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Anesthesiology Jan 2019Methylnaltrexone Reverses Chronic Opioid-induced Constipation: A Randomized, Controlled Trial. By Yuan CS, Foss JF, O'Connor M, Osinski J, Karrison T, Moss J, Roizen MF.... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Methylnaltrexone Reverses Chronic Opioid-induced Constipation: A Randomized, Controlled Trial. By Yuan CS, Foss JF, O'Connor M, Osinski J, Karrison T, Moss J, Roizen MF. JAMA 2000; 130:142-8. Reprinted with permission.
CONTEXT
Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.
OBJECTIVE
To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.
DESIGN
Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.
SETTING
Clinical research center of a university hospital.
PARTICIPANTS
Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.
MAIN OUTCOME MEASURES
Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.
RESULTS
The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study.
CONCLUSIONS
Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.
Topics: Adult; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Humans; Male; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 30277930
DOI: 10.1097/ALN.0000000000002428 -
Gastroenterology & Hepatology Jan 2013
Review
PubMed: 24707236
DOI: No ID Found -
Cancer Aug 2015Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective... (Review)
Review
Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid-induced constipation, can be used to target the mu opioid receptor.
Topics: Animals; Humans; Mice; Molecular Targeted Therapy; Naltrexone; Narcotic Antagonists; Neoplasms; Quaternary Ammonium Compounds; Receptors, Opioid, mu
PubMed: 26043235
DOI: 10.1002/cncr.29460 -
United European Gastroenterology Journal Oct 2018Chronic pain affects a large part of the global population, leading to an increase of opioid use. Opioid-induced constipation (OIC), a highly prevalent adverse effect of... (Review)
Review
Chronic pain affects a large part of the global population, leading to an increase of opioid use. Opioid-induced constipation (OIC), a highly prevalent adverse effect of opioid use, has a major impact on patients' quality of life. Thanks to the introduction of new drugs for chronic constipation, which can also be used in OIC, and the development of peripherally acting mu-opioid receptor blockers, specifically for use in OIC, therapeutic options have seen major development. This review summarises current and emerging treatment options for OIC based on an extensive bibliographical search. Efficacy data for laxatives, lubiprostone, prucalopride, linaclotide, oxycodone/naloxone combinations, methylnaltrexone, alvimopan, naloxegol, naldemedine, axelopran, and bevenopran in OIC are summarised.
PubMed: 30288274
DOI: 10.1177/2050640618796748 -
The Clinical Journal of Pain Feb 2019Opioid analgesics may be associated with chronic adverse effects, such as opioid-induced constipation (OIC). Available and emerging prescription medications for OIC in... (Review)
Review
OBJECTIVES
Opioid analgesics may be associated with chronic adverse effects, such as opioid-induced constipation (OIC). Available and emerging prescription medications for OIC in patients with chronic noncancer pain are described, including concerns and challenges associated with OIC management.
METHODS
Narrative review.
RESULTS
OIC is characterized by a change in bowel habits and defecation patterns that occurs when initiating opioid therapy and is associated with reduced bowel frequency, straining, sensation of incomplete evacuation, and/or patient distress related to bowel habits. Prescription medications are indicated when OIC persists despite conservative approaches (eg, increased fiber and fluid intake, exercise, over-the-counter laxatives and stool softeners). Phase 3 studies have demonstrated the efficacy of peripherally acting µ-opioid receptor antagonists (PAMORA; methylnaltrexone, naloxegol, naldemedine), and a chloride channel activator (lubiprostone) for improving OIC in patients with chronic noncancer pain. Although head-to-head studies are lacking, a meta-analysis demonstrated that μ-opioid receptor antagonists were more effective than placebo for the treatment of OIC. The most common adverse effects associated with prescription medications for OIC are gastrointestinal related (eg, nausea, diarrhea, abdominal pain, or distention), with most being mild or moderate in severity. Therapy currently in development for OIC includes the PAMORA axelopran.
DISCUSSION
Health care providers should be aware of this complication in patients receiving opioids and should monitor and address constipation-related symptoms to optimize pain management and improve patient quality of life.
Topics: Analgesics, Opioid; Chronic Pain; Constipation; Disease Management; Humans
PubMed: 30289777
DOI: 10.1097/AJP.0000000000000662 -
Scientific African Sep 2021The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent...
The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent need for the right therapeutic drug to curb the disease. However, there is time constraint in drug development, hence the need for drug repurposing approach, a relatively fast and less expensive alternative. In this study, 1,100 Food and Drug Administration (FDA) approved drugs were obtained from DrugBank and trimmed to 791 ligands based on illicitness, withdrawal from the market, being chemical agents rather than drugs, being investigational drugs and having molecular weight greater than 500 (Kg/mol). The ligands were docked against six drug targets of the novel SARS CoV-2 - 3-chymotrypsin-like protease (3CLpro), Angiotensin-converting enzyme (ACE2), ADP ribose phosphatase of NSP3 (NSP3), NSP9 RNA binding protein (NSP9), RNA dependent RNA polymerase (RdRp) and Replicase Polyprotein 1a (RP1a). UCSF Chimera, PyRx and Discovery Studio, were used to prepare the proteins, dock the ligands and visualize the complexes, respectively. Remdesivir, Lopinavir and Hydroxychloroquine were used as reference drugs. Pharmacokinetic properties of the ligands were obtained using AdmetSAR. The binding energies of the standard drugs ranged from -5.4 to -8.7 kcal/mol while over 400 of the ligands screened showed binding energy lower than -5.4 kcal/mol. Out of the 791 number of compounds docked, 10, 91, 132, 92, 54 and 96 compounds showed lower binding energies than all the controls against 3CLPro, ACE2, NSP3, NSP9, RP1a and RdRp, respectively. Ligands that bound all target proteins, and showed the lowest binding energies with good ADMET properties and particularly showed the lowest binding against ACE2 are ethynodiol diacetate (-15.6 kcal/mol), methylnaltrexone (-15.5 kcal/mol), ketazolam (-14.5 kcal/mol) and naloxone (-13.6 kcal/mol). Further investigations are recommended for ethynodiol diacetate, methylnaltrexone, ketazolam and naloxone through preclinical and clinical studies to ascertain their effectiveness.
PubMed: 34308004
DOI: 10.1016/j.sciaf.2021.e00845 -
The Journal of Emergency Medicine Feb 2022Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist indicated for the treatment of OIC.
OBJECTIVE
To assess the safety and efficacy of a single methylnaltrexone dose.
METHODS
Results were pooled from three randomized, placebo-controlled methylnaltrexone (MNTX) studies in opioid-treated patients with advanced illness and OIC, despite treatment with conventional laxatives. Baseline assessments included demographics, disease/treatment characteristics, and functional levels. Efficacy endpoints included rescue-free laxation (RFL) rates within 4 and 24 h, time to first RFL, pain score change, and adverse events (AEs) after a single MNTX dose or placebo.
RESULTS
The analysis included 281 patients receiving MNTX and 237 receiving placebo. Mean age was 66.2 years for MNTX and 65.8 for placebo; ∼50% were men. The most frequent primary diagnosis was cancer (MNTX = 70.5%; placebo = 66.2%) and most (∼98%) were receiving at least one laxative at baseline. RFL occurred in 61.4% vs. 16.0%, and 72.1% vs. 40.1% MNTX vs. placebo patients, within 4 and 24 h of the initial dose, respectively. Relative to placebo, MNTX use reduced the time to first RFL, with most MNTX-treated patients achieving RFL within 2 h. Baseline and posttreatment pain scores were similar (p = 0.9556 vs. placebo for current and worst pain change from baseline), demonstrating that MNTX did not negatively affect opioid analgesia. Most AEs were gastrointestinal related and dissipated by the second dose.
CONCLUSIONS
Methylnaltrexone provides early RFL without compromising analgesia in patients receiving chronic opioid therapy.
Topics: Aged; Analgesics, Opioid; Constipation; Humans; Male; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds
PubMed: 34893381
DOI: 10.1016/j.jemermed.2021.10.012 -
Frontiers in Oncology 2021Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour... (Review)
Review
Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.
PubMed: 35004315
DOI: 10.3389/fonc.2021.792290 -
Journal of the American Association For... May 2023Opioids are an integral component of pain management for nonhuman primates. These potent analgesics also adverse gastrointestinal (GI) effects that include constipation,...
Opioids are an integral component of pain management for nonhuman primates. These potent analgesics also adverse gastrointestinal (GI) effects that include constipation, bloating, and delayed gastric emptying. Methylnaltrexone bromide (MNTX) is a selective, peripherally acting μ- and κ-opioid receptor antagonist that can be used to mitigate the GI effects associated with opioid administration. Unlike naltrexone, a similar drug in this class, MNTX possesses an N-methyl-quaternary amine group that prevents it from crossing the blood brain barrier. This blockage allows inhibition of peripheral GI opioid receptors without affecting opioid-mediated analgesia in the central nervous system. We conducted a pharmacokinetic analysis of MNTX in serum and CSF of 6 healthy juvenile male rhesus macaques after subcutaneous administration of a 0.15-mg/kg dose. We hypothesized that the macaques would demonstrate a T of 0.5 h, similar to that of humans, and that no MNTX would be detected in the CSF. This treatment resulted in a peak serum concentration of 114 ± 44 ng/mL at 0.25 ± 0.00 h; peak CSF at concentrations were 0.34 ± 0.07 ng/mL at the T. These data show that subcutaneous administration of MNTX to rhesus macaques may block peripheral adverse effects of opioids without interfering with their central analgesic effects.
Topics: Humans; Male; Animals; Naltrexone; Macaca mulatta; Narcotic Antagonists; Analgesics, Opioid; Quaternary Ammonium Compounds
PubMed: 37080736
DOI: 10.30802/AALAS-JAALAS-22-000111 -
BMC Palliative Care 2014Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly...
Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone.
BACKGROUND
Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly more effective than placebo, but only in about fifty percent of the patients regardless of dose increase. Dose increases cause increased toxicity without additional efficacy, and are therefore not recommended. While methylnaltrexone is a μ-receptor antagonist, only a few opioids are solely μ-receptor agonists. Therefore, the response to methylnaltrexone may be determined by the receptor-profile of a specific opioid. In addition, methylnaltrexone may also affect the immune system and angiogenesis as was found in pre-clinical studies. Primary aim of this study is to determine differences in the efficacy of methylnaltrexone prescribed to resolve opioid induced constipation between three commonly used opioid subtypes: morphine sulphate, oxycodone and fentanyl. Secondary aim is to explore potential immunomodulatory and antiangiogenic effects of methylnaltrexone.
METHODS
In this multi-center, prospective, parallel group trial we will evaluate the efficacy of methylnaltrexone in resolving OIC occurring as a side effect of the most common opioid subtypes: morphine, oxycodone and fentanyl. In total 195 patients with OIC despite prophylactic laxatives will receive methylnaltrexone every other day up to fourteen days. Patients will report its effect in a laxation diary. Group allocation is based on the opioid type the patient is using. At the start and end of the study period patients complete the Bowel Function Index questionnaire. A subgroup of the patients will donate blood for analysis of immunomodulatory- and anti-angiogenic effects of methylnaltrexone.
DISCUSSION
In this study we aim to determine the efficacy of methylnaltrexone per opioid subtype to reduce constipation. We expect that the outcome of this study will improve the clinical use of methylnaltraxone.
TRIAL REGISTRATION
This trial is registered at clinicaltrials.gov: NCT01955213 and in the Dutch trial register: NTR4272.
PubMed: 25165428
DOI: 10.1186/1472-684X-13-42