Pharmacological treatments for fatigue associated with palliative care.

BACKGROUND: In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients fatigue can be severely debilitating, thereby impacting daily activity and quality of life, often with rest not counteracting fatigue. Fatigue frequently occurs in patients with advanced disease and modalities treating cancer often contribute or cause fatigue. Further complicating issues are its multidimensionality, subjective nature, and lack of a consensus definition of fatigue. Pathophysiology is not fully understood and evidence-based treatment approaches are needed. OBJECTIVES: The objective was to determine efficacy of pharmacological treatments on non-specific fatigue in palliative care. The focus was on patients at an advanced stage of disease, including cancer and other chronic diseases associated with fatigue, aiming to relieve fatigue. Studies aiming at curative treatment (e.g. surgical intervention for early breast cancer) were not included. SEARCH STRATEGY: We searched EMBASE; Psych Lit, CENTRAL and MEDLINE to June 2009. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) concerning adult palliative care with focus on pharmacological treatment of fatigue. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). DATA COLLECTION AND ANALYSIS: Results were screened and included if they met the selection criteria. If two or more studies were identified that investigated a specific drug in a population with the same disease, meta-analysis was conducted. In addition, comparison of type of drug investigated in a specific population as well as comparison of frequent adverse effects of fatigue treatment was done by creating overview tables. MAIN RESULTS: More than 2000 publications were screened, and 22 met inclusion criteria. In total, data from 11 drugs and 1632 participants were analysed. Studies investigating amantadine, pemoline, and modafinil in participants with Multiple Sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue could be used for meta-analysis. Amantadine in MS and methylphenidate in cancer patients showed a superior effect. Most studies had low participant numbers and were heterogenous. AUTHORS' CONCLUSIONS: Based on limited evidence, we cannot recommend a specific drug for treatment of fatigue in palliative care patients. Surprisingly, corticosteroids have not been a research focus for fatigue treatment, although these drugs are frequently used. Recent fatigue research seems to focus on modafinil, which may be beneficial although there is no evidence currently. Amantadine and methylphenidate should be further examined. Consensus regarding fatigue assessment in advanced disease is needed.

A population-based cohort study on chronic pain: the role of opioids.

OBJECTIVES: The aims of this study were 2-fold: (1) to investigate the consequences of opioid use in individuals with chronic pain in the Danish population, and (2) to investigate the development of and recovery from chronic pain from 2000 to 2005. METHODS: Data derived from the Danish Health Interview Survey in 2000, which were linked on the individual level with register-based follow-up data. The survey was based on a county-stratified random sample of 16,684 individuals, out of which 10,434 individuals (62.5%) completed a face-to-face interview and returned a self-administered questionnaire. In addition, a subsample of the sample in 2000 was reinvited to a follow-up survey in 2005. In total, 3649 individuals (61.7%) of this subsample completed the interview and returned the questionnaire at baseline in 2000. At follow-up, 2354 of these participants completed the interview and returned the self-administered questionnaire. Respondents with cancer diagnosis were excluded from all analyses. Respondents with chronic pain were identified as having chronic/long-lasting pain more than 6 months. RESULTS AND DISCUSSION: The annual incidence for the development of and the recovery from chronic pain was 2.7% and 9.4%, respectively. Increasing age up to 64 years, short education, poor self-rated health, high body mass index, and physical strain at work were predictors of chronic pain. The odds of recovery from chronic pain were almost 4 times higher among individuals not using opioids compared with individuals using opioids. In addition, use of strong opioids was associated with poor health-related quality of life. Furthermore, the results indicated that individuals with chronic pain using strong opioids pain had a higher risk of death than individuals without chronic pain (HR: 1.67; 95% CI: 1.03-2.70). However, this study cannot exclude disease severity as the primary cause of increased mortality.

[Quality of life more than five years after breast cancer--secondary publication]. / Livskvalitet mere end fem år efter brystkraeft--sekundaerpublikation.

In this national survey, long-term breast cancer survivors (BCS) (n = 1,316) reported quality of life comparable to data from the general Danish female population, but a significantly higher prevalence of chronic pain (42% versus 32%). Paraesthesia, phantom sensation, allodynia, and swelling of arm/shoulder were also reported, and every fifth woman felt that these sequelae limited her daily activities. Health care utilization indicated chronic morbidity. Relatively young age, short education, and former radiotherapy were risk factors for issues such as pain.

Epidemiology of chronic pain in Denmark: an update.

The most recent Danish health survey of 2005 is based on a region-stratified random sample of 10.916 individuals. Data were collected via personal interviews and self-administrated questionnaires. Respondents suffering from chronic pain were identified through the question 'Do you have chronic/long-lasting pain lasting 6 months or more?' The prevalence of chronic pain among individuals with a present or earlier cancer diagnosis was also assessed. In all, 7275 individuals (66.6%) completed a personal interview and 5552 individuals (50.9% of the original sample) completed and returned the self-administrated questionnaire. The same questions were included in the survey in 2000 and, hence, it was possible to evaluate the trends in the past five years. In all, 20.2% of the adult Danish population has chronic pain. From year 2000-2005 the prevalence of chronic pain has remained stable. Generally, chronic pain was associated with female gender and increasing age. Higher prevalence of chronic pain were associated with being divorced, separated or widowed, having less than 10 years of education and high BMI. Musculoskeletal diseases (66.8%) were the most common cause for chronic pain and most persons with chronic pain rated their health and quality of life as poor. Persons with earlier or present cancer diagnosis were more likely to report chronic pain. A substantial part of persons with chronic pain were not satisfied with the examinations and treatments offered. In conclusion, over a five-year period the prevalence of chronic pain in Denmark has remained stable, but high.

Alcohol and smoking behavior in chronic pain patients: the role of opioids.

The primary aim of this epidemiological study was to investigate associations between chronic non-cancer pain with or without opioid treatment and the alcohol and smoking behavior. The secondary aims were to investigate self-reported quality of life, sleeping problems, oral health and the use of different health care providers. The Danish health survey of 2005 was based on a region-stratified random sample of 10.916 individuals. Data were collected via personal interviews and self-administrated questionnaires. Respondents suffering from chronic pain were identified through the question 'Do you have chronic/long-lasting pain lasting 6 months or more?' The question concerning alcohol intake assessed the frequency of alcohol intake and binge drinking. Smoking behavior assessed the daily number of cigarettes. Individuals reporting chronic pain were stratified into two groups (opioid users and non-opioid users). In all, 7275 individuals completed a personal interview and 5552 individuals completed and returned the self-administrated questionnaire. Responders with a self-reported earlier or present cancer diagnosis were excluded from the study. Hence, the final study population consisted of 5292 individuals. We found, that individuals suffering from chronic pain were less likely to drink alcohol. In opioid users alcohol consumption was further reduced. Cigarette smoking was significantly increased in individuals suffering from chronic pain and in opioid users smoking was further increased. Poor oral health, quality of life and sleep were markedly associated with chronic pain and opioid use. The use of opioids was associated with significantly more contacts to healthcare care providers.

Health-related quality of life in long-term breast cancer survivors: nationwide survey in Denmark.

AIM: To investigate health-related quality of life (HRQOL) in a nationally representative sample of long-term breast cancer survivors (BCS) in Denmark. PARTICIPANTS AND METHODS: An age-stratified random sample of 2,000 female BCS > or = 5 years after primary surgery without recurrence was drawn from the Danish Breast Cancer Cooperative Group register, which is representative regarding long-term BCS in Denmark, and compared with 3,104 women of the nationally representative Danish Health and Morbidity Survey 2000. The Short Form-36 questionnaire assessed HRQOL and its association with BCS' sociodemography, type of surgery, systemic therapy, radiotherapy, time since operation, receptor status, and low/high risk protocol. RESULTS: The response rate was 79%. BCS tended to rate HRQOL better than the general female population. BCS reported significantly less "bodily pain" (P < 0.0001), better "general health" (P < 0.0001), but worse "mental health" (P < 0.0001). Age interacted significantly with four other subscales (P < 0.05): Younger BCS reported worse HRQOL than equally aged women of the general population, while older BCS reported better HRQOL. Poor HRQOL was significantly associated with being single (all subscales: P < 0.05), short education (all subscales: P < 0.05, except "social function"), and high body mass index ("physical function", "role physical": P < 0.05). Breast cancer (low/high risk, receptor status) and treatment did not affect HRQOL. CONCLUSION: HRQOL was similar between BCS and women of the general population. Potential long-term effects of breast cancer (low/high risk, receptor status) and treatment did not seem to impact HRQOL. However, predictors for worse HRQOL in BCS were being single, and having a short education.

Recent developments in cancer pain assessment and management.

Pain and other symptoms of advanced cancer are not treated effectively yet. This review of the literature discusses the needs and latest research findings about pain symptom assessment and management in palliative care. Pain assessment scores should not be followed blindly by a rigid therapeutic regimen. Instead, the health care provider should carefully consider the wide spectrum of possible underlying pain mechanisms. Unidimensional pain rating scales will not detect the impact of affective dimensions on pain expression as accurately as multidimensional rating scales that include various symptoms. Besides assessment tools like numeric rating scales or visual analogue scales, tools now frequently used in the daily clinical setting include the Edmonton Symptom Assessment System, the Mini Mental State Examination, and the CAGE questionnaire (Cutting down, Annoyance by criticism, Guilty feeling, and Eye-openers). Recent developments and findings in cancer pain management are illustrated by (1) the use of opioids like morphine, oxycodone, fentanyl, and especially methadone (which has been used increasingly as a secondline drug for opioid-resistant and neuropathic pain, and also for its low cost, long-acting nature, and low side-effect probability, especially in patients with renal failure resulting from the lack of active metabolites); (2) the use of adjuvant therapeutic agents like gabapentin, donepezil, dextromethorphan, and thalidomide; (3) the impact of the immune system on pain, with a concept of targeting immune cells that contain opioids to potentially enhance opioid production, the migration of these cells to tissue lesions, and the release of opioids at the peripheral site to achieve increased peripheral analgesia; and (4) approaches to pain imaging as well as the newly introduced interventions of vertebroplasty and kyphoplasty.

ATP-inhibition of M current in frog sympathetic neurons involves phospholipase C but not Ins P(3), Ca(2+), PKC, or Ras.

Suppression of the voltage-activated, noninactivating K(+) conductance (M conductance; g(M)) by muscarinic agonists, P(2Y) agonists or bradykinin increases neuronal excitability. All agonist effects are mediated, at least in part, via the Gq/(11) class of G protein. We found, using whole cell or perforated patch recording from bullfrog sympathetic B neurons that ATP-induced suppression of g(M) was attenuated by the phospholipase C (PLC) inhibitor, U73122 (IC(50) approximately 0.14 microM) but not by the inactive isomer, U73343. The ability of extracellularly applied U73122 to inhibit PLC was confirmed by its antagonism of ATP-induced elevation of intracellular Ca(2+) as measured by fura-2 photometry. ATP-induced g(M) suppression was not antagonized by the protein kinase C (PKC) inhibitor, chelerythrine (5 microM extracellular +10 microM intracellular), by the Ca(2+)-ATPase inhibitor, thapsigargin (5 microM), or by inositol trisphosphate (InsP(3)) receptor antagonists, heparin (approximaterly 300 microM) or xestospongin C (1.8 microM). The effect of ATP on g(M) was thus dependent on PLC yet independent of PKC and of InsP(3)-induced release of intracellular Ca(2+). We therefore tested the involvement of a PKC-independent action of diacylglycerol (DAG) that could occur via activation of Ras. This low-molecular-weight G protein is activated following DAG binding to Ras-GRP, a neuronal Ras-GTP exchange factor. However, impairment of Ras function by culturing neurons with isoprenylation inhibitors (perillic acid, 0.1 mM, or alpha-hydroxyfarnesyl-phosphonic acid, 10 microM) failed to affect ATP-induced g(M) suppression. Inhibition of MEK (mitogen-activated protein kinase), a downstream target of Ras, by using PD 98059 (10 microM) was also ineffective. The transduction mechanism used by ATP to suppress g(M) in frog sympathetic neurons therefore differs from the PLC-independent mechanism used by muscarine and from the PLC and Ca(2+)-dependent mechanism used by bradykinin and UTP in mammalian ganglia. The possibility remains that "lipid-signaling" mechanisms, perhaps involving PLC-induced depletion of phosphatidylinositol bisphosphate, are involved in PLC-mediated inhibition of g(M) by ATP in amphibian sympathetic neurons.