers adequate pain relief., Material and Method: The material consists of prospectively recorded outpatient colonoscopies in the period January 2003-December 2011 performed at Norwegian hospitals in the quality assurance network for gastrointestinal endoscopy (Gastronet). We analysed demographic patient data and data from colonoscopies. Patients' experience of pain (none, slight, moderate or severe pain) in connection with the examination was established with the aid of a validated questionnaire., Results: Data from 61,749 colonoscopies (55% on women) performed at 29 different hospitals were analysed. Colonoscopies were perceived as moderately or very painful by 33% of the patients (41% of the women, 24% of the men, p < 0.001). There were substantial differences between hospitals as to the percentage of colonoscopies that were perceived as moderately or very painful (from 9% to 43%, p < 0.001) and the use of sedatives and analgesics for the colonoscopies (from 1% to 92% of the examinations, p < 0.001). Only 23% of those who found the colonoscopy painful received analgesics. Pethidine was used in 95% of the cases in which analgesics were used during the examination., Interpretation: Many patients find colonoscopies painful. Pain relief practice varies substantially between hospitals. Pethidine is an analgesic with a slow onset of action, and should perhaps be replaced with more rapidly acting opiates.

Background: Standardized approaches for assessing and classifying cancer pain are required to improve treatment of patients with complex pain profiles. The Edmonton Classification System for Cancer Pain (ECS-CP) offers a starting point for the evolution of a standardized international classification system for cancer pain and was introduced into multisite research initiatives of the European Palliative Care Research Collaborative (EPCRC)., Objectives: The primary purpose of this study was to describe the prevalence of the five ECS-CP pain classification features: pain mechanism, incident pain, psychological distress, addictive behavior, and cognition--in a diverse international sample of patients with advanced cancer., Methods: A total of 1070 adult patients with advanced cancer were recruited from 17 sites in Norway, the United Kingdom, Austria, Germany, Switzerland, Italy, Canada, and Australia; 1051 of 1070 patients were evaluable. A clinician completed the ECS-CP for each enrolled patient. Additional information, including pain intensity, were also collected through patient self-reports, using touch-sensitive computers., Results: Of 1051 evaluable patients, 670 (64%) were assessed by a clinician as having cancer pain: nociceptive pain (n=534; 79.7%); neuropathic pain (n=113; 16.9%); incident pain (n=408; 60.9%); psychological distress (n=212; 31.6%); addictive behavior (n=30; 4.5%); normal cognition (n=616; 91.9%). The prevalence of ECS-CP features and pain intensity scores (11-item scale; 0=none, 10=worst; rated as now) varied substantially across sites and locations of care., Conclusion: The ECS-CP is a clinically relevant systematic framework, which is able to detect differences in salient pain classification features across diverse settings and countries. Further validation studies need to be conducted in varied advanced cancer and palliative care settings to advance the development of the ECS-CP toward an internationally recognized pain classification system.

Objective: The objective of the present study was to determine whether genetic variability in UDP-glucuronosyltransferase (UGT) genes, together with clinical factors, contribute to variability in morphine glucuronide (M6G and M3G) to morphine serum concentration ratios in patients with advanced cancer receiving chronic morphine therapy., Materials and Methods: A total of 41 polymorphisms and predicted haplotypes in the UGT2B7, UGT1A1, and UGT1A8 genes were analyzed in 759 patients who were recruited from the European Pharmacogenetic Opioid Study and received chronic morphine therapy by the oral route (n=635) or parenterally (n=124). The administration groups were analyzed separately by multiple linear regression analyses., Results: Two haplotypes in UGT1A1/UGT1A8 were weak predictors of reduced M6G/morphine and M3G/morphine serum ratios after oral administration (false discovery rate-corrected P-values<0.1). No effect of genotype was seen in the parenteral group. Of the clinical variables (age, sex, BMI, renal function, Karnofsky performance status, and presence of liver metastases), renal function was the major contributor to variation in serum concentration ratios. Concomitant administration of paracetamol predicted significantly higher morphine metabolic ratios after oral administration of morphine (false discovery rate-corrected P-values<2.1E-12). The regression models explained about 35% of the total variability in the data., Conclusion: Genetic variation in the UGT genes together with clinical factors influence morphine metabolic ratios in patients with advanced cancer disease and who are scheduled with oral morphine. This information may be included in future research that develop and test new classification systems for opioid treatment in patients with advanced cancer.

Introduction: Inflammation has been identified as a hallmark of cancer and may be necessary for tumorgenesis and maintenance of the cancer state. Inflammation-related symptoms are common in those with cancer; however, little is known about the relationship between symptoms and systemic inflammation in cancer. The aim of the present study was to examine the relationship between symptoms and systemic inflammation in a large cohort of patients with advanced cancer., Methods: Data from an international cohort of patients with advanced cancer were analyzed. Symptoms and patient-related outcomes were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire--Core Questionnaire. Systemic inflammation was assessed using C-reactive protein levels. The relationship between these symptoms and systemic inflammation was examined using Spearman rank correlation (ρ) and the Mann-Whitney U test., Results: Data were available for 1,466 patients across eight European countries; 1,215 patients (83%) had metastatic disease at study entry. The median survival was 3.8 months (interquartile range [IQR] 1.3-12.2 months). The following were associated with increased levels of inflammation: performance status (ρ = .179), survival (ρ = .347), pain (ρ = .154), anorexia (ρ = .206), cognitive dysfunction (ρ = .137), dyspnea (p= .150), fatigue (ρ = .197), physical dysfunction (ρ = .207), role dysfunction (ρ = .176), social dysfunction (ρ = .132), and poor quality of life (ρ = .178). All were statistically significant at p < .001., Conclusion: The results show that the majority of cancer symptoms are associated with inflammation. The strength of the potential relationship between systemic inflammation and common cancer symptoms should be examined further within the context of an anti-inflammatory intervention trial.

Background: Lung cancer and mesothelioma are malignant tumors with generally dismal prognosis and therefore palliative pain treatment constitutes a challenge for the clinician., Objectives: The aim of this study was to compare the outcomes of pain treatment with opioids among mesothelioma and lung cancer patients treated for palliation and assess factors which confound to optimal treatment., Patients and Methods: A sub-cohort of 373 lung cancer and 22 mesothelioma patients was identified in multi-center European Pharmacogenetic Opioid Study (EPOS) cohort. A nested case-control (1:4) setting was designed to estimate the pain and other covariates distinguishing 22 mesothelioma- (= cases) and 88 lung cancer patients (controls), analyzed using univariate- and multivariate conditional (fixed-effects) logistic regression models., Results: The mean total daily dose of opioids varied from 30.0 to 960.0 mg (mean 275, median 160 mg, SD 293) in mesothelioma, and from 10 to 5072 mg (mean 414, median 175, SD 788) in lung cancer patients (p = 0.420). In both groups, pain was mostly experienced as moderate and severe and it was frequently accompanied by depression, poor sleep, anxiety and fatigue. Four mesothelioma patients (18%) and seven lung cancer patients (10%) experienced complete pain relief with opioids by self-assessment. Assessments of pain severity by the patients and their physicians deviated significantly in mesothelioma (p = 0.039 McNemar test), as well as in lung cancer (p = 0.0001). In conditional logistic regression, no significant differences were found in distribution of pain covariates between lung cancer and mesothelioma patients., Conclusion: Pain perception by the patients was associated frequently with other symptoms and complete pain control with opioids was achieved only with minority of patients both with mesothelioma and advanced lung cancer. Adequate pain control requires continuous monitoring and tailoring the dose to patient's individual needs and tolerance, recognition of accompanying symptoms such as depression and poor sleep, and their management.

Objective: This study examined whether the choice of pain-related outcome to represent opioid efficacy influenced findings in a genetic association study. Data from the European Pharmacogenetic Opioid Study, which used opioid dose as the outcome, were analysed in respect of six alternative outcomes: average pain intensity, pain right now, worst pain intensity, pain at its least, pain relief and pain interference., Design: Cancer pain patients using an opioid for moderate or severe pain were included. The pain outcomes were obtained using the Brief Pain Inventory. Genetic variation was analysed for 112 single nucleotide polymorphisms (SNPs) in 25 candidate genes relevant for opioid efficacy. The patients were randomly divided into a development and a validation sample and linear regression was used to compare the equality of means in the six outcomes. The influence of non-genetic factors was controlled for, the regression analyses were stratified by country, and the results were corrected for multiple testing., Results: 2201 cancer pain patients were included. Their mean age was 62.4 years and mean average pain was 3.5. None of the examined SNPs exceeded p values corrected for multiple testing for any of the outcomes., Conclusions: None of the outcomes were associated with variation in the selected SNPs, as previously shown for opioid dose. Thus, we observed that findings related to associations between genetic variability and opioid efficacy were consistent for several alternative outcomes.

Purpose: Patients' involvement in the development of assessment tools is recommended, and the European Palliative Care Research Collaborative has adhered to this when developing a shared language for cancer pain, an international assessment and classification system. Study objectives were to investigate how patients ranked the relevance of several previously identified pain domains, to investigate patients' perception of the pain experience and to disclose additional, relevant pain domains for cancer pain classification to those identified in the literature., Methods: Semistructured interviews with advanced cancer patients treated with opioids were performed and analysed verbatim. Patients scored the relevance of predefined pain domains on an 11-point Numerical Rating Scale., Results: Thirty-three Norwegian and Austrian patients were included (16 females and 17 males); the mean age was 63 years, and the mean Karnofsky performance score was 65. The ranking of domains was as follows etiology (mean Numerical Rating Scale score, 8.5), duration (8.0), intensity (7.4), coping (7.1), physical (5.9) and psychological functioning (5.8). Sleep was identified as a new candidate domain to include in the system. The patients emphasised consequences of having pain, for example, poor physical functioning and psychological distress., Conclusions: Previously identified pain domains were confirmed to be relevant to the patients; however, the ranking differed from the experts' ranking. Sleep disturbances may be added as a domain in a future classification system.

Purpose: Our 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., Methods: Forty-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 C(SS) 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., Results: Thirty-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 C(SS) 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., Conclusion: The 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.

Context: Pain and discomfort arising from the routine care of intubated patients in the ICU is managed by continuous infusion of narcotic and sedative drugs. There is benefit in keeping infusion rates low because lightening sedation improves clinical outcome, but this risks breakthrough pain. Management of this discomfort by bolus administration could permit lower background infusion rates, but the lowest effective bolus dose of sufentanil to achieve this is unknown., Objective: The aim of this study was to determine the effective analgesic dose in 90% of intubated patients (ED90) in the ICU given bolus sufentanil. Pain was assessed using a Behavioural Pain Scale (BPS) requiring a score of 3-4 during moving to the lateral decubitus position., Design: Prospective, dose response study., Setting: A 16-bed multidisciplinary ICU in a French university hospital. Study period was from January to June 2010., Patients: Intubated and ventilated patients were eligible for the study once they had reached a BPS of 3 or 4 and Ramsay score of 3-5 within 48 h of admission to the ICU., Intervention: The analgesic efficacy of a sufentanil bolus was measured during successive lateral decubitus positioning over a 72-h study period, using the BPS scale. The dose was increased with each subsequent turn to lateral decubitus until a BPS score of 3-4 was obtained (dose escalation, starting at zero)., Main Outcome Measures: BPS, Ramsay score, heart rate and mean arterial pressure were collected before and during each procedure., Results: A total of 25 patients were enrolled over 6 months. The ED90 bolus for sufentanil was 0.15 μg kg, but 40% of the patients subsequently demonstrated increased BPS with this dose., Conclusion: The effective dose in 90% was 0.15 μg kg during the first 5 days of sedation. There were no adverse effects. A pre-emptive sufentanil bolus can be used to treat anticipated pain in the ICU. Regular and frequent assessments of acute pain and sedation are essential for adjusting the dose, on a case-by-case basis. This strategy may help clinicians to keep background infusions of sedatives and narcotics as low as possible and may improve clinical outcome., Trial Registration: ClinicalTrials.gov NCT01356732.

Context: The relationship between oxycodone and metabolite serum concentrations and clinical effects has not previously been investigated in cancer pain patients., Objectives: The aim of this study was to assess whether there is a relationship between oxycodone concentrations and pain intensity, cognitive functioning, nausea, or tiredness in cancer patients. Also, oxymorphone and noroxymorphone contributions to analgesia and the adverse effects of oxycodone were assessed., Methods: Four hundred fifty-six cancer patients receiving oxycodone for cancer pain were included. Pain was assessed using the Brief Pain Inventory. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30 was used to assess the symptoms of tiredness, nausea, constipation, and depression. Cognitive function was assessed using the Mini-Mental State Examination. Associations were examined by multiple linear or ordinal logistic regressions. Whether patients classified as being a "treatment success" or a "treatment failure" had different serum concentrations of oxycodone or metabolites was assessed using Mann-Whitney U-tests., Results: Serum concentrations of oxycodone and metabolites were not associated with pain intensity, nausea, tiredness, or cognitive function, with the exception that increased pain intensity was associated with higher oxymorphone concentrations. Patients with poor pain control and side effects had higher serum concentrations of the oxycodone metabolites, noroxycodone and noroxymorphone, compared with those with good pain relief and without side effects., Conclusion: This study of patients receiving oxycodone for cancer pain confirms previous observations that there is most likely no association between serum concentrations of opioid analgesics and clinical effects., (Copyright © 2012 U.S. Cancer Pain Relief Committee. All rights reserved.)

The overall aim of the present study was to further develop an evidence-based platform for the content of an international cancer pain classification system. Data from a multicentre, observational longitudinal study of cancer patients were analysed. Analyses were carried out in 2 samples: (A) Cross-sectional data of patients on opioids at inclusion, and (B) patients just admitted to palliative care. Outcome measures in the models we investigated were pain on average, worst pain, and pain relief at inclusion, and at day 14, respectively. Uni- and multivariate regression models were applied to test the explicative power on pain outcomes of a series of known pain domains, including incident pain, psychological distress, neuropathic pain, pain localisation, sleep disturbances, total morphine equivalent daily dose (MEDD), and cancer diagnosis. In the 2 analyses, 1529 (A) and 352 (B) patients were included, respectively. Incident pain, pain localisation, MEDD, use of nonsteroidal antiinflammatory drugs, and sleep were associated with one or more of the pain outcomes in analysis A, while initial pain intensity, initial pain relief, incident pain, localisation of pain, cancer diagnosis, and age were predictors in the longitudinal analysis. Identified domains explained 16% to 24% of the variability of the pain outcome. Initial pain intensity emerged as the strongest predictor of pain outcome after 2 weeks, and incident pain was confirmed to be a relevant domain. The regression models explained only a minor part of the variability of pain outcomes., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a new Movement domain, based on 16 items from the Global Physiotherapy Examination-52 (GPE-52) and 18 items from the Comprehensive Body Examination (CBE). Furthermore, we examined how well the new domain and its scales would discriminate between healthy individuals and different groups of patients, compared to the original methods. Two physiotherapists, each using one method, independently examined 132 individuals (34 healthy, 32 with localized pain, 32 with generalized pain, and 34 with psychoses). The number of items was reduced by means of correlational and exploratory factor analysis. Internal consistency was examined with Cronbach's alpha. For examination of discriminative validity, Mann-Whitney U-test and Area under the Curve (AUC) were used. The initial 34 items were reduced to two subscales with 13 items: one for range of movement and balance and one for flexibility. Cronbach's alpha was 0.84 and 0.87 for the two subscales. The new subscales showed very good to excellent discriminating ability between healthy persons and the different patient groups (p < 0.001; AUC 0.82-0.95). Furthermore, patients with localized pain had significantly less movement aberrations than the other patient groups. The new Movement domain had fewer items than the GPE-52 and CBE, without losing discriminative validity.

An increasing number of cancer patients live longer, and palliative care has become an important part of their treatment. Symptoms are often inadequately assessed and managed. A significant challenge in clinical trials is to control for the variability of the samples being studied. To overcome this problem, classification systems have been developed in order to characterise and stratify patients by grouping them according to major common characteristics. The lack of agreed methods for the assessment and classification of cancer pain has been clearly indicated in clinical trials and in clinical practice and may be one possible explanation for the inadequate treatment of cancer pain. This was the background to an international expert meeting arranged in September 2009 in Milan, Italy. The primary aims were to produce recommendations on how to assess and classify cancer pain and to recommend a strategy for the further development, validation and implementation of an international cancer pain classification and assessment system. The recommendations consisted of two basic working proposals, nine specific working proposals and seven recommendations for the further development of a cancer pain classification system. Examples of specific working proposals were to include pain intensity, pain mechanism, breakthrough pain and psychological distress as the core domains in this classification of cancer pain and to measure pain intensity with a 0-10 numerical rating scale with 'no pain' and 'pain as bad as you can imagine' as anchors. The proposed name for this international standard is Cancer Pain Assessment and Classification System (CPACS).

The European Palliative Care Research Collaboration is updating the EAPC recommendations on opioids in cancer pain management. A systematic literature search on Medline on the use of alternative routes for opioid application identified 242 papers, with 72 publications included in the final evaluation. Two or more alternative routes of opioid application were compared in 18 papers with a total of 674 patients. The best evidence base was available for the subcutaneous route. A comparison of subcutaneous and intravenous routes found no differences, confirming both routes as feasible, effective and safe. Efficacy and safety of the rectal route was comparable to the parenteral route. The side effect profile seemed to be very similar for the subcutaneous, intravenous, rectal or transdermal routes. Local side effects were reported for rectal application as well as for subcutaneous and transdermal administration. In conclusion, the systematic review found good evidence that subcutaneous administration of morphine or other opioids is an effective alternative for cancer patients if oral treatment is not possible. However, for a number of patients intravenous, rectal or transdermal therapy will offer a good alternative to the subcutaneous route. The review found no significant differences in efficacy or side effects between the alternative application routes.

Purpose: Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients., Experimental Design: We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients., Results: Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P < 1.0 × 10⁻³, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10⁻⁹). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system., Conclusion: Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain.

The European Association for Palliative Care recommendation for starting morphine for cancer pain is dose titration with immediate release (IR) oral morphine given every 4 h with additionally doses for breakthrough pain. As part of a EU 6th framework programme to revise the guidelines we review the evidence regarding starting treatment and dose titration of opioids in adult patients with moderate to severe cancer pain. Relevant papers were identified though a systematic search in Medline for papers published until the end of 2009. We identified 15 relevant papers. Thirteen papers were descriptive papers reporting the results from starting treatment with oral morphine (six studies), starting treatment with intravenous morphine (two studies) and starting treatment with transdermal fentanyl (four studies). All treatment strategies resulted in acceptable pain control and were well tolerated. Two randomized controlled trials were identified. One study compared starting opioid treatment with intravenous morphine versus IR oral morphine and one study compared IR oral morphine versus sustained release oral morphine.

Background: A systematic review, undertaken according to an initiative to revise European Association for Palliative Care guidelines on the use of opioids for cancer pain, which aimed to analyse analgesic efficacy and side effects of spinal opioids in adult cancer patients previously treated with systemic opioids., Methods: Search strategy elaborated with MeSH terms and words related to cancer, palliative care, pain, spinal route and opioids. PubMed, Embase and Cochrane assessed in Nov 2009. Studies were analysed and classified according to quality of evidence and strength of recommendation., Results: Out of 2939 abstracts, 44 articles were selected (nine randomized controlled trials (RCTs), two non-randomized cohort studies, 28 uncontrolled prospective studies, and five case series). Relief of pain and/or side effects were reported in 42 articles; however, there were few studies of high quality design (RCTs) and these studies had methodological limitations that reduced their quality of evidence to very low., Conclusion: There are few RCTs and these are of very low quality. As a result, they provide weak recommendation for using spinal opioids in adult cancer patients. Further studies are clearly needed.

According to a Cochrane review on opioid switching, sound evidence on the practice of substituting one strong opioid with another to improve pain control and reduce adverse effects was lacking in 2004. A systematic search strategy was developed to include studies after 2004, with adult cancer patients switching between strong opioids and reporting estimates of effect on pain and adverse effects. The search retrieved 288 publications (71 duplicates); 187 abstracts and 19 full papers were excluded. Eleven papers met the inclusion criteria; none were randomized controlled trials/meta-analyses. Studies comprised 280 patients (group size 10-32). A variety of opioids and switching strategies were studied. Pain intensity was significantly reduced in the majority of studies. Serious adverse effects were improved. Due to serious design limitations, the level of evidence was low (D). Randomized trials, with standardization of cohort classification, use of outcomes and analysis are warranted to establish the practice of opioid switching.

The accurate, precise, and consistent assessment of pain is of particular importance in palliative care. The European Palliative Care Research Collaborative is developing a computer-based pain assessment instrument and has been evaluating the content and dimensionality of existing pain questionnaires. The most important dimensions of pain are intensity and interference. However, since pain interference is a consequence of and largely reflects pain intensity, we postulated that it might either provide information to enhance the evaluation of intensity, or that an overall summary measure of pain severity could be constructed by combining the 2 dimensions. Cancer patients in palliative care (n=395) and chronic pain patients (n=168) completed questionnaires that included 23 pain items culled from existing questionnaires. Psychometric analyses confirmed the existence of 2 main dimensions, intensity and interference, and also guided identification of items that contributed most strongly to these dimensions. However, there was strong evidence that the relationship between the intensity and the interference items differs markedly in palliative care patients compared to chronic pain patients. As hypothesized, there was strong correlation between intensity and interference, lending support to the possibility that, for some purposes, these dimensions may be combined to provide a higher-level summary measure of patients' pain experience. We conclude that these dimensions should be kept distinct when assessing patients in general, although for a single type of patient (such as palliative care patients), it may be possible to regard intensity and interference as contributing to an overall measure of pain severity., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Context: The use of unidimensional pain scales such as the Numerical Rating Scale (NRS), Verbal Rating Scale (VRS), or Visual Analogue Scale (VAS) is recommended for assessment of pain intensity (PI). A literature review of studies specifically comparing the NRS, VRS, and/or VAS for unidimensional self-report of PI was performed as part of the work of the European Palliative Care Research Collaborative on pain assessment., Objectives: To investigate the use and performance of unidimensional pain scales, with specific emphasis on the NRSs., Methods: A systematic search was performed, including citations through April 2010. All abstracts were evaluated by two persons according to specified criteria., Results: Fifty-four of 239 papers were included. Postoperative PI was most frequently studied; six studies were in cancer. Eight versions of the NRS (NRS-6 to NRS-101) were used in 37 studies; a total of 41 NRSs were tested. Twenty-four different descriptors (15 for the NRSs) were used to anchor the extremes. When compared with the VAS and VRS, NRSs had better compliance in 15 of 19 studies reporting this, and were the recommended tool in 11 studies on the basis of higher compliance rates, better responsiveness and ease of use, and good applicability relative to VAS/VRS. Twenty-nine studies gave no preference. Many studies showed wide distributions of NRS scores within each category of the VRSs. Overall, NRS and VAS scores corresponded, with a few exceptions of systematically higher VAS scores., Conclusion: NRSs are applicable for unidimensional assessment of PI in most settings. Whether the variability in anchors and response options directly influences the numerical scores needs to be empirically tested. This will aid in the work toward a consensus-based, standardized measure., (Copyright © 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Objective: Oxycodone is widely used for the treatment of cancer pain, but little is known of its pharmacokinetics in cancer pain patients. The aim of this study was to explore the relationships between ordinary patient characteristics and serum concentrations of oxycodone and the ratios noroxycodone or oxymorphone/oxycodone in cancer patients., Methods: Four hundred and thirty-nine patients using oral oxycodone for cancer pain were included. The patients' characteristics (sex, age, body mass index [BMI], Karnofsky performance status, "time since starting opioids", "oxycodone total daily dose", "time from last oxycodone dose", use of CYP3A4 inducer/inhibitor, "use of systemic steroids", "number of medications taken in the last 24 h", glomerular filtration rate (GFR) and albumin serum concentrations) influence on oxycodone serum concentrations or metabolite/oxycodone ratios were explored by multiple regression analyses., Results: Sex, CYP3A4 inducers/inhibitors, total daily dose, and "time from last oxycodone dose" predicted oxycodone concentrations. CYP3A4 inducers, total daily dose, and "number of medications taken in the last 24 h" predicted the oxymorphone/oxycodone ratio. Total daily dose, "time from last dose to blood sample", albumin, sex, CYP3A4 inducers/inhibitors, steroids, BMI and GFR predicted the noroxycodone/oxycodone ratio., Conclusion: Women had lower oxycodone serum concentrations than men. CYP3A4 inducers/inhibitors should be used with caution as these are predicted to have a significant impact on oxycodone pharmacokinetics. Other characteristics explained only minor parts of the variability of the outcomes.

Purpose: To identify prevalence and associated factors of cognitive dysfunction in opioid-treated patients with cancer., Patients and Methods: EPOS (European Pharmacogenetic Opioid Study) is a prospective cross-sectional multicenter study in which adult patients with cancer who received treatment with opioids for moderate or severe pain for at least 3 days were included. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). MMSE scores were categorized into definite cognitive dysfunction (scores < 24), possible cognitive dysfunction (scores 24-26), and no cognitive dysfunction (scores > 26). Factors potentially associated with cognitive dysfunction were assessed. Associations between MMSE and explanatory variables were analyzed by ordinal logistic regression models., Results: We included 1,915 patients with cancer from 17 centers. MMSE scores less than 27 were observed in 32.9% of patients. Patients with lung cancer had higher odds (adjusted odds ratio, 1.46; 95% CI, 1.09 to 1.95) for having lower MMSE scores compared with patients with other cancer diagnoses. Patients receiving daily opioid doses of 400 mg or more (oral morphine equivalents) had 1.75 (95% CI, 1.25 to 2.46) times higher odds of having lower MMSE scores compared with those receiving daily doses less than 80 mg. Other risk factors for cognitive dysfunction were older age, low Karnofsky performance status (KPS), time since diagnosis (< 15 months), and absence of breakthrough pain (BTP)., Conclusion: One third of opioid-treated patients with cancer had possible or definite cognitive dysfunction. Lung cancer, daily opioid doses of 400 mg or more (oral morphine equivalents), older age, low KPS, shorter time since cancer diagnosis, and absence of BTP were predictors for cognitive dysfunction.

Background and Aims: A considerable number of Europeans suffer from chronic pain and are using opioids, particularly of the weak type. It is a clinical impression that many of these are driving or wish to drive a car. The aims of this study were to investigate if codeine influences driving ability in a simulator, and to examine if chronic pain per se might impair such functions., Methods: Twenty patients with chronic pain on long-term codeine therapy were compared to 20 chronic pain patients not using codeine in a video driving simulator test. The chronic pain patients were then compared to 20 healthy controls. The primary outcome measures were reaction time and number of missed reactions., Results: The patients using codeine 120-270 mg (mean 180 mg) daily showed the same driving skills as patients not using codeine, and the codeine level did not affect the results. This was the case both 1h after intake of a single dose of 60 mg codeine and five or more hours after the last codeine intake. The reaction times were significantly slower for the chronic pain patients, in both rural and urban driving conditions, compared to the healthy controls (difference 0.11s. and 0.12s., respectively). The chronic pain patients missed almost twice as many reactions to traffic signs. There were no difference between the groups in steering precision., Conclusion: The main finding in this simulator study was that codeine does not impair driving-related abilities over and above what is associated with chronic pain per se., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Background: This study is part of a research program to reach consensus on an international cancer pain classification system. A confirmative and explorative approach was applied to investigate which of the variables identified in the literature, by experts and patients that are associated with pain., Methods: Data from an international, multicentre, cross-sectional study of cancer patients treated with opioids were investigated. Dependent variables were: average pain, worst pain, and pain relief (11-point Numerical Rating Scales). Forty-six independent variables were chosen based upon previous studies. Bivariate analyses identified independent variables associated with at least one of the dependent ones; 21 were included in multivariate linear regression analyses., Results: Two thousand two hundred and seventy-eight patients were investigated; 52% males, mean age 62 years, mean Karnofsky Performance Status 59%, mean daily opioid oral equivalent dose 341 mg. Fifty-eight percent had breakthrough pain. Mean pain scores were: average pain 3.5, worst pain 5.3 and pain relief 74%. Variables most strongly associated with these three dependent variables were: breakthrough pain, psychological distress, sleep, and opioid dose., Conclusions: Breakthrough pain and psychological distress were confirmed as key variables of a future classification system. Candidate variables were: sleep, opioid dose, pain mechanism, use of non-opioids, pain localisation, cancer diagnosis, location of metastases, and addiction., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

The opioids morphine and oxycodone are potent analgesics that are available as extended-release and immediate-release tablets. Indications are the same for both; i.e. severe acute pain and chronic pain (non-malignant or malignant). Few clinical studies have compared morphine and oxycodone directly. There is no evidence to support that one is superior over the other.