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Background and Objective: Pain is a common symptom in patients who survive cancer and in those who live with progressive advanced disease. Evidence from meta-analyses suggests that pain remains poorly controlled for a large proportion of patients; barriers to good management include poor assessment of pain, inadequate support for patient self-management and late or inadequate access to strong opioid analgesia in those with advanced disease., Methods: The European Pain Federation (EFIC) established a Task Force in 2017 which convened a European group of experts, drawn from a diverse range of relevant clinical disciplines, to prepare a position paper on appropriate standards for the management of cancer-related pain. The expert panel reviewed the available literature and made recommendations using the GRADE system to combine quality of evidence with strength of recommendation. The panel took into account the desirable and undesirable effects of the management recommendation, including the cost and inconvenience of each when deciding the recommendation., Results and Conclusions: The 10 standards presented are aimed to improve cancer pain management and reduce variation in practice across Europe. The Task Force believes that adoption of these standards by all 37 countries will promote the quality of care of patients with cancer-related pain and reduce unnecessary suffering., Significance: Pain affects up to 40% of cancer survivors and affects at least 66% of patients with advanced progressive disease, many of whom experience poor pain control. These 10 standards are aimed to improve cancer pain management, promote the quality of care of patients and reduce variation across Europe., (© 2018 European Pain Federation - EFIC®.)

Opioid receptor agonists are known to relieve restless legs syndrome (RLS) symptoms, including both sensory and motor events, as well as improving sleep. The mechanisms of action of opioids in RLS are still a matter of speculation. The mechanisms by which endogenous opioids contribute to the pathophysiology of this polygenetic disorder, in which there are a number of variants, including developmental factors, remains unknown. A summary of the cellular mode of action of morphine and its (partial) antagonist naloxone via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the involvement of dendritic spine activation is described. By targeting pain and its consequences, opioids are the first-line treatment in many diseases and conditions with both acute and chronic pain and have thus been used in both acute and chronic pain conditions over the last 40 years. Addiction, dependence, and tolerability of opioids show a wide variability interindividually, as the response to opioids is influenced by a complex combination of genetic, molecular, and phenotypic factors. Although several trials have now addressed opioid treatment in RLS, hyperalgesia as a complication of long-term opioid treatment, or opioid-opioid interaction have not received much attention so far. Therapeutic opioids may act not only on opioid receptors but also via histamine or N-methyl-d-aspartate (NMDA) receptors. In patients with RLS, one of the few studies investigating opioid bindings found that possible brain regions involved in the severity of RLS symptoms are similar to those known to be involved in chronic pain, such as the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex, and orbitofrontal cortex). The results of this diprenorphine positron emission tomography study suggested that the more severe the RLS, the greater the release of endogenous opioids. Since 1993, when the first small controlled study was performed with oxycodone in RLS, opioids have been considered an efficacious off-label therapy in patients with severe RLS. A recent trial has proved the efficacy of a combination of prolonged release oxycodone/naloxone in patients with severe RLS as second-line therapy, with a mean dosage of 10/5 mg twice daily (mean difference of International Restless Legs Syndrome Study Group Rating Scale (IRLS) score between groups at 12 weeks: 8.15), and has now been licensed as the first opioid therapy in Europe. The current results from both short- and long-term trials and studies with opioids encourage optimism in alleviating RLS symptoms in patients with severe RLS, or possibly during or after augmentation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Constipation is a common adverse effect of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in people who are terminally ill and taking opioids. There is no reason to believe that people with chronic non-malignant disease who are prescribed opioids will be any less troubled by this adverse effect., Methods and Outcomes: We conducted a systematic overview and aimed to answer the following clinical question: What are the effects of opioid antagonists for constipation in people prescribed opioids? The population we studied included people with any condition, although most studies were in people with cancer pain. We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review)., Results: At this update, searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 37 full publications. Of the 37 full articles evaluated, two systematic reviews and one RCT were included at this update. We performed a GRADE evaluation for three PICO combinations., Conclusions: In this systematic overview we categorised the efficacy for three interventions based on information relating to the effectiveness of alvimopan, methylnaltrexone, and naloxone.

Aim: To evaluate the long-term safety and efficacy of prolonged-release oxycodone/naloxone (OXN PR) and its impact on quality of life (QoL), in patients with moderate-to-severe cancer pain., Methods: This was an open-label extension (OLE) of a 4 week, randomized, double-blind (DB) study in which patients with moderate-to-severe cancer pain had been randomized to OXN PR or oxycodone PR (OxyPR). During the OLE phase, patients were treated with OXN PR capsules (≤ 20/60 mg/day) for ≤ 24 weeks. Outcome measures included safety, efficacy and QoL., Results: One hundred and twenty-eight patients entered the OLE, average pain scores based on the modified Brief Pain Inventory-Short Form were low and stable over the 24-week period. The improvement in bowel function and constipation symptoms as measured by the Bowel Function Index and patient assessment of constipation in patients treated with OXN PR during the 4-week DB study was maintained. In patients treated with OxyPR during the DB phase, bowel function and constipation symptoms were improved during the OLE. In the DB and in the OLE, health status and QoL were similar for patients treated with OXN PR and OxyPR. There were no unexpected safety or tolerability issues., Conclusions: In patients with moderate-to-severe cancer pain, long-term use of OXN PR is well tolerated and effective, resulting in sustained analgesia, improved bowel function and improved symptoms of constipation.

Background: Pain is a common symptom in patients with multiple myeloma (MM). Many patients are dependent on analgesics and in particular opioids, but there is limited information on the impact of these drugs and their side effects on health-related quality of life (HRQoL)., Method: In a cross-sectional study, semi-structured interviews were performed in 21 patients attending the hospital with symptomatic MM on pain medications. HRQoL was measured using items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30., Results: Patients were able to recall a median of two (range 0-4) analgesics. They spontaneously identified a median of two (range 1-5) side effects attributable to their analgesic medications. Patients' assessment of HRQoL based on the EORTC QLQ-C30 questions 29/30 was mean 48.3 (95 % CI; 38.7-57.9) out of 100. Patients' assessment of their HRQoL in the hypothetical situation, in which they would not experience any side effects from analgesics, was significantly higher: 62.6 (53.5-71.7) (t test, p = 0.001)., Conclusion: This study provides, for the first time, evidence that side effects of analgesics are common in symptomatic MM and may result in a statistically and clinically significant reduction of self-reported HRQoL.

Background: Studies have demonstrated that whereas some opioids have little effect on immunity (eg, buprenorphine), others can be immunosuppressive (eg, morphine) or immunostimulatory (eg, tramadol). However, a variety of approaches have been used, especially in vitro and animal models, and the findings are variable. We hypothesised that opioids have differential effects on immunity via direct actions on neutrophils, monocytes, natural killer (NK) and T cells, and this is the first study to systematically evaluate the influence of eight opioids on neutrophil and monocyte phagocytosis and oxidative burst responses, NK cell cytotoxicity and T cell responsiveness in vitro., Methods: Peripheral blood was obtained from healthy volunteers, and the effects of clinically relevant concentrations of morphine, tramadol, fentanyl, buprenorphine, methadone, oxycodone, diamorphine and codeine on phagocytosis and oxidative burst responses were determined using whole blood flow cytometry. The influence of opioids on the capacity of resting and IL-2 stimulated isolated peripheral blood mononuclear cells (PBMCs) to kill NK cell-sensitive K562 cells, and the responsiveness of PBMC subpopulations to IL-2 and polyclonal stimulation were also evaluated., Results: Methadone, oxycodone and diamorphine inhibited the production of IL-6 by IL-2 stimulated PBMCs. None of the opioids consistently influenced the other measured immune parameters, although there was a trend for morphine, tramadol, fentanyl and buprenorphine to inhibit phagocytosis and oxidative burst responses to Escherichia coli., Conclusions: Preliminary studies using standardised in vitro methodologies have demonstrated that some therapeutic opioids suppress IL-6 production. Although this might potentially suppress bacterial defence mechanisms, it would have little direct effect on anticancer immunity. These findings should be confirmed in larger in vitro and clinical studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: An examination of whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate/severe cancer pain., Methods: Randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg/day of OXN PR or OxyPR over 4 weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), laxative and rescue medication use. Quality of life (QoL) and safety assessments were conducted., Results: After 4 weeks, mean BFI score was significantly lower with OXN PR; mean total laxative intake was 20% lower with OXN PR. Mean BPI-SF scores were similar for both treatments and the average rate of analgesic rescue medication use was low and comparable. QoL assessments were stable and comparable with greater improvements in constipation-specific QoL assessments with OXN PR. Overall, rates of adverse drug reactions were similar., Conclusions: OXN PR provides superior bowel function in cancer pain patients, compared with OxyPR, without compromising analgesic efficacy or safety. This study confirms that OXN PR is well tolerated and efficacious in cancer pain patients and results are in line with those seen in non-malignant pain patients.

Purpose of Review: Cancer patients with moderate-to-severe pain require opioids for analgesia. Whereas early guidelines recommend oral morphine as the 'drug of choice', newer synthetic opioids can be given by a reliable and effective nonoral transdermal route. We examine the mode of action of transdermal patches and we review the evidence on two drugs, which are currently available in this formulation - buprenorphine and fentanyl - covering physicochemical characteristics and pharmacokinetics of the patches, clinical efficacy data and adverse effects., Recent Findings: Both buprenorphine and fentanyl possess ideal characteristics for transdermal delivery, being small molecules with high lipophilicity. Studies of buprenorphine patches show benefits but there is poor randomized controlled trial evidence comparing them with oral opioids. Fentanyl patches have been used for longer and have a larger body of evidence supporting their use, with data to suggest improved pain relief and reduced opioid side effects compared with sustained release oral morphine. Patients who have used both oral morphine and transdermal fentanyl express a preference for the patch drug., Summary: Transdermal buprenorphine and fentanyl are now established for moderate-to-severe cancer pain. There is still a need for further comparative studies with other opioids, especially for buprenorphine.

Purpose of Review: Until recently management of sickle pain was the province of haematologists. However, a recent National Confidential Enquiry into Patient Outcome and Death report highlighted problems with the management of pain and opioid analgesia in this group and suggested a multiagency approach similar to that used in palliative care., Recent Findings: Pain is the most frequent complication of this haemoglobin disorder. Sickle cell disease is very variable with many patients leading full lives with long periods with little or no pain. At the other end of the spectrum there are those who exist in a sea of pain. The mechanisms of sickle pain are poorly understood and evidence for the best treatment modalities sparse. Historically there has been a dearth of clinical trials in sickle cell; however, this is starting to be addressed., Summary: In this review we will give a brief overview of the disease and its pathogenesis before examining the epidemiology, management of pain in sickle cell disease. We will also review recent evidence regarding quality of life and discuss the role of opioid hyperalgesia in sickle cell disease.

Introduction: Constipation is reported in 52% of people with advanced malignancy. This figure rises to 87% in people who are terminally ill and taking opioids. Constipation may be the most common adverse effect of opioids. There is no reason to believe that people with chronic non-malignant disease who take opioids will be any less troubled by this adverse effect., Methods and Outcomes: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: oral laxatives, rectally applied medications, and opioid antagonists for constipation in people prescribed opioids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA)., Results: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions., Conclusions: In this systematic review we present information relating to the effectiveness and safety of the following interventions: arachis oil enemas, bisacodyl, co-danthrusate/co-danthramer, docusate, glycerol suppositories, ispaghula husk, lactulose, liquid paraffin, macrogols plus electrolyte solutions, magnesium salts, methylcellulose, opioid antagonists, phosphate enemas, senna, sodium citrate micro-enema, and sodium picosulfate.

Opioids are the mainstay of management for patients with cancer-related pain. Although the analgesic efficacy of opioid therapy is well documented, the recent European Pain in Cancer survey demonstrated that the management of moderate-to-severe pain in patients with cancer is far from optimal. Bowel dysfunction, and importantly constipation, is a common side effect and has a significant impact on the patient's morbidity and quality of life. Nonpharmacological strategies and laxatives are often not effective in the management of opioid-induced constipation (OIC), making it necessary to search for new strategies for the treatment of opioid-induced bowel dysfunction. One promising strategy is the prevention of OIC with peripherally acting opioid antagonists that specifically target the underlying cause of this condition, without affecting centrally mediated analgesia. In recent studies, the novel combination of prolonged-release oral oxycodone and prolonged-release oral naloxone provided effective analgesia with improved bowel function in patients suffering from severe cancer-related and noncancer-related pain. The combination has the potential to improve the quality of pain management significantly in these patients.

Purpose of Review: Opioid analgesics are being increasingly used for pain control in both cancer and noncancer patients. Despite thousands of years of their use, the biological basis of their action and adverse effects are only now being understood. It is important to understand these agents better so that the potentially large sections of the population who may eventually be eligible to receive therapeutic opioids are treated rationally and safely., Recent Findings: Recent advances in pain physiology, molecular biology of neurotransmission, in-vivo neuroimaging and the study of genomic influences on drug receptors and metabolism are beginning to clarify how opioids work, how they differ from each other and how they may cause harm., Summary: Understanding the biological basis of how opioids work and produce adverse effects should help us to make better choices of which drugs to use for specific populations. Identifying individual genetic differences in opioid receptors and drug metabolism pathways may also pave the way to more targeted and safer medication in the future.

Introduction: Constipation is reported in 52% of people with advanced malignancy. This figure rises to 87% in people who are terminally ill and taking opioids. Constipation may be the most common adverse effect of opioids. There is no reason to believe that people with chronic non-malignant disease who take opioids will be any less troubled by this adverse effect., Methods and Outcomes: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: oral laxatives; rectally applied medications; and opioid antagonists for constipation in people prescribed opioids? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA)., Results: We found 19 systematic reviews, RCTs or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions., Conclusions: In this systematic review we present information relating to the effectiveness and safety of the following interventions: arachis oil enemas, bisacodyl, co-danthrusate/co-danthramer, docusate, glycerol suppositories, ispaghula husk, lactulose, liquid paraffin, macrogols plus electrolyte solutions, magnesium salts, methylcellulose, opioid antagonists, phosphate enemas, senna, sodium citrate micro-enema, sodium picosulfate.