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Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study).

ABSTRACT: Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphism (SNP) rs4680 in COMT required a significantly higher dose of morphine than a non-GG group. A biomarker for selection of opioids for cancer pain relief would be particularly useful clinically, and therefore we have planned a randomized comparative study of morphine and oxycodone, using the COMT rs4680 SNP as a biomarker. This study is aimed at verifying the assumption that patients in the GG group require an increased morphine dose for pain relief.The RELIEF study is a randomized, multi-institutional, open-label trial with a primary endpoint of the proportion of subjects requiring high-dose opioids, as calculated from the dose of a rescue preparation administered on day 0. Secondary endpoints include the Hospital Anxiety and Depression Scale, Short form McGill Pain Questionnaire-2, European Organization for Research and Treatment of Cancer QLQ-C15-PAL, Pain Catastrophizing Scale, and adverse events, Eligibility criteria are patients with advanced carcinoma with non-daily use of opioids in initial screening for registration; and cancer pain targeted for daily opioid treatment, NSAIDs or acetaminophen, NRS ?3(average over 24 h), opioid-treatment naive within 30 h, no chemotherapy, radiotherapy, or bisphosphonate administration newly started within 2 weeks, and written informed consent at the time of second registration. Between November 2014 and June 2017, an estimated 110 patients from two sites in Japan were randomized (1:1) to morphine or oxycodone in GG and non-GG groups.A method for selection of appropriate opioids in cancer patients is a high unmet medical need. This study was designed to evaluate the efficacy of different opioids in patients with cancer based on gene polymorphism, as the first potential multi-institutional registration trial to be conducted in cancer patients with pain.UMIN000015579 Date of registration: 4 November 2014. It is updated once every six months, the latest update is 30 June 2017. Trial status. The enrollment started in November 2014. At the time of manuscript submission (July 2017), Three-quarters of patients have participated. We thus expect to complete the recruitment by March 2018.

SUBMITTER: Matsuoka H

PROVIDER: S-EPMC5639590 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study).

Matsuoka Hiromichi H Tsurutani Junji J Chiba Yasutaka Y Fujita Yoshihiko Y Terashima Masato M Yoshida Takeshi T Sakai Kiyohiro K Otake Yoichi Y Koyama Atsuko A Nishio Kazuto K Nakagawa Kazuhiko K

BMC cancer 20171006 1

<h4>Background</h4>Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphi ...[more]

PMID: 28985716

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Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.

Project description:Data classification is a fundamental task in data mining. Within this field, the classification of multi-labeled data has been seriously considered in recent years. In such problems, each data entity can simultaneously belong to several categories. Multi-label classification is important because of many recent real-world applications in which each entity has more than one label. To improve the performance of multi-label classification, feature selection plays an important role. It involves identifying and removing irrelevant and redundant features that unnecessarily increase the dimensions of the search space for the classification problems. However, classification may fail with an extreme decrease in the number of relevant features. Thus, minimizing the number of features and maximizing the classification accuracy are two desirable but conflicting objectives in multi-label feature selection. In this article, we introduce a multi-objective optimization algorithm customized for selecting the features of multi-label data. The proposed algorithm is an enhanced variant of a decomposition-based multi-objective optimization approach, in which the multi-label feature selection problem is divided into single-objective subproblems that can be simultaneously solved using an evolutionary algorithm. This approach leads to accelerating the optimization process and finding more diverse feature subsets. The proposed method benefits from a local search operator to find better solutions for each subproblem. We also define a pool of genetic operators to generate new feature subsets based on old generation. To evaluate the performance of the proposed algorithm, we compare it with two other multi-objective feature selection approaches on eight real-world benchmark datasets that are commonly used for multi-label classification. The reported results of multi-objective method evaluation measures, such as hypervolume indicator and set coverage, illustrate an improvement in the results obtained by the proposed method. Moreover, the proposed method achieved better results in terms of classification accuracy with fewer features compared with state-of-the-art methods.

Project description:Introduction: Open-label placebos have been proposed as way of using long recognized analgesic placebo effects in an ethical manner. Recent evidence shows efficacy of open-label placebos for clinical conditions, but there is need for more research on open-label placebos in acute pain. In the treatment of acute postoperative pain, minimization of opioid related side effects remains one of the key challenges. Therefore, this study aims at investigating the potential of adding unconditioned open-label placebos to treatment as usual as a means of reducing opioid consumption and its related side effects in patients with acute postoperative pain. Methods and Analysis: This is the protocol of an ongoing single site randomized controlled trial. The first patient was enrolled in May 2020. In total, 70 patients suffering from acute postoperative pain following dorsal lumbar interbody fusion are randomized to either a treatment as usual group or an experimental intervention group. The treatment as usual group consists of participants receiving a patient-controlled morphine pump. On day 1 and 2 post-surgery, patients in the intervention group receive, in addition to treatment as usual, two open-label placebo injections per day along with an evidence-based treatment rationale explaining the mechanisms of placebos. The primary outcome is measured by means of self-administered morphine during day 1 and 2 post-surgery. Several other outcome measures including pain intensity and adverse events as well as potential predictors of placebo response are assessed. Analysis of covariance will be used to answer the primary research question and additional statistical techniques such as generalized linear mixed models will be applied to model the temporal course of morphine consumption. Discussion: This study will provide valuable insights into the efficacy of open-label placebos in acute pain and will potentially constitute an important step toward the implementation of open-label placebos in the clinical management of acute postoperative pain. In addition, it will shed light on a cost-efficient and patient-centered strategy to reduce opioid consumption and its related side effects, without any loss in pain management efficacy. Ethics and Dissemination: The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC2020-00099) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT04339023) and is listed in the Swiss national registry at kofam.ch (SNCTP000003720).

Project description:BackgroundEpidural analgesia offers greater pain relief compared to systemic opioid-based medications, but its effect on morbidity and mortality is unclear. This review was originally published in 2006 and was updated in 2012 and again in 2016.ObjectivesTo assess the benefits and harms of postoperative epidural analgesia in comparison with postoperative systemic opioid-based analgesia for adults undergoing elective abdominal aortic surgery.Search methodsIn the updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and five trial registers in November 2014, together with reference checking to identify additional studies.Selection criteriaWe included all randomized controlled trials comparing postoperative epidural analgesia and postoperative systemic opioid-based analgesia for adults who underwent elective open abdominal aortic surgery.Data collection and analysisTwo authors independently assessed trial quality and extracted data. We contacted study authors for additional information and data when required. We assessed the level of evidence according to the scale provided by the GRADE working group.Main resultsWe included 15 trials published from 1987 to 2009 with 1498 participants in this updated review. Participants had a mean age between 60.5 and 71.3 years. The percentage of women in the included studies varied from 0% to 28.1%. Adding an epidural to general anaesthesia for people undergoing abdominal aortic repair reduced myocardial infarction (risk ratio (RR) 0.54 (95% confidence interval (CI) 0.30 to 0.97); I(2) statistic = 0%; number needed to treat for one additional beneficial outcome (NNTB) 28 (95% CI 19 to 1423), visual or verbal analogical scale (VAS) scores up to three days after the surgery (mean difference (MD) -1.78 (95% CI -2.32 to -1.25); I(2) statistic = 0% for VAS scores on movement at postoperative day one), time to tracheal extubation (standardized mean difference (SMD) -0.42 (95% CI -0.70 to -0.15); I(2) statistic = 83%; equivalent to a mean reduction of 36 hours), postoperative respiratory failure (RR 0.69 (95% CI 0.56 to 0.85); I(2) statistic = 0%; NNTB 8 (95% CI 6 to 16)), gastrointestinal bleeding (OR 0.20 (95% CI 0.06 to 0.65); I(2) statistic = 0%; NNTB 32 (95% CI 27 to 74)) and time spent in the intensive care unit (SMD -0.23 (95% CI -0.41 to -0.06); I(2) statistic = 0%; equivalent to a mean reduction of six hours). We did not demonstrate a reduction in the mortality rate up to 30 days (RR 1.06 (95% CI 0.60 to 1.86); I(2) statistic = 0%). The level of evidence was low for mortality and time before tracheal extubation; moderate for myocardial infarction, respiratory failure and intensive care unit length of stay; and high for gastrointestinal bleeding and VAS scores.Authors' conclusionsEpidural analgesia provided better pain management, reduced myocardial infarction, time to tracheal extubation, postoperative respiratory failure, gastrointestinal bleeding, and intensive care unit length of stay compared with systemic opioid-based drugs. For mortality, we did not find a difference at 30 days.

Dataset Information

Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study).

Publications

Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study).

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