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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 -
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 -
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 -
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 -
JACC. Cardiovascular Interventions Aug 2019The aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor.
BACKGROUND
Morphine delays the onset of action of oral P2Y receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia.
METHODS
In this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein.
RESULTS
Only marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y reaction units by VerifyNow P2Y between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein.
CONCLUSIONS
In patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830).
Topics: Administration, Intravenous; Administration, Oral; Aged; Analgesics, Opioid; Blood Platelets; Cell Adhesion Molecules; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Florida; Gastric Emptying; Gastrointestinal Absorption; Humans; Male; Microfilament Proteins; Middle Aged; Morphine; Naltrexone; Narcotic Antagonists; Phosphoproteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Quaternary Ammonium Compounds; Ticagrelor; Treatment Outcome
PubMed: 31377269
DOI: 10.1016/j.jcin.2019.05.028 -
JACC. Cardiovascular Interventions Aug 2019
Topics: Analgesics, Opioid; Coronary Artery Disease; Humans; Morphine; Naltrexone; Quaternary Ammonium Compounds; Ticagrelor; Treatment Outcome
PubMed: 31377266
DOI: 10.1016/j.jcin.2019.06.029 -
A&A Practice Nov 2019This case study describes a patient with suspected opioid-induced bowel dysfunction who had improved pain control when treated with intravenous (IV) lidocaine. An...
This case study describes a patient with suspected opioid-induced bowel dysfunction who had improved pain control when treated with intravenous (IV) lidocaine. An 80-year-old man with failed back surgery syndrome managed with an intrathecal (IT) pump presented with protracted abdominal pain. The acute pain service initiated a lidocaine infusion at 1 mg·min, and the patient reported significant pain relief. The patient experienced refractory abdominal pain with 3 attempts to wean the lidocaine infusion. Eventually, a successful transitional regimen was achieved with methylnaltrexone and transdermal lidocaine patches. Lidocaine infusions may be an effective and underutilized multimodal adjunct for nonsurgical pain conditions.
Topics: Abdominal Pain; Aged, 80 and over; Analgesics, Opioid; Anesthetics, Local; Failed Back Surgery Syndrome; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Lidocaine; Male; Morphine
PubMed: 31361664
DOI: 10.1213/XAA.0000000000001071 -
Journal of the Advanced Practitioner in... 2019Opioid-induced constipation (OIC) is a common adverse effect associated with opioid therapy, with many patients never developing tolerance to this effect. There are many... (Review)
Review
Opioid-induced constipation (OIC) is a common adverse effect associated with opioid therapy, with many patients never developing tolerance to this effect. There are many traditional laxatives available to help patients combat this symptom, yet OIC may not reliably respond to conventional treatment. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have a place in the treatment of refractory OIC, when traditional laxatives have not resulted in effective laxation. There are a number of PAMORAs now available, and methylnaltrexone is the only PAMORA indicated for the treatment of OIC in adults with advanced illness, as well as for patients with chronic noncancer pain, including patients with chronic pain related to prior cancer treatment who do not require frequent opioid escalation. Advanced practitioners need to have an understanding of how and when to best use these medications for the different indications in patients with advanced illness or chronic noncancer-related pain.
PubMed: 31308989
DOI: No ID Found