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Drug Design, Development and Therapy 2020Peripherally acting μ-opioid receptor antagonists (PAMORAs) constitute a class of drugs which reverse opioid-induced constipation (OIC) with similar opioid analgesic... (Review)
Review
Peripherally acting μ-opioid receptor antagonists (PAMORAs) constitute a class of drugs which reverse opioid-induced constipation (OIC) with similar opioid analgesic effects. OIC differs from other forms of constipation in that it is an iatrogenic condition that occurs when an opioid acts on the dense network of μ-opioid receptors in the enteric system, which affect a variety of functions including gastrointestinal motility, secretion, and other factors that can cause bowel dysfunction. Unfortunately, laxative products, bowel regimens, dietary changes, and lifestyle modifications have limited effectiveness in preventing OIC, Opioid-associated adverse effect which occurs in 40% to 80% of opioid patients and may led to cessation of the treatment. PAMORAs are μ-receptor opioid antagonists specifically developed so that they have very limited ability to cross the blood-brain barrier and thus they are able to antagonize peripheral but not central μ-opioid receptors. PAMORAs are designed to have no effect on the analgesic benefits of opioid pain relievers but to relieve but antagonizing the effects of the opioid in the gastrointestinal system. The three main PAMORAS are methyltrexone (oral or parenteral), naldemedine (oral only), and naloxegol (oral only). Clinical studies demonstrate the safety and efficacy of these agents for alleviating constipation without diminishing the analgesic effect of opioid therapy. The aim of this narrative review to update the current status of PAMORAs for treating OIC in terms of safety and efficacy.
Topics: Analgesics, Opioid; Animals; Humans; Narcotic Antagonists; Opioid-Induced Constipation; Receptors, Opioid, mu
PubMed: 32210534
DOI: 10.2147/DDDT.S221278 -
Cureus Jan 2020Opioid antagonists in the ICU are often a last-line medication given to patients with opioid-induced constipation. Traditionally, patients have been administered...
Opioid antagonists in the ICU are often a last-line medication given to patients with opioid-induced constipation. Traditionally, patients have been administered nonopioid-based bowel regimens such as senna, peg, and docusate to treat constipation. Despite the obvious need to treat acute pain with opioids, side effects such as constipation can lead to multiple gastrointestinal (GI) complications such as bowel perforation and even death. Specifically, opioid-induced constipation (OIC) can be very difficult to treat. We examine naloxone and methylnaltrexone (MNTX) assessing GI complications and OIC as well as present a patient case which highlights the importance of treating OIC. We also evaluate the superior reversal agent of choice when treating OIC in the critical care and stepdown unit settings.
PubMed: 32181073
DOI: 10.7759/cureus.6829 -
Journal of Pain Research 2020Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are... (Review)
Review
Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are associated with several common AEs, but the most bothersome is opioid-induced constipation (OIC). OIC is often overlooked but has the potential to affect patient quality of life, increase associated symptom burden, and impede long-term opioid compliance. The peripherally acting µ-receptor antagonists (PAMORAs) are a class of drugs that include methylnaltrexone, naloxegol, and naldemedine. Collectively, each is approved for the treatment of OIC. PAMORAs work peripherally in the gastrointestinal tract, without impacting the central analgesic effects of opioids. However, each has unique pharmacokinetic properties that may be impacted by coadministered drugs or food. This review focuses on important metabolic and pharmacokinetic principals that are pertinent to drug interactions involving µ-opioid receptor antagonists prescribed for OIC. It highlights subtle differences among the PAMORAs that may have clinical significance. For example, unlike naloxegol or naldemedine, methylnaltrexone is not a substrate for CYP3A4 or p-glycoprotein; therefore, its plasma concentration is not altered when coadministered with concomitant medications that are CYP3A4 or p-glycoprotein inducers or inhibitors. With a better understanding of pharmacokinetic nuances of each PAMORA, clinicians will be better equipped to identify potential safety and efficacy considerations that may arise when PAMORAs are coadministered with other medications.
PubMed: 32158255
DOI: 10.2147/JPR.S220859 -
World Journal of Urology Dec 2020To assess the impact of N-methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted...
The association between N-methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, and clinical outcomes in patients undergoing robotic-assisted radical cystectomy.
PURPOSE
To assess the impact of N-methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted radical cystectomy for bladder cancer.
METHODS
We retrospectively reviewed patients undergoing robotic-assisted radical cystectomy by a single surgeon (KC) prior to (control group) and after (treatment group) the routine use of N-methylnaltrexone. Kaplan-Meier curves and the log-rank test were used to quantify time to flatus, bowel movement, and discharge. Daily mean opioid use, daily pain assessment rating, and episodes of severe pain (7-10/10) were compared. Gastrointestinal-related complications, including ileus, emesis, and/or need for post-op nasogastric tube placement, and 30-day readmissions were also compared between groups. Charge capture data were compared between groups to analyze cost impact.
RESULTS
29 patients each in the control and treatment group met inclusion criteria. Patients receiving N-methylnaltrexone had reduced length of stay compared with no N-methylnaltrexone (median 4 vs. 7 days, p < 0.01). Time to flatus and bowel movement, however, were similar. In a multivariable analysis controlling for possible confounders, however, the improvement in length of stay associated with N-methylnaltrexone use did not reach statistical significance (p = 0.11). Episodes of severe pain and composite gastrointestinal-related complications were reduced in the N-methylnaltrexone group (44.8% vs. 10.3%, p < 0.01). The reduction in length of stay was associated with approximately $10,500 in cost savings per patient.
CONCLUSIONS
In this study, N-methylnaltrexone was associated with reduced length of stay, fewer episodes of severe pain, and reduced costs. These results provide the impetus for further study.
Topics: Aged; Cystectomy; Female; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Postoperative Complications; Postoperative Period; Quaternary Ammonium Compounds; Retrospective Studies; Robotic Surgical Procedures; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 32072229
DOI: 10.1007/s00345-020-03117-y -
Intensive Care Medicine Apr 2020Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation.
METHODS
The MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality.
RESULTS
A total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82-2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1-3. However, during days 4-28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4-28 (p = 0.007).
CONCLUSION
We found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded.
Topics: Adult; Analgesics, Opioid; Constipation; Critical Care; Humans; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds
PubMed: 32016532
DOI: 10.1007/s00134-019-05913-6 -
Brain, Behavior, and Immunity Jul 2020We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance...
We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance increases blood-borne MPs by 8-fold, and by 10-fold in deep cervical lymph nodes draining brain glymphatics. MPs express proteins specific to cells including neutrophils, microglia, astrocytes, neurons and oligodendrocytes. Interleukin (IL)-1β content of MPs increases 68-fold. IL-1β antagonist administration diminishes blood-borne and cervical lymph node MPs, and abrogates tolerance induction. Intravenous polyethylene glycol Telomer B, a surfactant that lyses MPs, and intraperitoneal methylnaltrexone also inhibit MPs elevations and tolerance. Critically, neutropenic mice do not develop anti-nociceptive tolerance, elevations of blood-borne or cervical node MPs. Immunohistochemical evidence for microglial activation by morphine does not correlated with the MPs response pattern. Neutrophil-derived MPs appear to be required for morphine-induced anti-nociceptive tolerance. Further, patients entering treatment for opioid use disorder exhibit similar MPs elevations as do tolerant mice.
Topics: Animals; Humans; Mice; Analgesics, Opioid; Brain; Cell-Derived Microparticles; Drug Tolerance; Morphine; Nociception; Opioid-Related Disorders
PubMed: 32001343
DOI: 10.1016/j.bbi.2020.01.017 -
Paediatrics & Child Health 2021Opioid-induced constipation (OIC) is a common and important problem in paediatric palliative care, critical care, and postoperative settings. Treatment for OIC is often...
BACKGROUND AND OBJECTIVE
Opioid-induced constipation (OIC) is a common and important problem in paediatric palliative care, critical care, and postoperative settings. Treatment for OIC is often ineffective and limited by enteral intake. A new class of drugs called peripherally acting mu-opioid receptor antagonists (PAMORAs) have been shown to be effective treatments of OIC in adults, including the agents methylnaltrexone and naloxegol. Data in children are limited to several small case reports, mostly in the palliative care setting. The goal of this study was to evaluate the effectiveness and safety of methylnaltrexone and naloxegol in hospitalized children, including those with critical illness.
METHODS
We conducted a retrospective study of all children admitted to the Stollery Children's Hospital in Edmonton (Canada) who received either methylnaltrexone or naloxegol for OIC. The primary outcome was median time to first bowel movement (BM) after the first dose of PAMORA.
RESULTS
A total of 27 patients were included in the study. Kaplan-Meier survival analysis showed the median time to the first BM after the first dose of PAMORA was 15.5 hours. Seventeen (63%) patients had laxation within 24 hours of first dose. No significant adverse events were observed.
CONCLUSION
This study is the largest to date to evaluate efficacy and safety of PAMORAs in children. Future studies should be prospective and include larger numbers of patients with critical illness and postoperative OIC as indications for treatment.
PubMed: 33747318
DOI: 10.1093/pch/pxz165 -
Pain Management Mar 2020To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. This analysis comprises two Phase III, multicenter, double-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. This analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. study 301: NCT00401362; study 302: NCT00402038.
Topics: Adult; Aged; Cancer Pain; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Narcotics; Opioid-Induced Constipation; Outcome Assessment, Health Care; Quaternary Ammonium Compounds
PubMed: 31951150
DOI: 10.2217/pmt-2019-0045 -
ERJ Open Research Oct 2019Endogenous opioids (endorphins) have been reported to modulate exercise-induced breathlessness, but the relative contribution of peripheral opioid receptors has not been...
QUESTION ADDRESSED BY THE STUDY
Endogenous opioids (endorphins) have been reported to modulate exercise-induced breathlessness, but the relative contribution of peripheral opioid receptors has not been tested.
MATERIALS PARTICIPANTS AND METHODS
This was a double-blind, randomised, three-arm, cross-over trial in outpatients with spirometry-verified moderate to severe chronic obstructive pulmonary disease. Participants undertook an incremental symptom-limited treadmill test followed by five endurance treadmill tests at 75% of their maximal work rate; two tests for familiarisation and three tests 30 min after intravenous injection of either methylnaltrexone 0.3 mg·kg (blocking peripheral opioid receptors only) or naloxone 0.1 mg·kg (blocking both central and peripheral opioid receptors) or normal saline, in randomised order. The primary end-point was the regression slope between breathlessness intensity (0-10 numerical rating scale) and oxygen consumption (' ) during the walk tests, comparing methylnaltrexone and placebo using a paired t-test.
RESULTS
17 participants completed the trial: median (range) 66 (55-82) years; 15 males; mean±sd forced expiratory volume (FEV) 53.8±17.6% predicted; FEV/forced vital capacity ratio 0.55±15.9. There was no statistically or clinically significant difference in the primary end-point (regression slope of breathlessness intensity and ' ) for methylnaltrexone (p=0.498) or naloxone (p=0.804), compared to placebo. Secondary outcomes were similar between the three treatment groups, including peak and mean breathlessness intensity and unpleasantness, exercise capacity, endurance time and leg fatigue.
ANSWER TO THE QUESTION
Blocking peripheral opioid receptors (methylnaltrexone) or peripheral and central opioid receptors (naloxone) did not appear to modulate breathlessness intensity nor exercise capacity when compared with placebo (no blockade).
PubMed: 31886161
DOI: 10.1183/23120541.00153-2019 -
Journal of Medicinal Chemistry Nov 2019Genetic variants in the hepatic uptake transporter OCT1, observed in 9% of Europeans and white Americans, are known to affect pharmacokinetics and efficacy of tramadol,...
Genetic variants in the hepatic uptake transporter OCT1, observed in 9% of Europeans and white Americans, are known to affect pharmacokinetics and efficacy of tramadol, morphine, and codeine. Here, we report further opioids to be substrates and inhibitors of OCT1. Methylnaltrexone, hydromorphone, oxymorphone, and meptazinol were identified as OCT1 substrates. Methylnaltrexone is the strongest OCT1 substrate currently reported. It showed 86-fold higher accumulation in OCT1-overexpressing cells compared to control cells. We observed substantial differences in the inhibitory potency among structurally highly similar morphinan opioids (IC ranged from 6.4 μM for dextrorphan to 2 mM for oxycodone). The ether linkage of C4-C5 in the morphinan ring leads to a strong reduction of inhibitory potency. In conclusion, although polyspecific, OCT1 possesses a strong selectivity for its ligands. In contrast to methylnaltrexone and hydromorphone, oxycodone and hydrocodone do not interact with OCT1 and may be safer for use in individuals with genetic OCT1 deficiency.
Topics: Analgesics, Opioid; HEK293 Cells; Humans; Inhibitory Concentration 50; Models, Molecular; Organic Cation Transporter 1; Permeability; Protein Conformation
PubMed: 31597043
DOI: 10.1021/acs.jmedchem.9b01301