Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tramadol is a synthetic opioid that has been available in the Netherlands since 1992 and is usually used as a centrally-acting analgesic when paracetamol or an NSAID provides insufficient relief. In the period 1 January 1992--30 November 2003, the Netherlands Pharmacovigilance Centre Lareb received 299 reports concerning 522 adverse drug reactions associated with the use of tramadol. Some of the frequently reported side effects with a high reporting odds ratio were nausea, constipation and withdrawal symptoms. These side effects are very similar to those of the other opioids due to the affinity of tramadol for the micro-opioid receptor. Because tramadol is often not recognised as an opioid, it is important that such opiate effects be recognised as an adverse drug reaction on time.
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PMID:[Side effects of tramadol: 12 years of experience in the Netherlands]. 1583 26

Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.
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PMID:Morphine-6-glucuronide: actions and mechanisms. 1595 75

Remifentanil is a potent mu-opioid receptor agonist and has some unique pharmacokinetic characteristics compared to other anilidopiperidine opioids (e.g. fentanyl, alfentanil, and sufentanil). As remifentanil is metabolised rapidly by nonspecific esterases that are widespread throughout the plasma and tissuses, its duration of action is very short. It is cleared very rapidly, and its clearance is not affected by renal and hepatic function. The context-sensitive half-time of remifentanil remains consistently short, even after administration for a long time. Consequently, emergence is quick even after anesthesia of long duration. As other piperidine opioids, remifentnil has some adverse effects such as respiratory depression, muscle rigidity, bradycardia, and nausea as well as vomiting. Because of the rapid dissipation of analgesic effect following remifentanil discontinuation, postoperative analgesia should be provided before or soon after anesthesia using longer-acting opioid analgesics, non-opioid analgesics, or local as well as regional anesthesia.
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PMID:[Remifentanil]. 1685 41

Methylnaltrexone is a peripheral opioid receptor antagonist undergoing phase III clinical trials for the treatment of opioid-induced constipation in patients with advanced medical illness who are being treated with narcotics for pain. The compound does not cross the blood-brain barrier in humans and reverses the opioid effects without interfering with pain relief. Some opioid-induced adverse events that the drug may potentially target include constipation, nausea/vomiting, cough suppression and urinary retention. Methylnaltrexone was discovered by researchers at the University of Chicago, Chicago, Illinois, USA and is in joint development with Progenics Pharmaceuticals and Wyeth Pharmaceuticals. Progenics is conducting clinical trials with three methylnaltrexone dosage forms: subcutaneous, IV and oral. Progenics plans to complete the clinical development of methylnaltrexone alone, after which potential pharmaceutical or biotechnology partners will be looked at to provide financial support and marketing expertise, particularly outside the US market. In December 2005, Progenics and Wyeth Pharmaceutical (Wyeth) entered into an exclusive, worldwide agreement for the joint development and commercialisation of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and postoperative bowel dysfunction. Under the terms of the licensing agreement, Wyeth has worldwide rights to the compound and Progenics retains the option to co-promote methylnaltrexone in the US. The companies will collaborate on the worldwide development of methylnaltrexone. Under the terms of the agreement, Wyeth has made an up-front payment to Progenics and will also make additional milestone payments. Wyeth will also pay Progenics royalties on worldwide sales, and co-promotion fees within the US. Wyeth is also responsible for all future development and commercialisation costs. Wyeth will develop oral methylnaltrexone worldwide. Progenics will lead the US development of subcutaneous and intravenous methylnaltrexone, while Wyeth will lead development of these parenteral products outside the US.UR Labs licensed methylnaltrexone from the University of Chicago. In October 2001, Progenics in-licensed the methynaltrexone patent portfolio in exchange for rights to future methynaltrexone royalties. In December 2005, Progenics acquired a substantial portion of the royalty and milestone payments in exchange for 686,000 shares of Progenic's common stock and 2.6 million US dollars in cash. In April 2005, Progenics Pharmaceuticals made a public offering of 2 million shares of its common stock, pursuant to an effective shelf registration statement. Progenics intends to use the net proceeds from this offering to fund clinical trials of methylnaltrexone, to fund clinical trials of other product candidates and for other research and development programs. All primary and secondary endpoints were statistically significant in Progenic's second phase III trial of subcutaneous methylnaltrexone (0.15 mg/kg or 0.30 mg/kg). The trial was initiated in January 2004 in 133 patients with opioid-induced constipation at 27 nursing homes and hospices in the US. Enrollment was completed in September 2005 and results announced in February 2006. In March 2005, Progenics announced results from the pivotal phase III trial of subcutaneous methylnaltrexone for the reversal of opioid-induced constipation. This trial involved a total of 150 patients from 16 hospices in the US who had advanced medical illnesses and who were receiving occasional opioids. Progenics has completed a phase IIb dose-ranging study with subcutaneous methylnaltrexone for treatment of narcotic-induced constipation in patients with cancer or AIDS. Positive top-line results from a phase II clinical trial of methylnaltrexone in the management of postoperative bowel dysfunction were reported in January 2005. The endpoints of the study included restoration of bowel function and discharge eligibility. Reversal of urinary retention was a secondary endpoint in this study. Progenics plans to complete a more in-depth analysis of this phase II data and present the finding to the US FDA. Methylnaltrexone (IV) is scheduled to enter phase III clinical studies in this indication in 2006. An NDA is expected to be submitted for the intravenous formulation of methylnaltrexone in late 2007/early 2008. Progenics also plans to initiate a phase II study of methylnaltrexone in women who have undergone hysterectomies. This patient population is also at high risk for ileus. In May 2004, Progenics Pharmaceuticals completed phase I clinical trials using two different oral formulations of methylnaltrexone. Analysis of preliminary data from 61 healthy volunteers who received methylnaltrexone at three dose levels indicated that the drug was well tolerated and exhibited predictable pharmacokinetics. Based on these phase I studies, Progenics selected an oral formulation and dose levels of methylnaltrexone that will be tested in phase II clinical trials for relief of opioid-induced constipation in patients with chronic-pain. The technology licensed from UR Labs, Inc., is the subject of issued US and European patents and several related US and foreign patent applications relating to certain compositions, formulations and uses of methylnaltrexone filed by the University of Chicago. Progenics have continued to expand the patent coverage relating to methylnaltrexone with the filing of new patent applications.
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PMID:Methylnaltrexone: MNTX. 1707 20

Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.
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PMID:Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. 1816 18

The analgesic drug tramadol is bioactivated by CYP2D6 to the opioid receptor agonist O-desmethyltramadol. Case reports indicated that carriers of the CYP2D6 gene duplication may be at high risk for opioid adverse events. However, the effects of the CYP2D6 duplication on kinetics and dynamics of tramadol have not been systematically studied. Pharmacokinetics and effects were monitored after a single dose of 100 mg racemic tramadol in 11 carriers of a CYP2D6 gene duplication allele (ultrarapid metabolizer [UM]) and compared with 11 carriers of 2 active CYP2D6 genes (extensive metabolizer [EM]). Pharmacodynamics was measured by cold pressure test, pupillometry, and standardized adverse event recording. The maximum plasma concentrations of the active metabolite (+)R,R-O-desmethyltramadol were significantly higher in the UM group compared with the EM group (P = 0.005; t test) with a mean difference of 14 ng/mL (95% confidence limit of difference, 2-26 ng/mL). Median (+)R,R-tramadol area under the curve was 786 and 587 mug.h.L in EMs and UMs, and the corresponding median (+)R,R-O-desmethyltramadol area under the curve was 416 and 448 mug.h.L (P = 0.005, t test). There was an increased pain threshold and pain tolerance and a stronger miosis after tramadol in UMs compared with EMs. Almost 50% of the UM group experienced nausea compared with only 9% of the EM group. In conclusion, pharmacokinetic differences between EMs and UMs were smaller than expected; nevertheless, UMs were more sensitive to tramadol than EMs. Therefore, tramadol may frequently cause adverse effects in southern European and Northern African populations with a high proportion of UMs.
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PMID:Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. 1820 46

The aim of this literature review is to summarize and discuss the available evidence for a relationship between polymorphisms in human genes and variability in opioid analgesia and side effects among patients treated for moderate or severe pain. The evidence supporting a role of certain alleles, genotypes or haplotypes in modulation of opioid analgesia is derived from a limited number of studies, a limited number of genes and a limited number of opioids. Although several interesting candidates have emerged as potentially relevant factors, only for one polymorphism, the prevalent 118A>G of the micro-opioid receptor, the accumulated evidence is sufficient to suggest a clinically relevant effect for an opioid used for moderate or severe pain. Still the data are valid only at the group level and cannot be used to predict treatment outcome in individual patients. Only a few of the symptoms often seen as opioid adverse effects in palliative care, such as nausea, vomiting, constipation and sedation, have been associated with genetic variants in various genes, but the results have been based on case reports, healthy volunteers or post-operative patients. So far, there is no clear evidence that genetic markers can be used to predict opioid efficacy or adverse effects in palliative care patients. This reflects the general lack of studies performed in the context of palliative care, the lack of sufficiently scaled studies and the lack of international standards for the assessment of subjective symptoms.
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PMID:Variable response to opioid treatment: any genetic predictors within sight? 1854 35

Opioid analgesics are commonly used to manage moderate to severe postoperative pain. Classic mu-opioid receptor agonists, such as morphine, meperidine, and fentanyl, provide excellent analgesia. However, their use in the postoperative setting is often limited by adverse effects such as nausea, vomiting, and reduced gastrointestinal motility. Clinicians who care for postoperative patients need to be aware of the incidences, causes, risk factors, consequences, and management of these adverse effects. If these effects are not managed effectively, opioid-related complications may significantly increase patient morbidity, have a negative impact on patient outcomes, and increase the burden on the nursing staff. Strategies are available to minimize and treat opioid-related adverse effects. Implementation of these strategies should result not only in increased patient comfort and satisfaction, but also in decreases in lengths of stay, more effective nursing care, and decreases in associated hospital costs.
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PMID:A review of the incidence, causes, consequences, and management of gastrointestinal effects associated with postoperative opioid administration. 1964 58

Regard of functional pharmacogenetic polymorphisms may further the success of pain therapy by adopting individualized approaches. The mu-opioid receptor gene (OPRM1) 118A>G polymorphism is a promising candidate for both opioid effects and pain because of both biological reasonability and apparent experimental and clinical evidence. We analyzed its importance for pain therapy using a meta-analytic approach to studies relating it to opioid pain therapy. Data from suitable studies selected from hits of a PubMed search for "OPRM1" were independently extracted by two authors. The meta-analysis included phenotypes by OPRM1 genotype (opioid dosing, pain, and side effects), publication year, diagnostic status, proportion of male study participants, and whether genotype frequencies agreed with Hardy-Weinberg equilibrium. We found no consistent association between OPRM1 118A>G genotypes and most of the phenotypes in a heterogeneous set of eight clinical studies. Only weak evidence of an association with less nausea (effect size, Cohen's d=-0.21, p=0.037) and of increased opioid dosage requirements (d=0.56, p=0.018) in homozygous carriers of the G allele was obtained. This indicates that despite initially promising results, available evidence of the clinical relevance of the OPRM1 118A>G polymorphism does not withhold a meta-analysis. This discourages basing personalized therapeutic concepts of pain therapy on OPRM1 118A>G genotyping at the present state of evidence.
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PMID:Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment. 1967 95

Sensory evaluation of food involves endogenous opioid mechanisms. Bulimics typically limit their food choices to low-fat "safe foods" and intermittently lose control and binge on high-fat "risk foods". The aim of this study was to determine whether the oral sensory effects of a fat versus a non-fat milk product (i.e., traditional versus non-fat half-and-half) resulted in different subjective and hormonal responses in bulimic women (n=10) compared with healthy women (n=11). Naltrexone (50mg PO) or placebo was administered 1h before, and blood sampling began 30 min prior to and 29 min after, a 3 min portion controlled modified sham-feeding trial. Following an overnight fast, three morning trials (fat, naltrexone; fat, placebo; and non-fat, placebo) were administered in a random double-blind fashion separated by at least 3 days. Overall, there were no differences between Fat and Non-Fat trials. Hunger ratings (p<0.001) and pancreatic polypeptide levels (p<0.05) were higher for bulimics at baseline. Bulimics also had overall higher ratings for nausea (p<0.05), fatty taste (p<0.01), and fear of swallowing (p<0.005). Bulimics had approximately 40% higher total ghrelin levels at all time points (p<0.001). Hormones and glucose levels were not altered by the modified sham-feeding paradigm. Naltrexone, however, resulted in an overall increase in blood glucose and decrease in ghrelin levels in both groups (p<0.05, for both). These data suggest that bulimic women have different orosensory responses that are not influenced by opioid receptor antagonism, evident in hormonal responses, or dependent on the fat content of a similarly textured liquid.
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PMID:Oral sensory and cephalic hormonal responses to fat and non-fat liquids in bulimia nervosa. 2013 67


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